Select CTCL & PTCL Abstracts

Abstract Number: abs25-3952

Inhibitor of DNA binding 2 (ID2) is epigenetically regulated during lymphomagenesis and constitutes a novel therapeutic target in mature T-cell lymphoma

Presenter: Anouchka Laurent
Session: 621. Lymphomas: Translational – Molecular and Genetic - Subtyping strategies to unlock new therapeutic vulnerabilities

Abstract: Mature T-cell lymphomas (TCL) are a heterogeneous group of non-Hodgkin lymphomas arising from the malignant transformation of post-thymic T and NK cells. These lymphomas are characterized by poor response to chemotherapy, high relapse rates, and dismal survival outcomes. Genomic analyses of TCL have revealed recurrent alterations aﬀecting intracellular signaling pathways and epigenetic regulators. The frequent involvement of epigenetic modiﬁers suggests that epigenetic dysregulation is a critical step in TCL pathogenesis. To identify the epigenetic changes driving TCL transformation, we analyzed chromatin modiﬁcations and gene expression proﬁles in murine TCL models that closely recapitulate human disease. Our data revealed that Id2 , a repressor of basic helix-loop-helix proteins, is consistently overexpressed at both RNA and protein levels across multiple murine lymphoma models. Supporting this, analysis of the Cancer Cell Encyclopedia identiﬁed TCL as one of the tumor types with the highest ID2 expression, which we confirmed by Western blot in human TCL-derived cell lines. Furthermore, analysis of single-nuclei RNAseq data from a cohort of primary angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma not otherwise speciﬁed (PTCL, NOS) patient samples generated in our laboratory, demonstrated signiﬁcant ID2 overexpression in a subset of cases (12/27; 44%) compared to tonsil and lymph node controls. Interestingly, all relapsed TCL cases in our cohort showed signiﬁcant overexpression of ID2 . Based on our data, we hypothesize that ID2 is epigenetically regulated during transformation and contributes to T-cell lymphomagenesis. To deﬁne the mechanisms leading to ID2 overexpression in TCL, we performed H3K27ac and H3K4me1 ChIP-seq, ATAC-seq, reverse-ChIP coupled with mass spectrometry, and dual-luciferase reporter assays. These analyses identiﬁed a conserved region near the ID2 locus enriched for H3K27ac and H3K4me1 marks that co-localizes with ATAC-seq peaks and is ranked as a super-enhancer by the ROSE algorithm. This region is speciﬁcally activated in mature TCL cells compared to control CD4⁺ T cells. Reporter assays using the most conserved segment within the enhancer region showed more than twofold increased luciferase activity relative to a minimal promoter, conﬁrming its enhancer function. Interestingly, reverse- ChIP identiﬁed CTCF and ASCL1 as candidate regulators of enhancer looping and transcriptional activation, respectively. To characterize the proteins mediating the epigenetic function of ID2 in TCL, we employed a biotin ligase proximity labeling assay (BioID) approach coupled with mass spectrometry. Our results identiﬁed known ID2 partners, including the E-proteins TCF3, TCF4 and TCF12, key regulators of T- cell diﬀerentiation, as well as novel partners including elements of the SWI/SNF chromatin-remodeling complex, suggesting that ID2 overexpression indirectly regulates transcriptional programs critical for lymphomagenesis. To determine the functional role of ID2 in TCL, we characterized the eﬀects of both genetic and pharmacological inhibition of ID2, using shRNA and CRISPR-Cas9 mediated knockout and novel pan-ID inhibitors AGX51 and AGXA, respectively. Loss of ID2 leads to decreased cell viability and increased apoptosis in in vitro TCL models. Interestingly, RNA-seq analysis revealed enrichment in signatures associated with glucose metabolism, suggesting a novel role for ID2 in tumor metabolic regulation. Finally, in vivo treatment with the pan-ID inhibitor AGX51 in a murine lymphoma model induced a modest but consistent reduction in tumor burden, spleen weight, and activated CD69⁺ T cells population in AGX51-treated mice compared to vehicle-treated controls. In summary, we have identiﬁed a novel TCL-speciﬁc super-enhancer that drives ID2 overexpression in TCL and demonstrated an essential role for ID2 in supporting lymphoma proliferation and survival. More importantly, pharmacological targeting of ID2 reduces tumor burden in vitro and in vivo , highlighting its potential as a therapeutic target in mature T-cell lymphomas.

Link to Abstract abs25-3952

Abstract Number: abs25-11035

Low-dose chidamide maintenance therapy following allogeneic hematopoietic stem cell transplantation in T-cell acute lymphoblastic leukemia or lymphoma: A phase 2, open-label, multicenter, single-arm trial

Presenter: Yi Yu
Session: 723. Allogeneic Transplantation: Long-term Follow-up, Complications, and Disease Recurrence: Donor selection and maintenance strategies

Abstract: Introduction: T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphomas (TCL) are highly aggressive hematologic malignancies associated with poor prognoses. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides a potential curative opportunity and long-term survival for many patients, 20%–30% remain at risk of relapse following transplantation. Chidamide, a subtype-selective histone deacetylase (HDAC) inhibitor, has demonstrated significant antitumor activity and the ability to enhance immune cell-mediated cytotoxicity against T-cell malignancies in vitro and in mouse models. Clinically, chidamide is widely used to treat various T-cell malignancies. This study was conducted to evaluate the efficacy and safety of chidamide as a post-transplant maintenance therapy in patients with T-ALL/TCL.

Methods: This was a phase II, multicenter, single-arm clinical trial (NCT05991973) evaluating low-dose chidamide as maintenance therapy in patients with T-ALL/TCL after allo-HSCT. The key inclusion criteria were: (1) 14-70 years old; (2) diagnosed with T-ALL or T-cell lymphomas (mainly including peripheral T-cell lymphoma, NK/T-cell lymphoma, T-lymphoblastic lymphoma, etc) according to the 2016 WHO classification; (3) confirmed engraftment and achieved complete remission after allo-HSCT. Chidamide was initiated at 10 mg twice weekly (biw) between days 60 and 100 post-transplant, continued for up to 2 years, and could be escalated to a maximum of 20 mg biw at the physician’s discretion. The primary endpoint was 2- year relapse-free survival (RFS). Key secondary endpoints included incidence of aGVHD, chronic GVHD, hematological and non-hematological adverse events, non-relapse mortality (NRM), 2-year cumulative incidence of relapse (CIR), 2-year GVHD-free/relapse-free survival (GRFS), and 2-year overall survival (OS).

Results: Between July 2023, and August 2024, 62 patients were screened post-HSCT. A total of 44 patients were included and received the maintenance. The median age at transplant was 30 years (range, 15–59), and 65.9% were male. Diagnoses included T-ALL (n=27), T-cell lymphoblastic lymphoma (T-LBL, n=13), peripheral T-cell lymphoma (n=3), and EBV-positive TCL (n=1). At the time of transplant, 40 patients were in complete remission (CR), and 4 were no remission (NR). The median duration of chidamide treatment was 21.3 months (range, 1.5–24.2 months). The data cutoff was 31 July 2025. Four patients experienced relapse (range, 1.1–13.2 months), including 2 with NR at transplant. Relapses included hematologic (n=2) and extramedullary (n=2) events. The 2-year CIR was 9.6% (95%CI, 4.9%–18.8%) for patients with chidamide as maintenance therapy. At last follow-up, 40 patients were alive, while 4 had died. Causes of death were relapse (n=1), severe lung infection or pneumonia (n=2), and lung-involved cGVHD (n=1). The 2 years NRM, RFS, and OS were 8.2% (95%CI, 0%– 17.5%), 85.8% (95%CI, 75.8%–97.1%), and 89.4% (95%CI, 79.8%–100%), respectively. Among the 4 relapsed patients, one died from disease progression, one achieved CR with salvage therapy and donor lymphocyte infusion but later died of cGVHD, and the remaining two were in CR at last follow-up after salvage therapy. The 2-year cumulative incidence of cGVHD was 38.5% (95%CI, 21.2%–53.9%) after chidamide treatment. The majority of allo-HSCT recipients tolerated to low-dose chidamide. During our study, the most common treatment-related adverse events (TRAEs) were hematological toxicities, including neutropenia (9.1%), thrombocytopenia (9.1%), and anemia (6.8%), mostly grade 1 to 2. Other TRAEs involved dermatologic, gastrointestinal, hepatobiliary, renal, and infectious disease. No treatment-related deaths due to chidamide occurred.

Conclusion: Low-dose chidamide maintenance therapy following allo-HSCT demonstrated excellent efficacy and manageable safety in patients with T-ALL/TCL. This treatment strategy could be a suitable option for patients with T-ALL/TCL after allo-HSCT.

Link to Abstract abs25-11035

Abstract Number: abs25-7763

Real-world evaluation of ctdna for risk stratification across the spectrum of both aggressive and indolent lymphomas

Presenter: Natalie Galanina
Session: 803. Emerging Tools, Techniques, and Artificial Intelligence in Hematology: MRD Assays and Novel Drug Discovery Pipelines

Abstract: Introduction: Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for treatment response monitoring, risk stratification, and early recurrence detection for patients with lymphoma. Tumor-informed ctDNA testing for detecting molecular residual disease (MRD) is seeing early adoption in this setting, demonstrating technical feasibility and clinical need for personalized monitoring tools. However, the prognostic utility of ctDNA across indolent and aggressive subtypes of lymphoma remains poorly understood. Here, we present real-world data on ctDNA detection and clearance dynamics in patients with various lymphoma subtypes, including patients who are newly diagnosed and those in the relapsed/refractory setting receiving chimeric antigen receptor (CAR)-T therapy.

Methods: We performed a retrospective, real-world analysis of ctDNA testing in 148 patients with either B-cell (n=129) or T-cell lymphoma (n=19). Among the 129 patients with B-cell lymphoma, 113 patients had aggressive subtypes (n=84 with DLBCL; n=29 with other), and 16 had indolent lymphoma subtypes. ctDNA was analyzed using a tumor-informed 16-plex mPCR-NGS assay (Signatera TM , Natera, Inc.) from September 2020 - May 2025. Plasma samples (n=1,122; median: 7 per patient, range: 1-31) were collected at baseline, during therapy, at end-of-treatment (EOT), and during follow-up per physician’s discretion. ctDNA status at baseline and EOT, and clearance kinetics during first-line (1L) induction therapy were correlated with clinical outcomes.

Results: The median patient age was 61 years (range: 18.3–84), and median follow-up was 18.7 months (range: 0.6–54.4 months). Disease stage at diagnosis was available for 139 patients: stage I (n=15, 11%), stage II (n=31, 22%), stage III (n=16, 12%), and stage IV (n=77, 55%). Stage was unknown in 9 patients. Overall, ctDNA detection at baseline was 95.7% (90/94), including 100% in patients with indolent B-cell (11/11), and T-cell lymphomas (6/6), and 94.8% (73/77) in patients with aggressive B-cell lymphomas. Across all subtypes, EOT ctDNA status was strongly prognostic for event-free survival (EFS). Patients with ctDNA-positivity at EOT had significantly worse EFS (HR: 7.33, 95%CI: 2.8-19.18, p<0.0001). In aggressive lymphomas, particularly in DLBCL, ctDNA positivity at EOT was associated with a markedly worse prognosis (Aggressive: HR: 7.69, 95%CI: 2.62-22.56, p=0.0002; DLBCL only: HR: 5.74, 95%CI: 1.71-19.23, p<0.01). Among patients with evaluable ctDNA time points relative to 1L therapy (N=60), ctDNA clearance at any time point during treatment correlated with improved EFS. (HR: 18.55, 95%CI: 4.82-71.32, p<0.0001). All patients who did not clear ctDNA relapsed, yielding a positive predictive value of 100% (11/11); the negative predictive value for those who did clear was 88% (43/49). The remaining six patients turned positive during surveillance prior to relapse. Of 15 patients treated with CAR-T cell therapy, 11 had pre- and post-infusion timepoints for ctDNA analysis. Of these, 82% (9/11) were ctDNA-positive prior to CAR-T, and 55% (5/9) achieved post-infusion ctDNA clearance and a complete clinical response, though one became ctDNA-positive and relapsed (13.3 months post-CAR-T), and another suffered non-disease mortality (22.3 months post-CAR-T). In contrast, all 4 patients remaining ctDNA-positive post-CAR-T relapsed or died within a median of 3.3 months (range: 1.3–6.4 months). Two patients persistently ctDNA- negative remain disease-free. Taken together, the PPV and NPV for 12-month EFS following CAR-T therapy using a single ctDNA timepoint were both 100%.

Conclusions: This is the first report of the largest, real-world study evaluating the utility of ctDNA across a broad spectrum of heterogeneous lymphoma subtypes in patients receiving various standard of care therapies. ctDNA status at EOT and on-treatment clearance were strong predictors of clinical outcomes across multiple histological subtypes of lymphoma treated with standard-of-care agents including CAR-T cell therapy. The robustness of these findings across biologically distinct subgroups highlight the broad applicability of ctDNA testing for risk stratification and recurrence monitoring for both aggressive and indolent disease. Further prospective studies are needed to validate these findings.

Link to Abstract abs25-7763

Abstract Number: abs25-14461

Comprehensive classification of hematological malignancies by integrating genomic and immune repertoire profiles with explainable AI

Presenter: Amirsaman Ashtari
Session: 803. Emerging Tools, Techniques, and Artificial Intelligence in Hematology: Prediction Models and Novel Molecular Markers

Abstract: Background: Background: : Accurate classiﬁcation of hematologic malignancies remains challenging due to overlapping morphological, immunophenotypic, genomic, and immunological features. Shared mutational patterns among subtypes of lymphoid and myeloid malignancies further complicate accurate molecular classiﬁcation. Additionally, distinguishing between clonal driver mutations, subclonal events, and clonal hematopoiesis of indeterminate potential (CHIP) complicates interpretation of genomic proﬁles, often requiring extensive expert input and delaying deﬁnitive diagnoses. Developing robust and interpretable machine learning (ML) frameworks capable of integrating genomic and immune repertoire features will greatly benefit efforts to accelerate and standardize diagnostics.

Methods: : We curated a cohort of 11,090 specimens from 7,543 patients proﬁled using the Stanford Actionable Mutation Panel for Hematopoietic and Lymphoid Neoplasms (Heme-STAMP) between Oct. 2020 and Jun. 2025. Heme-STAMP is a targeted NGS panel curated for clinical relevance in myeloid and lymphoid malignancies and employing deep sequenc ing (~2000X coverage). Cases were initially annotated with 138 detailed diagnostic categories, and harmonized into 15 major malignant classes. Around 30% of cases lacked an established diagnosis at the time of testing (i.e., sequencing from diagnostic biopsy in parallel with pathology review) and therefore were excluded. Lastly, samples without clinical suspicion of malignancy comprised the benign class. Genomic features used for the classiﬁer training encompassed somatic mutations, canonical fusions/translocations, and focal copy number alterations (CNAs). To prioritize truncal mutations, we introduced an allele frequency-rank feature, capturing clonal dominance within each sample. TCR and IG sequencing data from 1,001 samples were used to derive immune repertoire features. Finally, we developed a comprehensive suite of ML models as well as advanced neural networks. We coupled this with an explainable AI framework, generating transparent, rule-based rationales alongside predictions, and called this framework Heme-xAIGen.

Results: : After excluding samples labeled as unknown malignancy, the training (80%) and validation (20%) cohorts comprised diverse malignancies, including AML (15.6%), MPN (15.5%), PCNs (11.3%), CLL/SLL (8.6%), MDS (8.9%), DLBCL (3.9%), and FL (2.8%). Benign cases accounted for ~13% of the entire dataset. As expected, TET2 (29.6%), ASXL1 (26.7%), and DNMT3A (20.5%) were the most frequently mutated genes in myeloid neoplasms. In the mature lymphoid neoplasms, we observed high frequencies of TP53 (17%), CREBBP (12.7%), MYD88 (10.9%), and BCL2 (5.2%). Analysis of the benign samples demonstrated known biological patterns, particularly a signiﬁcant correlation between patient age and CHIP-associated mutation burden (R=0.42, P <0.05). Furthermore, TCL cases exhibited a signiﬁcantly higher frequency of positive TCR clonality results than mature B-cell neoplasms (80.5% vs. 16.5 %; P < 0.001). The ML-based pipeline accurately classiﬁed hematological malignancies, with the best-performing model achieving an overall AUC of 0.89 and yielding high individual AUCs (e.g., AML: 0.80; MPN: 0.91; CLL/SLL: 0.89; DLBCL: 0.78). Feature importance analyses showed that all feature types contributed signiﬁcantly, with mutations and CNAs demonstrating the greatest impact. The Heme-xAIGen framework slightly improved discrimination (AUC = 0.90) while generating biologically coherent rules, for example, the presence of a CCND1::IGH fusion and absence of myeloid driver mutations ( FLT3 and NPM1 ) for MCL, or the presence of FLT3 and NPM1 mutations and absence of lymphoid drivers for AML. Remarkably, longitudinal application of Heme-xAIGen in patients with antecedent myeloid conditions assigned higher AML risk scores to patients with subsequent progression to AML ( P < 0.05). Conclusions Conclusions : We introduce Heme-xAIGen, an explainable AI framework that accurately classiﬁes hematologic malignancies by integrating genomic proﬁles, clonal dominance through VAF ranking, and immune repertoire data. Our approach demonstrates substantial predictive accuracy and delivers transparent diagnostic rationales. By eﬀectively distinguishing complex lymphoid and myeloid malignancies and identifying disease progression, our model addresses critical diagnostic gaps, supports clinical decision-making, and facilitates patient monitoring.

Link to Abstract abs25-14461

Abstract Number: abs25-9282

PRMT5 is a therapeutic vulnerability in cutaneous T-cell lymphoma

Presenter: Nicole Peterman
Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster I

Abstract: Background: Cutaneous T-cell Lymphoma (CTCL) is a type of T-cell non-Hodgkin’s lymphoma generally localized to the skin. Novel, more selective treatment strategies that target pathways driving CTCL growth and survival remain a significant unmet need. Protein arginine methyltransferase 5 (PRMT5) is a symmetric dimethyl arginine (SDMA) transferase which has been shown to be involved in several T-cell survival pathways, including cytokine responsiveness and T-cell receptor signal transduction. Loss of MTAP, a biomarker of PRMT5 inhibitor sensitivity, has been previously shown to be prevalent in several subtypes of T-cell lymphomas, including CTCL. Here, we report on the activity, function, and therapeutic targeting of PRMT5 using in vitro and in vivo models of CTCL.

Methods: All cell lines were validated by STR profiling. Genetic knockdown of PRMT5 was performed using Tet inducible SMART shRNA vectors (Horizon discovery). Pharmacological targeting of PRMT5 in vitro was performed with the PRMT5 selective SAM competitive inhibitor PRT382 with quantification of viable cells by flow cytometry. For in vivo treatment, the PRMT5 selective SAM competitive inhibitor PRT808, was given in a chow-based formulation at 10 mg/kg dosage on a 4-day on, 3-day off schedule. Tumor cells and normal immune cells were quantified by flow cytometry. SDMA protein analysis was performed using the scioSDMA profiling assay (Sciomics, Germany). Protein motif enrichment analysis was carried out with pLogo.

Results: Previously published CRISPR genetic screening of T-cell lymphoma cell lines (n=8) revealed that, among the PRMT family, both PRMT1 and PRMT5 are necessary for survival. CTCL cells have a significant increase in PRMT5 and SDMA-modified histone and non-histone proteins compared to resting and activated T-cells. We focused our attention on PRMT5 given the clinical feasibility of targeting PRMT5 in patients. We confirmed PRMT5 dependency in CTCL cell lines (Myla and Hut-78) using a Tet-inducible shRNA system. Treatment with PRT382 induced a dosage and time dependent decrease in SDMA levels across CTCL cell lines, with significant (> 90%) loss of SDMA by day 4, with 4 out of 5 cell lines having IC 50 values less than 200 nM on day 6 of treatment. Sensitive cell lines underwent G1 cell cycle arrest and cell death upon PRMT5 inhibition. As expected, loss of MTAP was frequent in T-cell lymphoma lines (6 of 8 cell lines) and all cell lines with loss of MTAP were sensitive to PRMT5 inhibition. We confirmed this activity in vivo in both a human cell lined derived xenograft model of CTCL (Myla) and in a murine immunocompetent model of tumor stage CTCL adoptively transferred from IL-15 transgenic mice. Importantly, in this immunocompetent model, we were able to get significant, selective CTCL suppression, with minimal reduction in normal peripheral T-cells(median survival vehicle vs PRT808: 29 days vs 66 days, p <0.001), confirming the specific activity of PRMT5 inhibition in CTCL cells over normal T- cells. Mechanistically, PRMT5 inhibition was able to lead to a dose dependent downregulation of CD132, the common gamma chain cytokine receptor, in CTCL cells, a mechanism previously shown in PRMT5 knockout mouse models. To uncover the SDMA-modified protein landscape in CTCL cells, we developed a novel immunoassay platform capable of detecting SDMA levels across a panel of 1438 unique targets. Proteins with high SDMA signal detection were associated with significant enrichment of (X)RG motifs (+1G enrichment: p<0.0001), the canonical site of arginine posttranslational modification, confirming the specificity of this platform. Using Myla cells treated with and without PRT382 treatment (200 nM, day 4), we found significant SDMA loss in 360 proteins (adjusted p value <0.05) with numerous proteins involved in pathways highly relevant to CTCL, including the Jak-STAT, TGF-beta, and MMP family members. Validation and functional studies of these proteins are ongoing and will be presented at the meeting.

Conclusions: Our data show that blockade of PRMT5 activity leads to significant CTCL suppression in in vitro and in vivo models of CTCL. PRMT5 targets multiple CTCL relevant pro-survival proteins for symmetric arginine dimethylation, thus underscoring its multifaceted oncogenic role in CTCL. Further clinical evaluation of PRMT5 inhibitors as a therapeutic strategy in patients with CTCL is warranted.

Link to Abstract abs25-9282

Abstract Number: abs25-10540

Targeting VDAC1 to induce mitochondrial DNA–STING signaling and lysosomal cell death in T-cell lymphoma

Presenter: Po Hu
Session: 603. Lymphoid Oncogenesis: Basic: Poster I

Abstract: The study investigates the crosstalk between mitochondria and Stimulator of Interferon Genes (STING) signaling in T-cell lymphoma (TCL), revealing a lysosome-dependent mechanism for cell death. STING expression in TCL is abnormally high compared to normal T cells, potentially driven by activated immune dysregulation or oncogenic stress. STING is involved in cytosolic DNA sensing through canonical cGAS– STING–IRF3 axis whereby it not only induces type I interferon (IFN-I) responses but also mediates its subsequent trafficking to lysosomal compartments which leads to lysosomal membrane permeabilization (LMP)-mediated non-canonical cell death. Notably, we revealed that mitochondrial dysfunction and metabolic reprogramming promoted STING-induced killing of TCL cells. Voltage dependent anion channel 1 (VDAC1), a pore-forming protein on the mitochondrial outer membrane. Functionally, the oligomerization of VDAC1 which induced by mitochondrial dysfunction resulted in the creation of large non-selective pores that allowed for cytosolic access and release into from mitochondria DNA (mtDNA). The released mtDNA acted as an endogenous ligand for cGAS to initiate the STING activation, IRF3 phosphorylation and subsequent ISGs expression. Pharmacological modulation of VDAC1 changed mtDNA efflux and STING activation, indicating its status as a druggable upstream regulator. Targeting VDAC1 to control mitochondrial membrane permeability may represent a novel strategy to potentiate STING-dependent cytotoxicity in malignant T cells. Moreover, activated STING subsequently translocated to lysosomes, where it induced LMP and triggered the release of cathepsins and other hydrolases, promoting protease-mediated cell death pathways. Accordingly, mitochondria are a dynamic hub that integrates metabolic stress with innate immune signaling, directly linking to lysosome-dependent cellular death by way of the VDAC1–STING axis. Our research reveals VDAC1-dependent release of mtDNA and STING activation to be a novel therapeutic strategy that can be exploited for eliminating malignant T cells.

Link to Abstract abs25-10540

Abstract Number: abs25-7459

Combination of golidocitinib with chidamide for peripheral T-cell lymphoma: Possible mechanisms and therapeutic potential in inhibiting tumor proliferation and modulating the immune microenvironment

Presenter: Li Li
Session: 622. Lymphomas: Translational - Non-Genetic: Poster I

Abstract: Background: Peripheral T-cell lymphoma (PTCL) is an aggressive and highly heterogeneous subtype of non-Hodgkin's lymphoma (NHL) derived from post-thymic mature T/NK cells, characterized by poor clinical outcomes and limited therapeutic options. As a novel highly selective JAK1 inhibitor, Golidocitinib has shown potent anti-tumor potential in some PTCL subtypes. This study conﬁrmed the core role of Golidocitinib in the treatment of PTCL, and proposed an innovative strategy of Golidocitinib combined with Chidamide, aiming to break through the limitations of monotherapy and provide a synergistic new therapeutic path for PTCL by simultaneously targeting the intrinsic signaling pathway of tumor cells and the immunosuppressive barrier of the microenvironment. Based on these preclinical ﬁndings, we initiated an exploratory clinical evaluation of this combination regimen in four patients with PTCL.

Methods: Four classical PTCL cell lines (human T-lymphocytic leukemia cells, Sezary syndrome, ALK+ anaplastic large cell lymphoma, NK/T-cell lymphoma) were treated with Golidocitinib and Chidamide with speciﬁed concentration and time gradients, respectively, cell viability was determined by CCK8 assay and 24H IC 50 was calculated. Then, four cell lines were treated with Golidocitinib and Chidamide in a ﬁxed ratio, and the combined index (CI) was calculated based on the Chou-Talalay method. For NK/T cell lymphoma (NKTCL) cell lines with signiﬁcant synergistic eﬀects, RNA sequencing was performed after Golidocitinib single agent, Chidamide single agent and combined drug treatment (2H/12H/24H) to analyze the cytokine expression dynamics. The transwell co-culture model of THP-1-derived macrophages and NKTCL cells was further established, the tumor cell monoculture group, tumor cell monotherapy group (Golidocitinib or Chidamide), macrophage monoculture group, co-culture group and co-culture dosing group (Golidocitinib, Chidamide monotherapy and combination) were set up, and the polarization of macrophages was observed after 48 hours of co-culture, and the tumor cells in the co-culture model were counted and ﬂow cytometry (Annexin V/ PI double staining) to evaluate the eﬀect of Golidocitinib monotherapy and its combination in the tumor immune microenvironment. Subsequently, we evaluated the clinical eﬃcacy of golidocitinib (150 mg once daily) combined with chidamide (20 mg twice weekly) in four patients with PTCL. The cohort included two chemo-free ﬁrst-line treatment patients (1 PTCL-NOS, 1 AITL) and two fourth-line treatment patients (1 PTCL-NOS, 1 AITL).

Results: In PTCL cell lines, Golidocitinib targeted inhibition of the JAK/STAT3 pathway and signiﬁcantly reduced the expression of pro-inﬂammatory factors (IL-6, IL-10, TNF- α , IFN- γ ) and induced apoptosis in tumor cells. Importantly, the combination of Golidocitinib and Chidamide showed a signiﬁcant synergistic mechanism: at the cellular level, the combination enhanced antiproliferative activity in a dose-dependent manner (CI < 1); at the microenvironment level, when NKTCL cells were co-cultured with macrophages, Golidocitinib monotherapy could partially overcome the microenvironmental protection to induce apoptosis and reverse the M2 polarization of tumor-associated macrophages, while the combination could amplify this eﬀect - the tumor apoptosis rate of the combination group in the co-culture system far exceeded that of the single agent and single culture dosing group, and the cell count simultaneously conﬁrmed the synergistic killing eﬀect. Building on these preclinical ﬁndings, we translated this combination regimen into clinical practice. Two chemo-free ﬁrst-line treatment patients achieved partial responses (PR) after two cycles, while two fourth-line treatment patients attained complete remission (CR) following four cycles.

Conclusion: This translational study demonstrates Golidocitinib's dual PTCL therapeutic mechanism— inhibiting JAK/STAT3-driven tumor proliferation while reprogramming the immunosuppressive microenvironment. The drug's synergy with Chidamide is evidenced by dose-dependent cytotoxicity (CI<1), macrophage polarization reversal, and enhanced apoptosis induction in preclinical models, mirrored by clinical responses across all four PTCL patients (including refractory cases achieving complete remission). These consistent bench-to-bedside outcomes position the Golidocitinib-Chidamide combination as a promising new PTCL treatment paradigm.

Link to Abstract abs25-7459

Abstract Number: abs25-11370

Deep learning-based histopathological subtyping of peripheral T-cell lymphoma (PTCL) on H&E-stained whole slide images

Presenter: Thomas Weber
Session: 622. Lymphomas: Translational - Non-Genetic: Poster I

Abstract: Introduction: Peripheral T-cell lymphomas (PTCL) are rare and highly heterogenous malignancies. The diagnosis can be challenging for pathologists. Accurate subtyping of PTCL is crucial for therapy decision making and clinical outcome prediction. Here we demonstrate that a deep learning (DL) model can reliably identify common subgroups of PTCL using histopathological images. Methods We trained a DL model on 223 H&E stained whole slides images (WSIs) from the German National T-Cell Lymphoma Registry and Biobank of the GLA and OSHO study groups. The training cohort included 144 patients with the following subtypes: anaplastic large cell T-cell lymphoma (ALCL) n=31; peripheral T-cell lymphoma with T follicular-helper phenotype (TFH-NHL) n=46; peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) n=23; other subtypes n=44. We trained a weakly supervised, open-source DL pipeline comprising UNI model as feature extractor and a vision transformer architecture for multiclass prediction. The DL model was trained to differentiate between the four subgroups: ALCL, TFH-NHL, PTCL- NOS and a group of other T-NHL entities. External validation was performed using an independent cohort of 118 WSIs from 118 patients (ALCL n=25; TFH-NHL n=75; PTCL-NOS n=18). To assess the quality of the model we used area under the receiver operating characteristic curve (AUROC). Heatmaps highlighting the most important image areas leading to correctly and incorrectly predicted cases were evaluated by hematopathologists to identify patterns for incorrectly and correctly categorized cases. Results In the five-fold cross-validation the DL model significantly distinguished the subgroups with an AUROC of 0.9 (95% confidence interval 0.84-0.96) for ALCL, TFH-NHL with 0.77 (0.59-0.95), PTCL-NOS with 0.55 (0.41- 0.69) and other subtypes with 0.81 (0.71-0.90), even in different tissues types. When applied to the external validation cohort, the model maintained high predictive performance with AUROCs of 0.85 (0.74- 0.95) for ALCL, 0.87 (0.79-0.94) for PTCL-TFH and 0.69 (0.52-0.85) for PTCL-NOS. A comparison of the most important image areas for DL-based classification was carried out with reference pathologists. This showed that the DL model successfully recognized the characteristic morphological areas, resulting in highly accurate classification for ALCL and PTCL-TFH. Conclusions The DL model was able to classify main PTCL subtypes on H&E stainings with high accuracy. This model needs prospective validation as a supportive tool for PTCL diagnosis. HE-based DL-based subtyping could assist pathologists in decision-making and help to guide effective diagnostics, addressing a critical unmet need.

Link to Abstract abs25-11370

Abstract Number: abs25-14497

Single-nucleus dissection of peripheral T-cell lymphomas reveals distinct microenvironmental ecosystems and therapeutic vulnerabilities

Presenter: Wen-Hsuan Wendy Lin
Session: 622. Lymphomas: Translational - Non-Genetic: Poster I

Abstract: Peripheral T-cell lymphomas (PTCL) are aggressive hematologic cancers characterized by complex tumor microenvironments (TME) with rich hematopoietic and non-hematopoietic elements. A deeper understanding of both the malignant T cells and the TME could reveal therapeutic vulnerabilities in these lymphomas, which respond poorly to conventional chemotherapy. However, the cellular architecture, transcriptional programs and tumor cell-TME interactions have not been comprehensively characterized in PTCL. Here, we performed an integrated, multiomic analysis, including single-nucleus RNA sequencing (snRNA- seq), bulk RNA sequencing, and targeted mutational profiling, on archival samples from 29 frozen PTCL biopsies- including T follicular helper cell lymphoma (TFHL) and PTCL, not otherwise specified (PTCL, NOS), along with six control lymph nodes and tonsils. After rigorous quality control, a total of 230,174 cells were analyzed. Unsupervised clustering following dimensionality reduction revealed 13 distinct benign and malignant T-cell states and 42 transcriptionally unique cell types (14 B-cell subsets, 14 myeloid subsets, 6 endothelial cell subsets, and 8 non-endothelial stromal cell subsets), many of which have not been previously characterized in PTCL. Analysis of malignant T cells revealed substantial heterogeneity in PTCL, NOS, linked to chromosomal abnormalities, while TFHL tumors exhibited less genetic and transcriptional variability and were associated with specific transcriptional programs driven by RHOA G17V and IDH2 mutations. Both subtypes showed enrichment in MYC targets, TNF-α signaling, mTOR signaling, mitosis, and cell cycle pathways, whereas MAPK and STAT5 signaling were uniquely enriched in TFHL. TME analysis revealed shared hallmarks across PTCL, NOS and TFHL, including B-cell depletion and expansion of exhausted CD8+ T cells and tumor-associated macrophages (Mφ). In contrast, enrichment of immunoblasts, regulatory T cells, and non-endothelial stromal cells represents a disease-specific alteration in TFHL. Decomposition of transcriptomic profiles from all cell types present in PTCL and control samples using non-negative matrix factorization (NMF) identified 104 gene expression programs, 36 of which showed differential per-sample activity between PTCL TME and normal controls. Correlation analysis of PTCL-specific gene programs revealed five multicellular modules, including two non- overlapping modules: one characterized by follicular dendritic cells (FDCs) and inflammatory Mφ, and the other by cancer-associated fibroblasts (CAFs) and M2-like Mφ. Cell-cell communication analysis further identified TNF-α and TGF-β as key ligands orchestrating these TME modules. Finally, computational modeling and in vivo perturbation of these interactions uncovered therapeutic vulnerabilities, including a previously unrecognized role for the TGF-β pathway in supporting PTCL tumor growth. Together, these findings provide new insights into PTCL biology and establish a foundation for TME-informed therapeutic strategies, offering potential avenues for patient stratification and targeted intervention.

Link to Abstract abs25-14497

Abstract Number: abs25-12988

CD7 CAR-T cell therapy based on “Natural Selection” for the treatment of Relapsed or Refractory CD7-positive Hematologic Malignancies: A large cohort study

Presenter: Na Kuang
Session: 801. Gene Therapies: Poster I

Abstract: Background: Background: Relapsed or refractory (R/R) hematologic malignancies, including T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL), remain a therapeutic challenge due to limited treatment options and poor clinical outcomes. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising immunotherapeutic approach for hematologic malignancies. Previous studies have demonstrated that autologous anti-CD7 CAR-T cells generated using the "Natural Selection" (NS) platform (NS7CAR) exhibit manageable toxicity profiles and good efficacy in patients with R/R T-ALL/LBL and CD7- positive acute myeloid leukemia (AML). This pooled analysis evaluates the efficacy and safety of NS7CAR-T therapy based on data from 5 clinical trials (https://clinicaltrials.gov, NCT04572308, NCT05626400, NCT04916860, NCT04928105, and NCT04938115) involving patients with CD7-positive hematologic malignancies.

Methods: This study represents a pooled, cohort analysis of subjects enrolled in clinical trials evaluating NS7CAR therapy. Eligible participants included patients with R/R CD7-positive hematologic malignancies who received at least one infusion of autologous NS7CAR-T cells and were observed between November 9, 2020, and May 21, 2025. Baseline demographic and clinical characteristics, CAR-T cell dosing, and post- infusion outcomes were systematically collected. Efficacy and safety assessments included overall response rates (ORR), overall survival (OS), progression-free survival (PFS), and the incidence of adverse events. Descriptive statistics were used to summarize key variables.

Results: The analysis included a total of 334 patients with R/R CD7-positive hematologic malignancies. The cohort comprised 159 cases (47.6%) of T-ALL and 121 cases (36.2%) of T-LBL, mixed phenotype acute leukemia accounted for 24 cases (7.2%), AML for 21 cases (6.3%), and peripheral T-cell lymphoma (PTCL) for 9 cases (2.7%). The median age was 24 years (range: 2–67 years), with 255 males (76.3%) and 79 females (23.7%). At enrollment, 88 patients (26.3%) were relapsed from prior transplants, including 4 patients who relapsed after 2 nd transplants. The median time to relapse post-transplantation was 265 days (range: 31-2432 days). Regarding baseline disease involvement before NS7CAR-T infusion, 128 patients (38.3%) showed isolated bone marrow (BM) involvement, 56 patients (16.8%) presented with isolated extramedullary disease (EMD), and the remaining 137 patients (41.0%) demonstrated concurrent involvements of both BM and EMD. Among those with BM involvement, 29.8% (79/265) had ≥20% blasts. Patients received three dose levels of NS7CAR-T cells, 15.3% (51/334) of 5×10⁵ cells/kg, 83.2% (278/334) of 1×10⁶ cell/kg, and 1.5% (5/334) of 1.5–2×10⁶ cells/kg. The median dose of NS7CAR-T cell infusion administered to patients was 1×10⁶ cells/kg. After NS7CAR-T therapy, among 329 evaluable patients as of August 1, 2025, the ORR reached 86.3% (284/329), with a complete remission/complete remission with incomplete hematologic recovery (CR/CRi) rate of 84.5% (278/329). Post-treatment evaluation revealed that 245 patients (73.4%) underwent consolidation/salvage transplantation following CAR-T therapy, with a median interval of 57 days (range: 28-227 days) between CAR-T infusion and transplantation. Survival analysis demonstrated a median PFS of 547.5 days (range: 45-1694 days) and median OS of 567.5 days (range: 45-1694 days). Safety assessment of the full cohort (n=334) showed cytokine release syndrome (CRS) occurring in 95.8% of patients (320/334), with the majority (85.6%, 286/334) experiencing grade 1-2 events and 10.2% (34/334) developing grade ≥3 CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 3.3% of cases (11/334), including 0.9% (3/334) with grade 1-2 and 2.4% (8/334) with grade ≥3.

Conclusion: s s This large pooled cohort analysis demonstrates that NS7CAR-T therapy exhibits very promising clinically efficacy, achieving an 84.5% CR rate, along with a manageable safety profile in patients with R/R CD7- positive hematologic malignancies, including T-ALL/LBL, AML, MPAL and PTCL. While a small subset of patients experienced grade ≥3 CRS and ICANS, the robust response rates and survival outcomes position NS7CAR-T as a potentially transformative treatment option for R/R CD7-positive hematologic malignancies, including post-transplant relapsed patients.

Link to Abstract abs25-12988

Abstract Number: abs25-4232

CD7 chimeric antigen receptor T cells for relapsed/refractory T-cell lymphomas: Single-arm, open-label, phase I study

Presenter: Rui Liu
Session: 704. Cellular Immunotherapies: Early Phase Clinical Trials and Toxicities: Poster I

Abstract: Background: The prognosis of refractory/relapsed T-cell lymphoma is extremely poor, especially for the patients who failed to allogeneic hematopoietic stem cell transplantation(alloHSCT). Aims Aims : : In this single-center Phase I study (ChiCTR2200058969), we administered CD7 CAR T cells to evaluate extended safety, PK, tolerability and efficacy in patients with r/r T-cell lymphoma.

Methods: CD7 CAR T-cells is a product in which collected mononuclear cells have been transduced with the lentiviral vector carrying a CD7 CAR construct binding domain fused to a domain for anchoring in the endoplasmic reticulum, allowing CD7 to be retained intracellularly, thereby preventing CAR T cell fraticide. CD7 CAR T-cells was evaluated in a phase Ia study with a 3+3 dose-escalation design followed by cohort expansion.The phase Ia study is being conducted with different dose levels (DL): 1×10 4 (DL1), 5×10 4 (DL2), 1×10 5 (DL3) (±30%) CAR+ cells/kg.Data from phase Ia trial will be used to determine the dosing for the phase Ib trial. Infusion of donor-derived CD7 CAR-T cells in patients who have relapsed after alloHSCT, whereas infusion of autologous CAR-T cells in other patients.

Results: From August 2020 to August 2024, forty-Eight patients were screened, of which 40 were enrolled. The median age was 32(18-72) years old. The diagnosis included T-LBL(n=35),HSTL(n=1),MEITL(n=1) ,SS(n=1),Extranodal NK/T-cell lymphoma(n=1)and CTCL( n=1).The disease status was progressive disease in all patients who failed to multi-line therapies, including autoHSCT (n=5), and alloHSCT(n=17).24 patients(60%) had a diffused disease and 8 patients(20%) had central nervous system involvement.In order to reduce the tumor burden, 34(85%) patients were treated with bridging therapy before CAR-T cell infusion. 9 patients in dose escalation for three patients were included in each group from DL1 to DL3 in sequence. No dose-limiting toxicity (DLT) occurred.31 paitients in the cohort expansion with a dose of 1×10 5 (DL3) (±30%) CAR+ cells/kg as a phase Ib study. The incidence of cytokine release syndrome (CRS) was 80% (7.5% grade 3-4).One grade 4 immune effector cell-associated neurotoxicity syndrome events (2.5%). The most common treatment-related adverse event (AE) was neutropenia (77.5%; 75% grade 3-4), thrombocytopenia (65%; 62.5% grade 3-4) , infections (65%; 45% grade 3-4) .Two grade 3-4 aGVHD event occurred (5%). AE was independent of whether CART cells are sufficiently donor-derived(P=0.402). Among 40 evaluable patients, the overall response rate (ORR) at 1-month post-infusion was 92.5% (37/40), with a complete remission (CR) rate of 77.5% (31/40). In the autologous CD7 CAR-T group (n=23), ORR and CR rates were 86.9% (20/23) and 73.9% (17/23), while the donor-derived group (n=17) achieved 100% ORR (CR 14/17, 82.4%). With a median follow-up of 16.34 months (95% CI: 1.78–48.07), the 3-year PFS and OS rates for the overall population were 28.9% and 36.3%, respectively. Of the 23 patients infused with autologous CD7 CAR-T, the 3-year PFS was 31.3% and OS was 47%, respectively. 15/23(65.2%) bridged alloHSCT and 9/15(60%) survived disease-free.2/15(6.7%) relapsed after transplantation and died, 1/23(4.3%) underwent bridging autoHSCT and died of relapsed, and 4/15(26.7%) died of infection and hemorrhage. The other seven patients without bridging transplantation, 1/7(14.3%) survived disease-free and 4/7(57.1%) died of disease recurrence and 2/7(28.6%) died of infection. Of the 17 patients infused with donor-derived CD7 CAR-T, the 3-year PFS was 20.6% and OS was 28.2%, respectively. 4/17 (23.5%) bridging second alloHSCT and 1/4 (25%) survived disease-free, 2/4 (50%) died of relapse and 1/4 (25%) died of PTLD.Of the 13 patients who did not receive a bridging transplant, 2/13(15.4%) survived without disease and 1/13(7.7%) was not followed up. 3/13(23.1%) died of disease relapse and 7/13(53.8%) died of infection. The peak time of CD7 CART cells in vivo was on median 11(range,7-21) days after CAR-T cell infusion.The median peak of CAR-T cells in peripheral blood by flow cytometry was 23.65(range,1.56-219)×10 6 /L, which was no correlation with the T-cell origin of CAR-T cells (P=0.15) .Although CD7-positive normal T cells were depleted, CD7-negative T cells expanded in all patients.

Conclusion: Our study showed promising efficacy of CD7 CAR-T cell therapy in r/r T-cell lymphoma.CD7 CAR-T therapy to achieve CR after bridging allogeneic transplantation section improved survival.

Link to Abstract abs25-4232

Abstract Number: abs25-12653

Improved survival outcomes in angioimmunoblastic T-cell lymphoma linked to care at academic cancer centers: A national cancer database study.

Presenter: Vanessa Velazquez
Session: 906. Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster I

Abstract: Intro Intro Angioimmunoblastic T cell lymphoma is a unique subtype of peripheral T cell lymphoma (PTCL), often associated with poor prognosis . It accounts for ∼ 2% of all non-Hodgkin lymphomas and ∼ 15% to 20% of PTCL ( Blood, PMID: 34292324 ). Given its rarity, t here is minimal data that analyzes the difference in demographics, treatment patterns, and outcomes of angioimmunoblastic T cell lymphoma among different types of cancer centers. In this study we outline the key differentiating factors seen between Academic Cancer Programs (ACPs) and Community Cancer Programs (CCPs).

Methods: We performed a retrospective analysis of AITL cases diagnosed in the United States between the years 2004-2022 using the National Cancer Database (NCDB) between the years of 2004-2022. Patient’s demographics, clinical characteristics and outcomes were compared between ACPs and CCPs. ACPs included academic and research programs, including NCI-designated comprehensive cancer centers. CCPs comprised community, comprehensive community, and integrated network cancer programs. Kaplan-Meier and Cox proportional hazards models were used to compare overall survival (OS), adjusting for age, race/ethnicity, insurance status, comorbidity score (Charlson-Deyo), and distance from treating facility.

Results: A total of 6,663 patients were identified , with 3 , 967 (60%) treated at ACPs and 38% treated at CCPs. CCP- treated patients were older, with a median age 71 vs. 68 years, and a greater proportion of patients age 75 or older (40% vs. 29%, p<0.001). ACPs cared for more patients under 60 years of age (25 vs. 20%). More patients at ACPs were diagnosed at stage III or IV vs CCPs (83% vs 78.4%). Race/ethnicity distribution showed that patients affected by AITL were mostly white (82% in ACPs and 87% in CCPs). ACPs saw slightly more Black patients compared to CCPs (10% vs. 7% respectively ) . There were no significant differences between income and education levels between the two facility types. Patients treated at ACPs lived further from treatment facility compared to patients being treated at CCPs (12 miles vs. 8 miles ). Insurance status demonstrated significant differences , with CCPs seeing more Medicare patients (62% vs. 53%), whereas ACPs having more private insurance rat es (34% vs. 29%) (p <0.001 . Additionally, ACPs saw slightly more Medicaid-covered patients compared to CCPs (7% vs. 4% , respectively ) . There were significant differences in treatment patterns, with ACP s being more likely to provide treatment compared to CCPs (72% vs. 62%, p<0.001). The m edian ti me-to-treatment initiation was 22 days for both facility types. Survival analysis revealed an overall survival at 2, 5, and 10 years consistently favored ACPs , with the most pronounced differ ences observed in the earlier years . At 2 years, survival was 51% for ACPs versus 46 % for CCPs; at 5 years, 3 6 % versus 33 %; and at 10 years, 24% versus 2 2 %, respectively . In a multivariable Cox model—adjusting for age, race/ethnicity, insurance status, great-circle distance to care, and Charlson–Deyo comorbidity score—receiving care at an ACP remained independently associated with improved OS (2.14 years vs. 1.52 years, p=0.005) .

Conclusion: In this large , retrospective analysis of 6,663 patients diagnosed with AITL across the United States, treatment at academic center programs (ACP s) was associated with improved survival compared to community cancer programs (CCPs), even after adjusting for key demographic and clinical factors. Patients treated at ACPs were younger , more likely to present with advanced stage disease , and lived further away from their treatment facility. Despite comparable time-to-trea tment initiation, ACPs demonstrated higher rates of treatment initiation. Moreover, ACPs led to higher 2-, 5-, and 10-year survival rates, with the most notable differences seen in early survival. These findings suggest that early referral to academic centers may confer a survival advantage in this rare lymphoma, potentially reflecting key differences in access to specialized care, clinical trial a vailability and supportive infrastructure.

Link to Abstract abs25-12653

Abstract Number: abs25-15143

Comparable outcomes after autologous hematopoietic cell transplantation in T-cell lymphoma regardless of pre-transplant response: A key finding in resource-limited countries.

Presenter: Byron Figueroa
Session: 906. Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster I

Abstract: Introduction. T-cell lymphomas represent about 10% of non-Hodgkin lymphomas (NHL), are a rare type and the incidence is variable around the world. These are tumors of mature T-lymphocytes with generally poor outcomes, with registers a 5-year survival rate of 30% to 40%. Over time, we have been learning and understanding the biology of the origin cell of these lymphomas, which has led to new classifications, opening opportunities for specific treatments. In resource-limited countries are still CHOP-like regimens the first line treatment for this group of patients and consolidation with Autologous hematopoietic cell transplantation (AHCT) after the first line may provide a survival benefit, demonstrating a 3-year overall survival (OS) of 51% and progression-free survival (PFS) of 44%. In limited resources countries, AHCT is a very important tool due to its extensive availability, in contrast with target treatment, highlighting the need to know and improve the results of the available therapies in our population. Methods. Study type: Retrospective, analytical, multi-institutional study including all adult transplantation centers in Uruguay. Database: An Ad-HOC database was developed, including patients’ data from 2000 to 2024 diagnosed with T-cell NHL (T-NHL). Primary aim: To describe PFS and OS in the subgroup of T-NHL patients who underwent AHCT. Exclusion criteria: Patents diagnosed with cutaneous, hepatosplenic, enteropathy-associated or lymphoblastic subtypes of T-NHL. Results. A total of 93 patients underwent AHCT across the three adult transplantation centers in Uruguay. Patients were stratified by disease according to distinct clinical profiles (see exclusion criteria). Eighty patients were eligible for analysis, encompassing Anaplastic, Angioimmunoblastic and not otherwise specified (T-NOS) subtypes of T-NHL. Forty-nine patients (61.3%) were man; the median age was 51 years (range 24 – 72y), 27 patients (33.8%) were aged 60 years or older. Regarding the subtypes of T-NHL, 40 patients (50.0%) had T-NOS, 27 patients (33.7%) anaplastic, (ALK- 23 patients), and 13 patients (16.32%) angioimmunoblastic. Fifty-three patients (66.4%) classified as an Ann Arbor stage III or IV at diagnosis. The frontline therapy was CHOP (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) in 27 patients (33.8%) and 29 patients (36.3%) received additional Etoposide (CHOEP). The median lines of treatment before AHCT was 1 (range 1-4), thirty patients (37.5%) had received 2 or more lines before AHCT. Positron emission tomography (PET) evaluation was performed in 31 patients (38.8%). Regardless of imaging modality, PET or computed tomography (CT), complete response (CR) prior to transplant was achieved in 42 patients (53.2%), and partial response (PR) in 33 patients (41.8%). After AHCT a further deepening of response was observed in 23 patients (28.8%). We conducted logistic regression analysis to identify factors associated with relapse. Age ≥60 years (OR 2.21 IC 95% 0.86 – 5.70 p=0.09), ≥2 prior treatments lines (OR 2.44 IC 95% 0.97 – 6.18 p= 0.058) and failure to achieve metabolic CR prior AHCT (OR 1.40 IC 95% 0.48 – 4.17 p=0.53), showed trends toward increased risk but did not reach statistical significance. Survival analysis similarly demonstrated no significant differences for age ≥60 years (OR 1.41 IC 95% 0.56 - 3.60 p=0.46), ≥2 prior lines (OR 1.31 IC 95% 0.53 – 3.27 p= 0.56) or lack of metabolic CR (OR 2.95 IC 95% 0.87 – 10.0 p=0.083). Among patients achieving CR after AHCT, the median duration of response (DOR) was 104 months. Five years PFS was 59% and OS was 62%. PFS at 5 years according to subtype was 69% for anaplastic, 60% for T-NOS and 34% for angioimmunoblastic (p = 0.060). Subtype specific OS rates at 5 years were 79%, 53% and 56% for anaplastic, T-NOS and angioimmunoblastic, respectively (p = 0. 048). Conclusion. In countries with limited resources, conventional chemotherapy followed by AHCT remains a feasible and affordable consolidation strategy for patients with T-NHL. In this national cohort (AHCT candidates), both PFS and OS appear more favorable compared to previous international reports. Data on T-NHL treated with AHCT in Latin America is notably scarce, highlighting an unmet need to improve outcomes in setting where access to novel agents is not commonly available. Nevertheless, our finding suggests that AHCT continues to be a valuable therapeutic tool, even though CR is not achieved before transplantation.

Link to Abstract abs25-15143

Abstract Number: abs25-2548

Dynamic monitoring of circulating tumor DNA for real-time risk assessment in early-stage natural killer/t-cell lymphoma

Presenter: Tongyu Lin
Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster I

Abstract: Background: Background: Although early-stage natural killer/T-cell lymphoma (NKTCL) typically responds to radiation therapy (RT) and asparaginase-based chemotherapy, treatment-related clonal evolution may eventually lead to therapeutic failure. Prognostic stratiﬁcation based on baseline features fails to capture emerging resistance during therapy. Circulating tumor DNA (ctDNA) oﬀers a potential tool for real-time monitoring, but its clinical utility in NKTCL remains unclear. Method Method Clinical data from 1,825 consecutive patients diagnosed with NKTCL between January 2014 and December 2022 were collected from ﬁve hospitals within the Chinese Southwest Oncology Group (CSWOG). Patients with early-stage NKTCL who received asparaginase-based induction chemotherapy (IC) followed by RT, along with longitudinal monitoring of cell-free EBV DNA (cfEBV-DNA), were included in the analysis. We assessed patterns of appearance, disappearance and re-appearance cfEBV-DNA which we correlated with progression-free survival (PFS) and overall survival (OS). The latter were assessed using the Kaplan-Meier method and compared using the log-rank test. Multi-variable Cox regression analysis was used to identify prognostic co-variates and hierarchical clustering analysis used to determine distinct cfEBV-DNA response patterns.

Results: A total of 710 patients were included. Pretreatment cfEBV-DNA was positive in 487 patients (68.6%), 258 of whom became negative after the ﬁrst cycles of IC. During chemotherapy the percentage of patients becoming cfEBV-DNA-negative increased, whereas the velocity of cfEBV-DNA clearance decreased. Achieving cfEBV-DNA negative during diﬀerent treatment phases (post-IC1 to post-IC6, and post-RT) was signiﬁcantly associated with better PFS and OS compared with those who remained positive (all P < 0.01). Next, using unsupervised clustering analysis, patients were classiﬁed into four cfEBV-DNA response phenotypes: (1) consistently negative; (2) early response; (3) late response; and (4) no response. These cohorts had signiﬁcantly diﬀerent 5-year PFS (94% [95% Conﬁdence Interval, 90, 98%], 83% [77, 88%], 57% [47, 68%] and 18% [11, 29%]; P-value for trend < 0.001) and OS (98% [96, 99%], 91% [87, 95%], 70% [60, 81%], and 33% [23, 45%]; P-value for trend < 0.001). In Cox multi-variable analyses cfEBV- DNA response phenotype was still independently correlated with PFS and OS.

Conclusion: In conclusion, in patient with early-stage NKTCL, dynamic monitoring of cfEBV-DNA response and pattern thereof correlates with PFS and OS. Our study highlights the unique patterns of longitudinal on- treatment ctDNA and underscores its potential for real-time risk monitoring, providing valuable guidance for risk-based treatment strategies in NKTCL patients.

Link to Abstract abs25-2548

Abstract Number: abs25-8836

Integrated multi-omic profiling identifies molecular subtypes and predicts outcomes in newly diagnosed peripheral T-cell lymphomas

Presenter: Cristiana Carniti
Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster I

Abstract: Introduction: Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of aggressive hematological malignancies, accounting for 10–15% of all Non-Hodgkin Lymphomas (NHLs). Despite therapeutic advances, prognosis remains poor for most patients. In this context, the PTCL-13 study was designed to evaluate the addition of Romidepsin to anthracycline-based chemotherapy (Ro-CHOEP) followed by autologous stem cell transplantation (SCT) ( NCT02223208) . Notably, the clinical analysis of this cohort found no significant improvement by adding romidepsin (Chiappella et al. Leukemia, 2023), highlighting the need for new drugs as well as molecular profiling to guide patient stratification and possibly therapeutic decision-making. To address this, we performed an integrative multi-omics analysis of patients enrolled in the PTCL13 clinical trial with the aim of identifying molecular signatures associated with outcomes. Material and Methods Material and Methods Formalin-fixed, paraffin-embedded (FFPE) tissue and plasma were prospectively collected at baseline from 73 newly diagnosed PTCL patients with different histologies [nodal T-follicular helper lymphoma (nTFHL;n=27); Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS;n=29); Anaplastic Lymphoma Kinase-negative Anaplastic large-cell lymphoma (ALK neg ALCL;n=17)]. Targeted sequencing was performed on paired FFPE and plasma samples (Illumina NextSeq 550) using a panel of 60 genes (Roche) to identify somatic mutations. RNA from FFPE was used to perform gene expression profiling using the nCounter 780-gene panel (NanoString) and bulk RNA-sequencing (Illumina NextSeq 550 platform). Clustering analysis of multi-omic datasets was performed on R (version 4.5.0).

Results: Unsupervised clustering of transcriptomic data identified three distinct clusters (Cluster A, Cluster B, and Cluster C). Cluster A had significantly higher proportion of nTFHL patients (58%; p<0.0001), but also included some PTCL-NOS (35%) and ALK neg ALCL (7%) patients. Consistent with this, genes associated with T-follicular helper (TFH) and B-cells ( TCF7, CD22, MS4A1 ) (adjusted p<0.01) were significantly upregulated in Cluster A. Interestingly, there was also a significant downregulation of genes associated with myeloid cells, including CD14, CD163, and CD33 (adjusted p<0.05) in Cluster A. Conversely, genes related to M2 macrophages ( CCL13, CCL17 ) (adjusted p<0.05) and exhausted T cells ( PDL2, CD276 ) (adjusted p<0.05) were significantly upregulated in Clusters B and C, respectively. Notably, patients in Cluster A had superior progression-free survival (PFS) as compared to patients in Clusters B and C (p<0.05). To better define the molecular landscape of PTCLs, an integrated multi-omic analysis combining genomic and transcriptomic profiles was conducted. The Cluster-of-Clusters analysis (COCA) approach identified two principal clusters (Cluster 1 and Cluster 2). Cluster 1 closely mirrored the transcriptional and histological profile of Cluster A. Furthermore, there was a higher frequency of gene mutations in epigenetic regulators, including TET2 (36%) , RHOA (18%), IKZF2 (14%) , and DNMT3A (14%), and a significant co-occurrence of RHOA and TET2 in this group (p<0.01). In contrast, Cluster 2 closely resembled Clusters B and C in terms of gene expression profile and histological subgrouping. Additionally, mutations in oncogenic drivers such as CARD11 (7%), TP63 (4%) and MYC (4%) with significant co-occurrence between CARD11 and NOTCH1 genes (p<0.01) were found to be associated with Cluster 2. Patients in Cluster 1 had significantly higher complete response (CR) rates to Ro-CHOEP as compared to Cluster 2 (46% CR in Cluster 1 vs. 18% CR in Cluster 2; p<0.05). Additionally, Cluster 1 patients demonstrated a trend toward prolonged PFS (p=0.06), and significantly improved overall survival (p<0.05). Conclusions Conclusions Multi-omic clustering identified a subset of patients likely to benefit from Ro-CHOEP treatment, characterized by a less immunosuppressive tumor microenvironment and higher frequency of mutation in epigenetic regulators. Collectively, our findings underscore the potential of integrative molecular profiling as a tool to guide risk stratification and provide biological insights beyond conventional histological sub-classification. Ongoing studies integrating bulk RNA sequencing and whole genome sequencing data into this model will be presented, allowing us to further refine molecular characterization of PTCLs.

Link to Abstract abs25-8836

Abstract Number: abs25-9457

Prognostic impact of cytogenetic abnormalities in aggressive T-cell lymphomas: Defining high-risk subgroups through conventional karyotyping.

Presenter: Ahmad Kiwan
Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster I

Abstract: Introduction: Mature T-cell lymphomas, including aggressive nodal PTCL, advanced stage CTCL, and extranodal cytotoxic lymphomas, are associated with poor outcomes. While karyotype (KT) abnormalities are frequently detected in these diseases, limited data exist on their prognostic significance. We evaluated the impact of KT abnormalities, including complex KT and specific chromosomal lesions, along with clinical and demographic factors, on overall survival (OS) in a single-center cohort.

Methods: We retrospectively reviewed 189 patients (pts) diagnosed with T-cell lymphoma who had successful metaphase KT at diagnosis from peripheral blood (PB), bone marrow (BM), or tumor tissue. T-cell lymphomas were classified according to WHO 2022 into nodal, extranodal/cytotoxic, and cutaneous subtypes. CTCLs were stratified into indolent (Early-stage CTCL, IA–IB) and aggressive (Sézary syndrome, transformed mycosis fungoides). KTs classified as normal, abnormal, and complex (≥3 abnormalities), and recurrent abnormalities were recorded. Baseline clinical and lab data were collected. OS was estimated using the Kaplan-Meier (KM) method with 95% confidence intervals (CI). Univariate Cox proportional hazards (CPH) model identified factors associated with OS, and significant variables were entered into multivariate CPH models.

Results: The median age was 66 years (IQR 55-74); 65% were male and 35% were female. Overall, 58% of pts were alive at analysis. Nodal PTCL was the most common subtype (113 pts, 60%), followed by early CTCL (30, 16%), aggressive CTCL (24, 13%), and extranodal lymphomas (22, 12%). KT was obtained from 166 BM (86%), 26 PB (13%), and 2 tissue (1%) specimens. Among abnormal KTs, 63% were from BM, 35% from PB, and 2% from tissue. Specific abnormalities included gain of chr1 (5%), gain of chr3 (5%), gain of chr7 (5%), gain of chr8 (5%), monosomy 5 or del(5q) (4%), monosomy 9 or del(9q13q22) (4%), Monosomy 10 (4%), loss of chrY (5%), and presence of marker chromosomes (5%).Of the 189 pts, 48 (25%) had an abnormal KT, while 141 (75%) had a normal KT. Complex KT was observed in 31 (16%) pts. Abnormal non-complex and complex KTs were seen respectively in: aggressive CTCL (8%, 42%), nodal PTCL (4%, 13%), extranodal (9%, 14%), and early CTCL (27%, 10%). KM survival analysis showed a median OS for the entire cohort of 95 months (95% CI: 65-245). Pts with a normal KT had a median OS of 143 months (95% CI: 81-inf) compared with 34 months (95% CI: 18-83) for those with an abnormal KT. Pts without a complex KT had a median OS of 144 months (95% CI: 85-inf), whereas those with a complex KT had 14 months (95% CI: 4-25). For specific abnormalities, pts with gain of chr7 had OS of 3 months, gain of chr8 had 19 months, monosomy 5 or del(5q) had 4 months, loss of chrY had 30 months, gain of chr1 had 4.5 months, gain of chr3 had 7.5 months, monosomy 9 or del(9q13q22) had 2 months, monosomy 10 had 17 months, and marker chromosome presence had 5.5 months. Univariate CPH identified complex KT (HR = 3.9, p < 0.001), gain of chr1 (HR = 5.7, p < 0.001), gain of chr3 (HR = 4.6, p < 0.001), monosomy 5 or del(5q) (HR = 4.6, p < 0.001), gain of chr7 (HR = 4.2, p < 0.001), gain of chr8 (HR = 3.3, p < 0.001), monosomy 9 or del(9q13q22) (HR = 4.9, p < 0.001), monosomy 10 (HR = 2.8, p = 0.008), and marker chromosomes (HR = 4.6, p < 0.001) as adverse factors. Higher platelet count was protective (HR = 0.9, p < 0.001), while greater number of abnormalities increased hazard (HR = 1.1, p < 0.001). In multivariate CPH model, complex KT (HR = 3.1, 95% CI: 1.2-8.2, p = 0.019), monosomy 9 or del(9q13q22) (HR = 4.4, 95% CI: 1.2-15.4, p = 0.022), gain of chr1 (HR = 3.5, 95% CI: 1.1-11.8, p = 0.042), and low platelet count (HR = 0.98, 95% CI: 0.97-0.99, p = 0.006) remained independent predictors of poor OS.

Conclusion: We demonstrate that cytogenetic abnormalities detected in PB or BM, most notably complex KTs, confer a markedly poor prognosis in aggressive T-cell lymphomas. The integration of KT data with clinical parameters, such as platelet count, offers a powerful approach to refine risk stratification, identify biologically high-risk subgroups, and potentially guide personalized therapeutic strategies in this challenging disease spectrum. To our knowledge, this is one of the largest single-center studies assessing the prognostic significance of KT in mature T-cell lymphomas, providing novel insights into the role of specific chromosomal lesions in patient outcomes.

Link to Abstract abs25-9457

Abstract Number: abs25-11614

A novel CD94-targeting CAR T cell therapy for cytotoxic subtypes of T/NK-cell malignancies

Presenter: Cuong Le
Session: 702. CAR-T Cell Therapies: Basic and Translational: Poster I

Abstract: Introduction: Chimeric antigen receptor (CAR) T cell therapy targeting pan-B-cell antigens has shown unprecedented efficacy in B-cell malignancies and is clinically tolerable despite the induction of B-cell aplasia as an on-target, off-tumor effect. But targeting pan-T-cell antigens with CAR-T for T-cell lymphomas (TCL) is risky as induction of T-cell aplasia could lead to life-threatening infections and may require rescue with allogeneic stem cell transplantation. To address this challenge, we developed a CAR-T product to target a cell-of-origin antigen in T/NK-cell malignancies. Specifically, we describe a CAR-T product against CD94, a C-type lectin receptor expressed on subsets of normal NK (40-70%), gd (40-60%), and CD8 T cells (<10%), with the goal of targeting T/NK-cell neoplasms arising from these cytotoxic immune cells. Methods and Results: Methods and Results: Consistent with its known expression profile, evaluation of 33 normal human tissues by immunohistochemistry (IHC) showed CD94 expression in rare lymphocytes in secondary lymphoid organs but absent in all other cell types and tissues. This result was also supported by scRNAseq data from 25 normal human tissues from the Human Protein Atlas. By contrast, evaluation T/NK-cell lymphomas (N=46) by IHC showed that CD94 is highly expressed in all NK/TCLs (N=15) and hepatosplenic TCLs (N=7) and a few other subtypes such as enteropathy-associated TCL and primary cutaneous CD8+ cytotoxic TCL. CD94 was also found to be high in aggressive NK cell leukemia, T-cell large granular lymphocytic leukemia (T-LGL), and NK-LGL by flow cytometry. To develop an anti-CD94 CAR, we generated a high affinity mouse monoclonal antibody (mAb) against human CD94 (Kd ~1 nM). Specificity of the mAb was demonstrated by testing against isogenic NK leukemia cell lines (NKL and KHYG-1) with or without CD94 and screening against >5,000 proteins representing >94% of the human membrane proteome. Next, we constructed a bicistronic lentiviral vector to express a second-generation CAR consisting of single chain variable fragment derived from the mAb and a 4-1BB co-stimulatory domain, and a truncated BCMA (tBCMA) molecule lacking g-secretase cleavage site and intracellular signaling domain to serve as a safety switch. In co-culture assays, the CAR- T were highly cytotoxic to CD94+ but not CD94 negative (neg) isogenic NK leukemia cell lines in both short-term and long-term serial killing assays over >14 days (P<0.0001). Complete eradication of the tumor by CD94 CAR-T was observed in vivo in two NK cell leukemia xenografts, one patient-derived xenograft (PDX) of hepatosplenic TCL, and one PDX of NK/TCL, whereas progressive tumor growth was noted in mice treated with untransduced T cells (P<0.01 for total flux and/or survival). Importantly, complete and sustained elimination of disseminated tumors was seen with CAR-T doses as low as 0.2x10 6 cells/mouse when 3-day rapid manufacturing conditions were employed for CAR-T production. Using super-resolution fluorescence microscopy, we showed that when CD94 and the anti-CD94 CAR were co-expressed, CD94 is sequestered intracellularly and this prevented fratricide of the CAR-T cells. In co-cultures with autologous peripheral blood mononuclear cells, the CAR-T eliminated CD94+ NK, gd, and CD8 T cells but had no effect against the corresponding CD94neg subsets. Consistent with this, the CAR-T eliminated CD94+ NK and rare subset of CD94+ T cells in humanized mice but spared the CD94neg counterparts. Notably, when the allogeneic CAR-T cells were eliminated due to rejection by the recipient immune system, CD94+ fractions of NK and T cells were restored in the humanized mice. Lastly, in vitro and in vivo studies showed that the CAR-T cells could be rapidly eliminated by targeting the tBCMA safety switch with teclistamab or elranatamab anti-BCMA bispecific T-cell engagers or with belantamab mafodotin anti-BCMA antibody drug conjugate.

Conclusions: Our findings suggest that anti-CD94 CAR-T is likely to be highly effective against cytotoxic subtypes of T/NK-cell neoplasms. The restricted expression in normal tissues indicates that this therapy will be safe and unlikely to cause T or NK cell aplasia. The integrated tBCMA molecule in the CAR-T cells serves as a safety switch in case of unexpected toxicity. Together, these results support evaluation of this CAR-T product in a planned phase 1 clinical trial in patients with CD94+ T/NK-cell malignancies, who have a significant unmet clinical need.

Link to Abstract abs25-11614

Abstract Number: abs25-12005

Pentostatin/TBI conditioning for allogeneic transplantation in T-cell lymphomas

Presenter: Cristian Taborda
Session: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment, and Acute Toxicities: Poster I

Abstract: Background: Aggressive T-cell lymphomas are rare, biologically heterogeneous malignancies with a poor prognosis in the relapsed or refractory setting. Allogeneic stem cell transplantation (allo-SCT) offers curative potential through cytoreduction and a graft-versus-lymphoma (GVL) effect. While most reduced- intensity conditioning regimens rely on fludarabine, pentostatin is a purine analog with a distinct mechanism of action and a favorable immunosuppressive profile that supports donor engraftment with reduced toxicity. When combined with low-dose total body irradiation (TBI), this platform offers both lymphodepletion and potential disease control. We previously reported 3-year outcomes in 40 patients treated with pentostatin/TBI for T-cell lymphomas. This updated 75-patient analysis includes broader histologic representation, 5-year survival estimates, and evaluation of prognostic factors including remission status at transplant, age, histology, and donor type.

Methods: This retrospective study included 75 patients with the following histologies: angioimmunoblastic T-cell lymphoma (AITL)=12, peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) =12, T-cell prolymphocytic leukemia (T-PLL)=11, mycosis fungoides (MF) / Sézary syndrome (SS)=14, anaplastic large cell lymphoma (ALCL; ALK-positive and ALK-negative)=4, hepatosplenic T-cell lymphoma (HSTCL)=2, and rare subtypes (subcutaneous panniculitis-like T-cell lymphoma [SPTCL], extranodal NK/T-cell lymphoma [ENKTL], primary cutaneous gamma delta T-cell lymphoma [PCGD-TCL], adult T-cell leukemia/lymphoma [ATLL], primary cutaneous CD4+ and CD8+ lymphomas [PCSM-TCL and PC8-AECTCL], aggressive NK-cell leukemia [ANKL]) = 20. Patients received a conditioning regimen of continuous infusion pentostatin (8 mg/m² over 48 hours) and TBI (600 cGy in 3 fractions). Outcomes included engraftment, acute and chronic GVHD, and overall survival (OS). Kaplan-Meier and cumulative incidence methods were used.

Results: The median age was 53 years (range, 20-77). Of the 75 patients, 68% were in complete remission (CR) at the time of transplant, and 35%, 45%, and 20% had matched related, matched unrelated, and mismatched donors, respectively. All patients received calcineurin inhibitor–based GVHD prophylaxis, and 12% also received post-transplant cyclophosphamide. Fourteen patients (19%) had undergone prior autologous transplant. The median follow-up was 75.2 months (range, 1-194; 95% CI: 67,119). The median overall survival (OS) for the cohort was 60 months (95% CI: 18.7, NR). The 1-year, 3-year, and 5- year OS rates were 71.5%, 58.5%, and 49%, respectively. At 5 years, OS was 54% for patients in CR and 39% for those not in CR (NCR) at the time of transplant. OS significantly differed by age, with patients >65 having inferior outcomes compared to younger patients (10.4 vs 112 months, p = 0.0174). OS did not significantly differ by remission status at transplant (CR: 109.6 months [95% CI: 13, NR] vs NCR 38.3 months [95% CI: 7.6, NR], p = 0.40), or by donor type (matched: 110 months [95% CI: 19, NR] vs mismatched: 18.7 months [95% CI: 3.4, NR] p= 0.29). There was no significant difference by histology; however, there was a trend of inferior survival in rare subtypes. The median OS was not reached for PTCL and MF/SS, with 5-year OS of 65% and 68%, respectively. The median OS for rare subtypes was 13 months, with a 5-year OS 37%. All patients engrafted. The 100-day non-relapse mortality was 9.3%. The cumulative incidence of grade II– IV acute GVHD was 34.7% and that of extensive chronic GVHD was 43%. The most common causes of death were relapse or progression (20%) and infection (5%).

Conclusion: This 20-year institutional experience demonstrates that pentostatin and TBI is a well- tolerated and effective reduced-intensity conditioning platform for allogeneic transplant in T-cell lymphomas. The regimen was associated with full engraftment, low early mortality, and a 5-year OS of 49%—a result that compares favorably to published outcomes in this historically high-risk population. Notably, over 32% of patients underwent transplant not in remission and still experienced meaningful long-term survival, suggesting this regimen offers GVL efficacy even in chemoresistant disease. These results support the continued use and further prospective evaluation of pentostatin/TBI in T-cell lymphomas, particularly among older adults and those with rare subtypes.

Link to Abstract abs25-12005

Abstract Number: abs25-1439

Outcomes in octo- and nonagenarians treated with mogamulizumab-based regimens for cutaneous T-cell lymphoma

Presenter: Omar Elghawy
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Introduction: Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL), with a median age at diagnosis of 55 years old. However, many patients (pts) are older, and its incidence is four-fold increased among pts over 70. As life expectancy rises, octogenarians will comprise an increasing proportion of the CTCL population; however, there are currently no consensus guidelines for managing this older demographic. Mogamulizumab (moga), a monoclonal antibody targeting C-C chemokine receptor 4 (CCR4),demonstrated remarkable efficacy in CTCL in the phase 3 MAVORIC trial. We sought to evaluate the effiacy and tolerability of moga-based regiments in patients aged 80 and older that were under-represented within this trial cohort.

Methods: This single-center retrospective observational study included CTCL pts aged ≥80 who initiated moga therapy between December 2017 and December 2024, with at least 6 months of follow-up.Global treatment response was assessed by 2022 consensus criteria, and toxicity per CTCAE v5.0. Baseline characteristics were analyzed using independent t-tests, Fisher’s exact tests, or Pearson’s chi-square tests. Overall survival (OS) and progression-free survival (PFS) were co-primary endpoints analyzed via Kaplan-Meier log-rank and Cox proportional hazards models.

Results: Nineteen pts were identified (13 SS [68%], 6 MF [32%]); median age was 82 (range:80–94). Ten (53%) were male and 16 (84%) were White. Thirteen (68%) had ECOG 0-1 and 15 (79%) had advanced stage disease. LDH was elevated in 15 pts (79%) and 8 (42%) had a history of large cell transformation. Median line s of treatment prior to moga was 3 (range:1-8). All pts received moga at 1 mg/kg on days 1, 8, 15, and 22 of cycle 1, then biweekly; 8 pts (42%) later transitioned to 3–4-week intervals. Combination therapy was used based on institutional practice in 13 pts (68%) including interferon alpha (6/13,46%), bexarotene (6/13,46%), interferon gamma (7/13,54%) and extracorporeal photopheresis (8/13, 62%). Two pts (11%) received total skin electron beam therapy during their treatment course. Median duration of moga treatment was 9 months (range 2-51 months). Seventeen pts (89%) achieved a global response (6/17 [35%] complete, 11/17 [65%] partial), while two (11%) had stable disease. Compartmental responses were highest in blood (15/16, 94%), followed by skin (17/19,89%) and nodes (2/3,67%). No pts exhibited visceral disease. Median length of follow up was 14.4 months (range: 6-72 months). Median duration of response was 10 months (range 3-49 months). Median PFS was 12.6 months (95% CI 6.8-32.3 months). Thirteen pts (68%) were alive at last follow-up; and median OS was not reached. Cause of death was attributable to CTCL in only one patient (5%) and there were no treatment-related deaths. Six pts (32%) experienced grade 1-2 infusion reactions, all manageable with subsequent additional premedication. Cytopenias were observed in 15 pts (79%) with 7/15 ( 46%) having grade 3 or 4 cytopenias. Biopsy confirmed moga-associated rash (MAR) was observed in 9 pts (47%) all of which resolved with topical corticosteroids (7/9, 78%) and/or oral methotrexate (2/9, 22%). Other notable non-hematologic adverse events included grade 2 thyroiditis in one patient (5%) and Grade 1-2 diarrhea in two pts (10.5%). Reasons for cessation of moga therapy included MAR (4,21%), progression of disease (5/19,26%) or patient preference (4/19, 21%). Six pts (32%) remained on therapy at last follow-up. Discussion: Discussion: To our knowledge, this is the first real-world study to evaluate moga-based regimens in patients 80 or older with MF/SS. Notably, this patient population was largely not represented within the MAVORIC trial which led to moga approval for MF/SS. Our results suggest that moga-based treatment regimens have a significant therapeutic role in elderly pts with MF/SS, with an observed response rate of 89%, in line with our previously reported institutional experience. Given its safety and efficacy profile, moga -based regimens can play an important role in CTCL in elderly pts. However further investigation in prospective clinical trials is warranted to more clearly delineate efficacy in this patient population.

Link to Abstract abs25-1439

Abstract Number: abs25-1916

Azacytidine combined with CHOP regimen for the treatment of newly diagnosed angioimmunoblastic T-cell lymphoma

Presenter: Chunmei Yang
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Introduction: Angioimmunoblastic T-cell lymphoma (AITL) represents an aggressive malignancy derived from follicular helper T cells. Characteristic genetic mutations, including alterations in TET2, DNMT3A, IDH2, and the RHOA G17V variant, underpin the pathogenesis of this lymphoma subtype. Comprehensive investigations underscore the transformative potential of epigenetic-targeting agents in exerting pronounced anti- lymphoma activity. Methods This prospective study evaluates the therapeutic potential and safety proﬁle of azacitidine combined with CHOP chemotherapy (ACHOP) in previously untreated AITL patients. Inclusion criteria encompassed patients aged 18–75 years with untreated AITL and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–3. The therapeutic regimen administered azacitidine (75 mg/m², days 1–5) alongside CHOP chemotherapy every 21 days for four cycles. Patients achieving complete remission (CR) proceeded to an additional four ACHOP cycles, followed by recommendations for autologous stem cell transplantation (ASCT) in eligible patients aged under 65 years. Maintenance therapy with the histone deacetylase (HDAC) inhibitor chidamide was advised for two years for all participants. The study's primary endpoint assessed the CR rate, while secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety evaluation. Results Fifty-two treatment-naïve AITL patients were sequentially enrolled, with a median age of 63 years (range: 41–75 years). Advanced disease was prevalent, with 96.2% (50 patients) classiﬁed as stage III or IV per the Ann Arbor staging system. Constitutional symptoms such as high-grade fever were present in 13 patients at baseline. Extranodal involvement was noted in 75% (39 patients), and 80.8% (42 patients) presented with an International Prognostic Index (IPI) score ≥2. Elevated Epstein-Barr virus (EBV) DNA levels (>500 copies/mL) were detected in 36 participants. All 52 participants received at least one cycle of azacitidine plus CHOP as of July 11, 2025. Of 48 evaluable patients, an ORR of 87.7% (43/49) was observed, comprising a CR rate of 73.4% (36/49) and a partial remission (PR) rate of 14.3% (7/49). Eleven patients experienced CR relapse, with seven relapsing within 12 months. The median follow-up period was 22 months. Median PFS reached 27 months, whereas median OS had not been reached at analysis time. Two-year PFS and OS rates stood at 63.2% and 83.7%, respectively. The ACHOP regimen displayed an acceptable safety proﬁle. Common adverse events included leukopenia, anemia, and thrombocytopenia. Grade 3 or higher toxicities predominantly involved neutropenia, thrombocytopenia, infections, and pneumonia. No treatment-related deaths occurred. Conclusions The combination of azacitidine and CHOP presents a compelling therapeutic option with robust eﬃcacy and manageable toxicity as a first-line treatment for AITL.

Link to Abstract abs25-1916

Abstract Number: abs25-2072

Favorable safety and efficacy in a phase II trial using duvelisib maintenance after autologous stem cell transplant in T-cell and B-cell non-Hodgkin lymphomas

Presenter: Hunter Cochran
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Introduction: Peripheral T-cell lymphoma (PTCL) is a rare, aggressive group of non-Hodgkin lymphomas (NHL), including PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL). For patients who achieve remission, autologous stem cell transplant (ASCT) is the standard consolidative approach. However, relapse remains common, and no post-ASCT maintenance therapies are currently approved. In the NLG-T-01 study, the 5-year progression- free survival (PFS) following upfront ASCT was 44%, and overall survival (OS) was 51%, underscoring the need for strategies to prolong remission in this high-risk population. Duvelisib, an oral dual PI3K-δ/γ inhibitor, has demonstrated clinical activity in relapsed/refractory PTCL. In the PRIMO study, duvelisib achieved an overall response rate (ORR) of 48% and complete response rate (CRR) of 33%, with a manageable safety profile using a dose-optimized approach. Given its clinical activity across PTCL subtypes and manageable toxicity, we hypothesized that maintenance therapy with low-dose duvelisib following ASCT could improve PFS. We conducted a study to evaluate the safety and efficacy of post- transplant duvelisib maintenance in patients with PTCL.

Methods: This single-center, phase II trial enrolled duvelisib-naive patients with TCL or B-NHL who underwent consolidative ASCT. Following a safety lead-in, enrollment was limited to TCL. Duvelisib maintenance began after hematologic recovery (day +30) and continued for up to 11 cycles. Due to tolerability, the initial dosing (25 mg BID, days 1–28) was amended after 7 patients with a modified schedule (25 mg BID, days 1–14 of a 28-day cycle). Response assessment scans occurred at the end of cycle 2 and subsequently every 3 cycles. Those with stable (SD) or progressive disease (PD) were taken off study. All patients received PJP and herpesvirus prophylaxis.

Results: Seventeen patients were enrolled from July 2020 to July 2024. Histologic subtypes included PTCL-NOS (n = 6), ALCL (n = 4), AITL (n = 2), and transformed follicular lymphoma (tFL, n = 5). Ten patients were male; the median age at ASCT was 59 years (range, 24–69). Twelve patients had stage III/IV disease at diagnosis. Pre-transplant responses included 16 in complete remission (CR) and 1 in partial remission (PR). Among the 12 patients with TCL, 11 (92%) were in first CR/PR and 1 was in CR2 at the time of transplant. The median treatment durations for Schedules 1 and 2 were 5.4 months (Interquartile Range [IQR], 2.8–11.1) and 11.3 months (IQR, 7.5–11.8), respectively, with median follow-up of 17.2 (IQR, 14.6–22.5) and 19.0 months (IQR, 8.7–23.3), respectively. All twelve patients with TCL were included in the efficacy analysis. Median progression-free survival (PFS) was not reached (NR) (95% CI, 5.9–NR), and median overall survival (OS) was 35.6 months (95% CI, NR– NR). At 12 months, PFS and OS were 83.3% (95% CI, 48.2–95.6%) and 91.7% (95% CI, 53.9–98.8%), respectively. All 17 patients were included in the safety analysis. Three of 7 patients treated on Schedule 1 discontinued duvelisib due to toxicity: one grade 3 elevated liver enzymes, one grade 3 diarrhea, and one muscle weakness (unlikely related to duvelisib nor disease progression). This prompted a protocol amendment to Schedule 2, with subsequent improvement in tolerability. The most common adverse events (AEs) were hematologic, gastrointestinal, and hepatic. Grade 3 treatment-related AEs were observed in 9 patients, including febrile neutropenia (n = 1), lymphopenia (n = 3), diarrhea (n = 1), pneumonia (n = 1), and elevated liver enzymes (n = 3). There was one Grade 4 AE, lymphopenia, and no treatment-related deaths. Infectious events occurred in 7 patients, including thrush (n = 2), upper respiratory tract infections (n = 3), sinusitis (n = 1), and pneumonia (n = 1); none of these infections led to treatment holds or dose reductions. Four patients have relapsed (TCL, n = 2; tFL, n = 2), and 15 of 17 remain alive to date.

Conclusion: Duvelisib maintenance for up to one-year post-ASCT was safe and generally well tolerated, especially with the modified intermittent dosing schedule (25 mg BID, days 1–14 of a 28-day cycle). In patients with TCL, duvelisib maintenance yielded promising disease control and compares favorably to historical outcomes in this high-risk population. Given the promising results, a larger multicenter phase 3 trial is warranted.

Link to Abstract abs25-2072

Abstract Number: abs25-3872

Pembrolizumab and pralatrexate for relapsed or refractory peripheral T-cell lymphomas

Presenter: Christina Poh
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Background: T-cell lymphomas (TCL) have limited treatment options and poor prognosis, representing an unmet medical need. Pralatrexate and pembrolizumab have each demonstrated modest single-agent efficacy in TCL. Preclinical data suggest that antifolates may induce immunogenic cell death and modulate the tumor microenvironment to enhance antigen presentation and reduce immunosuppression, while immune checkpoint inhibitors may restore T-cell function, together synergistically promoting robust anti- tumor immunity (Schaer et al, Clin Cancer Res 2019). Based on this rationale, we hypothesized that the combination of pralatrexate and pembrolizumab could improve therapeutic efficacy. We report the safety, tolerability, and efficacy of this regimen in patients with TCL. Methods We conducted a multicenter, prospective, phase I/II, single-arm, open-label trial in patients aged ≥18 years with relapsed or refractory (R/R) mature peripheral T-cell or NK-cell lymphomas, including transformed mycosis fungoides (MF), who had received at least one prior line of therapy. Patients with prior exposure to anti–PD-1 or pralatrexate without evidence of objective response were excluded. The study included a dose-escalation phase followed by a dose-expansion phase once the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) of pralatrexate was determined, using a modified rolling 6 design. Pralatrexate was administered IV at escalating doses (Dose Level [DL] 1: 20 mg/m², DL 2: 30 mg/m²) on Days 1 and 8 of a 21-day cycle, combined with pembrolizumab 200 mg IV on Day 1 of each cycle. Supportive care, including leucovorin, was provided per institutional standards. Dose-limiting toxicities (DLTs) were defined as grade ≥4 hematologic or grade ≥3 non-hematologic treatment-related adverse events, with protocol-specified exceptions, occurring during the first two cycles of therapy. The primary endpoints were determination of the MTD/RP2D of pralatrexate and overall response rate (ORR). Secondary endpoints included complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and safety. Results Thirteen patients initiated study treatment. Histologic subtypes included anaplastic large cell lymphoma (n=6), transformed MF (n=3), angioimmunoblastic T-cell lymphoma (n=1), T-follicular helper lymphoma, NOS (n=1), extranodal NK/T-cell lymphoma (n=1), and cutaneous T-cell lymphoma, NOS (n=1). The median age was 63 years (range, 49–84). Nine patients (69%) had advanced-stage disease, and one (8%) had undergone prior autologous stem cell transplant. Five patients were treated at DL 1. Two were not evaluable for DLT due to clinical progression during the DLT assessment window. Among the 3 evaluable patients, no DLTs were observed, allowing for escalation to DL 2. Six patients were subsequently treated at DL 2; one was inevaluable due to progression after one cycle. Among the five evaluable patients, two experienced DLTs: one had Grade 3 fatigue lasting >2 weeks, and another developed Grade 3 hypertension that resolved to Grade 1 after >7 days. As per protocol, the occurrence of ≥2 DLTs at this level prompted de-escalation back to DL 1. Two additional patients were enrolled at DL 1 following de- escalation. One experienced a DLT (Grade 3 rash >7 days), while the other was inevaluable due to disease progression before completing the DLT period. The median number of treatment cycles administered across all patients was 3 (range, 1–7). No on-treatment deaths occurred. The ORR and CR rate were 23% and 15%, respectively. Median PFS was 2.4 months (95% CI: 0.72-2.9) and median OS was 5.6 months (95% CI: 3.5-15.7). At a median follow-up of 5.7 years, 1 patient remains alive and progression-free. Conclusion The combination of pralatrexate and pembrolizumab was not well tolerated in R/R TCL, with an unacceptable rate of DLTs across dose levels, despite the absence of unexpected toxicities. Furthermore, the ORR observed with this combination was lower than historical benchmarks for pralatrexate monotherapy, which may be attributable to the reduced pralatrexate dosing in this study and potential direct growth stimulation of malignant T cells by pembrolizumab. Given the limited efficacy and safety concerns, further development of this regimen as studied is not warranted.

Link to Abstract abs25-3872

Abstract Number: abs25-4590

The charlson comorbidity index as a predictor of survival in peripheral T-cell lymphoma: A multicenter analysis from the gifu hematology study group

Presenter: Naoki Hayase
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Background: Peripheral T-cell lymphoma (PTCL) is one of the most aggressive subtypes of non-Hodgkin’s lymphoma, with a 5-year survival rate less than 40%. Commonly used prognostic models, such as the International Prognostic Index (IPI) and the Prognostic Index for T-cell lymphoma (PIT), often fail to capture the impact of non-oncological comorbidities. This is a significant limitation in Japan, where almost half of PTCL patients are aged 70 years or older. The Charlson Comorbidity Index (CCI) is a validated tool for quantifying the baseline comorbidity burden; however, its prognostic value in PTCL remains unclear. A multicenter, real-world study to assess the impact of the CCI on treatment decisions and survival outcomes in patients with PTCL was conducted.

Methods: Consecutive adult patients with pathologically confirmed PTCL diagnosed between January 2004 and December 2022 across eight institutions in the Gifu Hematology Study Group (N = 185) were retrospectively reviewed. After excluding eight patients due to insufficient data for comorbidity scoring, 177 patients were included in the final analysis. The CCI was calculated at diagnosis and analyzed as both a categorical (0, 1, 2, or ≥3) and a dichotomous (0 vs ≥1) variable. The primary endpoint was overall survival (OS). Survival analyses were performed using Kaplan-Meier methods with log-rank tests. Multivariable Cox proportional hazards models were constructed, adjusting for sex, age ≥61 years, ALK- positive anaplastic large-cell lymphoma (ALCL), ECOG performance status (PS) 2-4, B symptoms, LDH elevation, Ann Arbor stage III-IV, extranodal sites ≥2, bone marrow involvement, and receipt of best supportive care (BSC).

Results: The cohort included PTCL not otherwise specified (n = 112, 63.3%), angioimmunoblastic T-cell lymphoma (n = 33, 18.6%), ALK-negative ALCL (n = 17, 9.6%), and other subtypes (n =15, 8.5%). The median follow-up for survivors was 7.0 (interquartile range 2.7–12.2) years. The CCI distribution was as follows: CCI 0 (n = 111, 62.7%), CCI 1 (n = 40, 22.6%), CCI 2 (n = 21, 11.9%), and CCI ≥3 (n = 5, 2.8%). The median age increased across the CCI groups (CCI 0: 67 years; CCI 1: 72 years; CCI 2: 78 years; CCI ≥3: 75 years). The overall median OS was 2.1 (95% confidence interval [CI] 1.6-4.7) years, with a 5-year OS rate of 41.8%. Of various thresholds, dichotomization at CCI = 0 versus CCI ≥1 demonstrated the clearest survival separation (median OS 5.3 vs 1.4 years; 5-year OS 50.6% vs 26.7%; log-rank p = 0.007). A significant trend was also observed across increasing CCI levels (p for trend = 0.001), with a 1-year OS of 40% and median OS of 140 days in patients with CCI ≥3. On multivariable analysis, CCI ≥1 remained independently associated with inferior OS (hazard ratio [HR] 1.54, 95% CI 1.02-2.33, p = 0.039), along with ECOG PS 2-4 (HR 2.17, 95% CI 1.38-3.40, p < 0.001) and BSC (HR 3.18, 95% CI 1.56-6.48, p = 0.002). Compared with patients with CCI = 0, those with CCI ≥1 were more likely to receive BSC as initial therapy (15.2% vs. 3.6%, p = 0.009) and also at relapse (32.4% vs. 15.4%, p = 0.078), and they were less likely to undergo upfront autologous stem-cell transplantation (3.0% vs. 10.8%, p = 0.084). Although not statistically significant, the complete response rate tended to be higher in CCI 0 than in CCI ≥1 (53.3% vs 46.4%, p = 0.42). On exploratory receiver-operating characteristic curve analysis, the combination of PS and CCI yielded a significantly higher area under the curve (AUC) (0.725, 95% CI 0.651–0.799) than PS alone (0.683, 95% CI 0.610–0.757; p = 0.048). Although the difference was not statistically significant, the PS + CCI model showed a higher AUC than the IPI (0.700, 95% CI 0.625-0.775) and the PIT (0.681, 95% CI 0.606-0.757).

Conclusions: This multicenter, real-world study demonstrated that the CCI is an independent and readily available predictor of OS in PTCL. The comorbidity burden significantly affects both survival and treatment selection, particularly in elderly or frail patients. In addition, the combination of PS and the CCI, both non- tumor-related factors, provided prognostic stratification comparable to established scores such as the IPI and the PIT. Given the limited availability of effective treatments specifically for PTCL, incorporating comorbidity assessment into routine clinical evaluation, alongside PS, may enhance predictive ability and guide more individualized treatment strategies in PTCL.

Link to Abstract abs25-4590

Abstract Number: abs25-7104

Chidamide in combination with azacitidine, mitoxantrone liposomes, and prednisone (CAMP regimen) for treatment-naïve TFH-derived peripheral T-cell lymphoma

Presenter: Huimin Liu
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Objective: Objective: Peripheral T-cell lymphoma (PTCL) is a rare but challenging malignancy, in which the TFH (T follicular helper)-derived PTCL subtype has a poor prognosis and limited treatment options. In this study, chidamide in combination with azacitidine, mitoxantrone liposomes and prednisone (CAMP regimen) was used for the treatment of treatment-naïve TFH-derived peripheral T-cell lymphoma, aiming to evaluate the efficacy and safety of this treatment regimen and provide a new treatment option for clinical practice.

Methods: This study is a multicenter, prospective phase II clinical trial (clinical trial ID: IIT2023003), the main purpose of which is to investigate the safety and preliminary efficacy (ORR rate) of chidamide in combination with azacitidine, mitoxantrone liposome and prednisone (CAMP regimen) in the treatment of treatment-naïve TFH-derived PTCL. Eligible treatment-naïve TFH-derived PTCL patients were included in the program who received CAMP regimen combination therapy, the specific regimen was: chidamide 30mg/day orally, biw; azacitidine 75mg/m2 subcutaneously, d1-d7; mitoxantrone liposome 16mg/m2 d1; prednisone 60mg/m2, d1-5; 28 days is a cycle of treatment. Patients who achieve CR/PR after four-six cycles could choose to undergo autologous hematopoietic stem cell transplantation, followed by chidamide maintenance therapy for 2 years.

Results: A total of 20 treatment-naïve patients with TFH-derived PTCL were enrolled, of whom 45% were male, with a median age of 56 (39-70) years, 95% of whom had Ann Arbor stage III-IV, 45% of the patients had B symptoms, 75% of the patients had extranodal involvement, and 55% of the patients were EBER- positive. 40% of patients were IPI score 3, and 50% of patients were PIT score≥2. The median number of treatment courses was 5 (4-8), and 4 patients (20%) underwent autologous hematopoietic stem cell transplantation, with a complete response (CR) rate of 95%a partial response (PR) rate of 5% and an overall best objective response rate (ORR) of 100%. At a median follow-up of 10 (3- 17) months, the estimated 1-year PFS and OS rate of all patients was 61% and 78% respectively. During CAMP regimen therapy, 13 patients (65%) developed myelosuppression, with a 25% incidence of grade 3- 4 myelosuppression, which could be recovered after supportive therapy. Eight patients (40%) developed pulmonary or urinary tract infections and were cured with active anti-infective therapy.

Conclusion: Chidamide combined with azacitidine, mitoxantrone liposome and prednisone (CAMP regimen) in the treatment of treatment-naïve TFH-derived PTCL has a high complete response rate and a controllable safety profile, which is expected to become a new treatment option for treatment-naïve TFH- derived PTCL, but the cohort needs to be further expanded to verify its safety and efficacy.

Link to Abstract abs25-7104

Abstract Number: abs25-7357

Outcomes of relapsed or refractory mature T/NK-cell lymphomas in the era of novel agents: A nationwide observational Study in Japan

Presenter: Hideki Uryu
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Background: Mature T-cell and natural killer-cell lymphomas (MTNKLs) are often refractory to conventional treatment and associated with a poor prognosis. Between March 2014 and March 2024, nine novel agents were approved in Japan as single agents (SAs) for relapsed or refractory (R/R) MTNKL. However, the real-world treatment patterns and prognosis of patients with R/R MTNKL in this new treatment era remains unclear. This study aimed to elucidate the outcomes of 2nd-line therapy and treatment patterns in patients with R/R MTNKL, for whom nine SAs are available. Methods: T Methods: T his nationwide, retrospective observational study was conducted across 23 institutions in Japan (ClinicalTrials.gov, ID: NCT06422247). Key inclusion criteria included: age ≥ 18 years and initiation of 2nd-line therapy for R/R MTNKL between April 2018 and March 2023. Eligible diagnoses included peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), nodal lymphomas of T follicular helper cell origin (TFHL), including angioimmunoblastic T-cell lymphoma, ALK-positive anaplastic large cell lymphoma (ALK+ALCL), ALK-negative ALCL (ALK-ALCL), breast implant-associated ALCL (BIA-ALCL), extranodal NK/T-cell lymphoma (ENKTL), and mycosis fungoides (MF) with large cell transformation (LCT), according to the revised 4th World Health Organization classification. The primary endpoint was overall survival (OS) after 2nd-line therapy initiation (OS-2L), and the secondary endpoints included time to next treatment (TTNT) and treatment patterns.

Results: A total of 256 patients were analyzed. The median age was 66 years (range, 55–77 years), and 66% were male. The histological subtypes included PTCL-NOS (40%), TFHL (38%), ENKTL (11%), ALK+ALCL (6%), ALK-ALCL (3%), MF with LCT (2%), and BIA-ALCL (0%). Among all patients, 54% exhibited extranodal involvement, 41% had high International Prognostic Index scores (3–5), and 40% had disease refractory to 1st-line therapy. The overall median OS-2L (in months [mo], 95% confidence interval [CI]) was 18.3 (14.8–27.9), and by histological subtype, it was 14.9 (11.6–27.9) for PTCL-NOS; 19.7 (12.9–49.1) for TFHL; not reached (NR) (14.8–not estimable [NE]) for ALK+ALCL; 28.1 (4.6–NE) for ALK-ALCL; 15.9 (3.7–31.8) for ENKTL; and 22.9 (13.7–NE) for MF with LCT. Fifty-four percent and 12% of patients aged ≥ 65 and < 65 years, respectively, received SAs as 2nd-line therapy. Thirteen percent of patients underwent autologous hematopoietic stem cell transplantation (HSCT), and 18% underwent allogeneic HSCT during 2nd- or later-line therapies. OS-2L was significantly longer in patients who received HSCT after 2nd- or later-line therapies than in patients who did not receive HSCT (median OS [mo, 95% CI]: NR [28.3-NE] vs. 13.1 [9.6- 16.8]). No difference in OS-2L or TTNT after 2nd-line treatment initiation (TTNT-2L) was observed between patients who received SAs and those who received conventional multiagent-chemotherapies (CCs) (median OS-2L [mo, 95% CI]: SAs, 16.8 [13.1-38.9]; CCs, 18.3 [13.7-28.3]; p=.99; median TTNT-2L: SAs, 5.9 [4.0-9.9]; CCs, 3.9 [2.7-5.1]; p=.25). It was consistent in different subgroups except for patients with refractory disease to 1st-line therapy or with Eastern Cooperative Oncology Group performance status ≥2, where SAs showed longer TTNT than CCs. The median TTNT of each SA after 2nd- or later-line therapies (mo, 95% CI) was 10.7 (3.9–17.3) for brentuximab vedotin (BV; n = 53, 21%), 5.0 (2.7–7.1) for tucidinostat (n = 36, 14%), 3.9 (2.6–4.8) for romidepsin (n = 80, 31%), 2.1 (0.4–5.2) for darinaparsin (n = 7, 3%), 1.8 (1.3–2.5) for pralatrexate (n = 58, 23%), 1.5 (0.6–NE) for forodesine (n = 8, 3%), 1.1 (0.4–2.4) for mogamulizumab (n = 22, 9%), 0.7 (0.4–3.5) for denileukin diftitox (n = 5, 2%), and NR (NE–NE) for alectinib (n = 1, 0.4%). In patients with TFHL, romidepsin (44%) and tucidinostat (18%) yielded median TTNTs (mo, 95% CI) of 4.0 (2.6–8.7) and 5.5 (1.9–7.8), respectively. Among the SAs, BV showed the longest median TTNT following 2nd- or later-line therapies in both TFHL (10.7 mo; 95% CI, 3.2–24.0) and PTCL-NOS (4.4 mo; 95% CI, 1.0–NE).

Conclusion: To the best of our knowledge, this study reports the most recent treatment patterns and prognoses for patients with R/R MTNKL. No standard of care has been established, as diverse treatment patterns have been observed. SAs resulted in similar survival outcomes to CCs in 2nd-line therapy, despite distinctive clinical Background: of the groups.

Link to Abstract abs25-7357

Abstract Number: abs25-7391

Health-related quality of life (HRQoL) in real-world patients with cutaneous T cell lymphoma (CTCL): Evaluation of patient reported outcomes using the Skindex-16 in a multidisciplinary CTCL clinic

Presenter: Elisa Hofmeister
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Background: Cutaneous T-cell lymphomas (CTCLs) are a rare group of heterogenous lymphomas that affect the skin and blood, causing significant symptom burden due to skin itching, rash, and peeling. CTCL negatively affects the HRQoL of patients and their care partners, with profound impacts on physical, social, and emotional functioning. Although CTCL guidelines recommend evaluation of patient-reported outcomes (PROs) when selecting treatment and assessing symptomatic response to therapy, these studies are scant in real-world patients treated outside of the clinical trial setting. At the University of Colorado, patients evaluated in our multidisciplinary CTCL clinic complete serial Skindex-16 PRO questionnaires as part of routine clinical care. In this study, we evaluated Skindex-16 scores and treatment information to examine symptom burden and HRQoL in real-world patients with CTCL. Methods In this cross-sectional, retrospective study, we extracted demographics, staging, and treatment information at the time of patients’ first visit with recorded Skindex-16 scores. The Skindex-16 is a validated PRO questionnaire that addresses HRQoL in patients with skin disease in symptom, emotional, and functional domains (Chren 2011), with published norms for mild, moderate, and severe scores (Prinsen 2011). Patients with a diagnosis of CTCL (mycosis fungoides [MF], Sezary syndrome [SS], lymphomatoid papulosis [LyP], and subcutaneous panniculitis-like T-cell lymphoma [SPTCL]) and with Skindex-16 scores at a multidisciplinary CTCL clinic visit between January 1, 2024 and June 30, 2025 were included. Patients with B-cell lymphomas and anaplastic large cell lymphomas were excluded. Two-tailed t-tests and multiple regression analyses were utilized to compare Skindex-16 scores and to determine associations between clinical variables and HRQoL. Results There were 132 patients: mean age 64 years (range 19-93), 44% female, 80% White, 5% Black, 3% American Indian/Alaska Native, 12% other, and 11% Hispanic. Most had Medicare (51%), followed by private insurance (40%). Most patients had MF (76%), followed by SS (9%), LyP (8%), SPTCL (5%), and other CTCL types (2%). At the time of their visit, 26% had advanced-stage disease, although 38% previously had advanced-stage CTCL. Most (52%) were on systemic therapy (oral, intravenous, or extracorporeal photopheresis), and 48% were on skin-directed therapy only (topical or ultraviolet). For the entire cohort, total Skindex-16 mean score was 33 (SD 28), indicating a moderate impact on HRQoL. Skin-related symptoms were rated as mild (mean 32, SD 30), as was functional impact of CTCL (mean 23, SD 29). However, patients reported severe emotional burden related to CTCL (mean 43, SD 34). Highest individual items within the emotional domain were worry about persistence/recurrence (mean 3.3 out of 6, SD 2.3), worry about disease (mean 2.4, SD 2.4), and annoyance at disease (mean 2.8, SD 2.4). Participants rated depression (mean 1.8, SD 2.1) and embarrassment (mean 2.2, SD 2.4) as less bothersome. There were no significant differences in total Skindex-16 scores or symptom, emotional, or functional domain scores between early- vs advanced-stage CTCL. Patients on systemic therapy had worse symptom domain scores ( β 15.6, p=.05, SD 30), including hurting ( β 1.1, p=0.04, SD 1.7), as well as difficulty showing affection in the functional domain ( β 1.1, p=0.02, SD 1.9). We also found that patients on Medicaid had worse total Skindex-16 scores than those on Medicare ( β 48.8, p=0.004, SD 28.1). Conclusions Our cross-sectional analysis of Skindex-16 scores in a cohort of CTCL patients highlights a substantial emotional burden associated with the disease, even when physical symptoms and functional impairments are rated as mild to moderate. The emotional burden of CTCL is high, even for those with early-stage disease and on skin-directed therapy only. Individual items rated highest within the emotional domain were fear of recurrence, as well as worry about disease. These findings emphasize the importance of routinely integrating HRQoL assessments into CTCL care. Further, the psychological effects of CTCL may be an unmet need requiring tailored supportive interventions to address emotional distress as well as fear of recurrence. Future prospective studies are needed to examine how HRQoL scores change over time with different treatment options in this rare disease.

Link to Abstract abs25-7391

Abstract Number: abs25-8673

Integrated analysis of mogamulizumab trials for mature T-cell lymphomas, investigating differences in longitudinal effects between responders and non-responders

Presenter: Nobuaki Nakano
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Introduction: Mogamulizumab (moga), an anti-CC chemokine receptor 4 (CCR4) antibody, is approved in Japan for CCR4 + adult T-cell leukemia/lymphoma (ATL) and peripheral and cutaneous T-cell lymphomas (PTCL, CTCL). As moga affects CCR4 + cells, longitudinal changes in these cells and its ligands, CCL17 and 22, are likely to be found with moga treatment and/or associated cutaneous adverse events (cAEs). Although moga’s effects on immune cells were previously reported for CTCL (Ni X, et al. Clin Cancer Res. 2015) and solid tumors (Maeda Y, et al. Nature Commun. 2021), differences based on response and a relationship with cAEs were not shown. We analyzed past clinical trials for ATL/PTCL/CTCL to investigate the effects of moga over time on cells and ligands based on response and occurrence of cAEs.

Methods: Cohorts of relapsed or refractory (r/r) ATL, r/r PTCL and r/r CTCL were taken from 6 moga trials. Each cohort was separated by responders (R) (complete response, unconfirmed complete response, partial response) and non-responders (N) (stable disease, disease progression) subpopulations based on best overall response. A linear mixed model (LMM) including subpopulation, time points, and baseline (BL) values in each cohort as fixed effects and subjects as a random effect was used to estimate the differences between subpopulations. Interactions between subpopulations and time points were not included in the LMM as they were not significant. As this was an ad hoc exploratory study, no adjustments were made for multiple testing.

Results: The efficacy analysis set comprised 69 patients (pts) with ATL, 64 with PTCL (31 PTCL-not otherwise specified, 23 angioimmunoblastic T-cell lymphoma, 7 anaplastic large cell lymphoma, 3 transformed mycosis fungoides [MF]), and 221 with CTCL (126 MF, 94 Sézary syndrome, 1 primary cutaneous anaplastic large-cell lymphoma). The LMM showed changes over time for only the CTCL cohort for lymphocytes (−1174/µL; 95% confidence interval [CI]: −1809, −538.9; p=0.0003), CD4 + cells (−1042/µL; 95% CI: −1694, −309.3; p=0.0019) and CCL17 (−1846 ng/L; 95% CI: −3254, −439.4; p=0.0105) during the observational period. Lymphocyte and CD4 + cell count changes plateaued in R at Week 4 (mean ± standard error [SE], CD4 + cell counts at BL: 3921±879.7/µL; Week 4: 489.8±75.9/µL). ATL and PTCL showed a different trend at BL. CD4 + cell count differences at BL were far greater for ATL (mean±SE, R: 6754±1723/µL vs N: 1118±276.2/µL) and PTCL (R: 286.3±90.7/µL vs N: 1498±752.4/µL) vs CTCL (R: 3921±879.7/µL vs N: 3268±885.3/µL). No LMM results were obtained for CD4 + CD25 + FoxP3 + cells, but BL counts for ATL were higher for R than N (R: 3829±1248/µL vs N: 586.6±312.7/µL, p=0.0188, unpaired t-test), with no differences for PTCL or CTCL. Moga efficacy in the skin was investigated through longitudinal changes in modified Severity-Weighted Assessment Tool (mSWAT) scores. An LMM was obtained for the CTCL cohort, but the interaction term reached p<0.0001. Actual values showed mean mSWAT scores±SE for R were 97.6±6.5 at BL, 71.0±6.2 at Week 4 (% change ± SE from BL: −29.8±3.71%, p<0.0001) and 34.9±4.9 at Week 24 (−62.6±5.26%, p<0.0001), showing response in the blood precedes response in the skin. An estimated difference of CCL17 serum levels between R and N (−1846.4 ng/L; 95% CI: −3223.6, −439.4) was seen only for CTCL, suggesting CCL17 decreased from BL in response to moga (R: 4028±844.2 ng/L and N: 5425±809.9 ng/L). In r/r ATL at Week 4, CCL17 serum levels increased to 2213±870.8 from 584.9±291.4 ng/L for R and to 1662±913 from 791.5±285.7 ng/L for N. When the association of ligand increase with cAEs occurrence was analyzed, CCL17 % change±SE from BL was higher for pts with cAEs than without (465±135%, p=0.0043; 301±131%, p=0.0545, respectively, one-sample t-test), with a significant change in CCL22 (94±20%, p=0.0004; −0.46±19%, p=0.9815, respectively) at Week 4. No such differences were seen for r/r CTCL.

Conclusions: This analysis shows the effect of moga on CCR4 + cells and its ligands. In CTCL, longitudinal decreases in lymphocyte counts, CD4 + cell counts and CCL17/22 serum levels preceded mSWAT score decrease in R. In ATL and PTCL there are clear differences in BL counts for lymphocytes, CD4 + and/or FoxP3 + cells in R vs N. Additionally, CCL17/22 increases are seen in pts with r/r ATL with cAEs. These results further suggest that moga’s effects on CCR4 ligands and the ligands’ usefulness as response biomarkers differs between lymphomas.

Link to Abstract abs25-8673

Abstract Number: abs25-9213

Adding selinexor to ifosfamide, etoposide and desametasone does not improve the outcome in relapsed and refractory peripheral T-cell lymphomas: First report of phase II S-ide study.

Presenter: Annalisa Chiappella
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Introduction: The prognosis of relapsed or refractory (R/R) Peripheral T-cell lymphomas (PTCL) is very poor, except for CD30+ ALK positive PTCLs patients treated with brentuximab-vedotin and chemotherapy. Selinexor is an oral, ﬁrst in class, potent selective inhibitor of nuclear exportin (SINE), that is overexpressed in many malignancies, including PTCLs. In a small phase I study, selinexor in combination with high-dose dexamethasone, ifosfamide, carboplatin and etoposide (D-ICE) has shown promising overall response rate (ORR, 91%) and complete response (CR, 82%) in R/R PTCLs, (Tang et al. Haematologica 2021). On these bases, we designed the pilot phase II study PTCL S-IDE (selinexor, ifosfamide, etoposide, dexamethasone, without carboplatin to reduce hematologic toxicity), EudraCT number 2021-006229-23.

Methods: Key inclusion criteria were: age 18-75 years, R/R histologically conﬁrmed PTCL (PTCL-NOS, angioimmunoblastic T cell lymphoma - AITL, anaplastic large cell ALK negative - ALK neg, T-helper follicular - TFH) after at least one course of anthracycline containing regimen chemotherapy (including or not high dose chemotherapy and stem cell transplantation [SCT]), PS ECOG <=2, adequate organ function. All patients received S-IDE on a 21-day cycle: Selinexor (40 mg on day 3, 5 and 7); Ifosfamide 5g/mq on day 2; Etoposide 100 mg/mq on days 1-3; Dexamethasone 20 mg/day on days 3-7. Patient in CR at the end of the 4 courses received a maintenance with 60 mg selinexor weekly, until progression or unacceptable toxicity, or proceeded to allo-SCT or auto-SCT according to donor availability, previous SCT, patient age and comorbidities. The primary endpoint was ORR at the end of 4 courses of S-IDE; the secondary endpoints were duration of response, 18-months progression-free survival (PFS) and overall survival (OS) and safety. Exploratory biological analyses have been planned to evaluate the role of GATA3 and TBX21 expression; loss of tumor suppressor genes on the CDKN2A/B-TP3 axis and PTEN-PI3K pathways as well as genetic gains and ampliﬁcation of STAT3 and MYC; the presence of mutations described as associated with a poor prognosis, including CD28 mutations in AITL; TP63 rearrangement, loss of TP53, and loss of PRDM1 in ALK− ALCL; GATA3 , TP53, and/or CDKN2A in ALK− ALCL; and alterations in histone methyltransferase genes KMT2A, KMT2B, or KDM6A and FAT1 in PTCL-NOS; XPO1 expression; circulating tumor DNA (ctDNA). A sample size of 30 patients was calculated to achieve a statistical power of more than 90% (94%) to test an increase of 30% of ORR (from 50% under null hypothesis to 80% under the alternative one) using a two-sided one sample binomial test with alpha = 5%.

Results: From August 2022 to April 2025, 30 patients were enrolled in 9 Italian centers; one patient was a screening failure and 29 were eligible and evaluable for response. Median age was 66 years (IQR 60;70); 22 (76%) had stage III-IV and 6 (21%) PIT score >2. Histological subgroups were: 14 (48%) PTCL-NOS, 8 (28%) ALK negative and 7 (24%) AITL/THF. All patients received one prior line of therapy and 48% (14/29) were primary refractory; 24% (7/29) failed a prior auto-SCT. All patients were evaluable for response after 2 courses of S-IDE: ORR 48% (14/29), with 21% CR. At the end of induction, ORR was 41% (12/29), with 31% (9/29) patients in metabolic CR. Considering the 9 patients in CR at the end of therapy, one elderly patient not eligible for transplant received selinexor maintenance; 6 out of 9 patients received allo-SCT as consolidation, one patient did not for donor unavailability, and one patient developed a West Nile infection. At a median follow-up of 10.1 months (IQR: 5.1, 13.09), the 12-months PFS was 30% (95% CI: 15.3%-58.7%) and the 12-months OS was 40.7% (95% CI: 23.7%-69.7%). Hematological adverse events were reported in 31% (9/29) patients; 3 patients died during induction, one due to West Nile infection not related to the treatment, and 2 due to pulmonary infection.

Conclusions: In the pilot phase II study S-IDE, the primary end-point was not met, with ORR of 41% at the end of induction. The addition of selinexor to ifosfamide, etoposide, dexamethasone did not ameliorate prognosis in relapsed/refractory PTCLs, the clinical outcome is similar to standard therapies available in this setting. Biological analyses are ongoing.

Link to Abstract abs25-9213

Abstract Number: abs25-10345

Diagnostic and therapeutic patterns in cutaneous T-cell lymphomas (CTCL): Real-world data from the lymphoma epidemiology outcome-molecular epidemiology resource (LEO-MER) prospective cohort study.

Presenter: Muhammad Saad Hamid
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Introduction: CTCLs are rare, heterogeneous non-Hodgkin lymphomas (NHL) with significant regional variability in treatment patterns. Prospective studies characterizing CTCL management, particularly in racially and ethnically diverse populations, remains limited. The LEO-MER multi-center prospective cohort study (NCT02736357) is designed to address the persistent disparities in outcomes research by enrolling historically underrepresented groups of patients diagnosed with lymphoma across the United States (US). Here, we present a real-world analysis of CTCL patients that reflects US academic practice, evaluating treatment patterns, as well as prognostic factors influencing survival outcomes.

Methods: Patients aged ≥18 years with newly diagnosed CTCL were prospectively enrolled in either the University of Iowa/Mayo Clinic MER cohort (2002-2015) or the expanded LEO cohort (2015-2020), which included 8 US academic centers. Standardized protocols were used to abstract clinical, pathologic, treatment, and outcome data from medical records. ANOVA/Kruskal-Wallis and Fisher’s/chi-square tests were used to compare patient distribution across demographic and clinical characteristics based on data distribution and sample size. Overall survival (OS) was calculated from diagnosis to death or last follow-up. Survival analyses employed Kaplan-Meier estimation supplemented by Cox proportional hazards modeling.

Results: The LEO-MER cohort enrolled 223 CTCL patients (91 MER and 132 LEO). Subtypes included mycosis fungoides (MF, n=155, 69.5%), Sézary syndrome (SS, n=22, 9.9%), primary cutaneous anaplastic large-cell lymphoma (n=17, 7.6%), subcutaneous panniculitis-like T-cell lymphoma (n=11, 4.9%), cutaneous CD4+ small/medium T-cell lymphoproliferative-disorder (n=9, 4%), and other rarer CTCL subtypes (n=9, 4%). Among the MF/SS cohort, median age was 64 years (Range: 18-89 years), 58.2% (n=103) were male and race/ethnicity distribution included White (n=123, 69.5%), Black (n=29; 16.4%) and others/unknown (n=25; 14.1%). Stage distribution included 62.7% with early-stage (ES) MF (IA-IIA, n=111), 37.2% with advanced- stage (AS) MF (IIB-IVB, n=66). To complete diagnostic workup, T-cell receptor (TCR) testing was performed in 52.6% of skin biopsies (n=92) and 62.5% of blood samples (n=110), with clonal detection rates of 75% (69/92) in skin and 51.8% (57/110) in blood. Paired TCR matching between skin and blood samples was performed in 31.6% (n=56) of cases, demonstrating 53.6% (30/56) concordance. Blood flow cytometry data were reported in 80.1% (89/111) and 84.4% (56/66) of ES and AS MF cases, with T-cell population being detected in 7.2% (8/111) and 62.1% (41/66) of ES and AS cases. Nodal biopsies were obtained in 23.4% (n=41) of patients and clonality assessment was reported in 18.6% (33/177) of these cases. The MF/SS cohort’s lifetime treatment exposure data (n=160) revealed topical skin-directed therapies alone (n=49, 31.8%) as the most common approach followed by lifetime exposure to topical skin-directed and systemic therapies (n=45, 29.2%) followed by multimodal exposure of topical skin-directed, radiation and systemic treatments (n=30, 19.5%). Only 5.6% of patients were enrolled in a clinical trial. First-line (1L) systemic regimens were predominantly a) immunomodulatory agents (n=47, 29.3%); including oral retinoid (n=20), extracorporeal photopheresis (n=18), interferon (n=9) followed by b) chemotherapy (n=30, 18.7%) and c) targeted therapies (n=17, 10.6%) including Brentuximab Vedotin (n=6), Romidepsin (n=5), Mogamulizumab (n=3), Vorinostat (n=2) and Pralatrexate (n=1). Multivariable analysis predicting 1L systemic treatment initiation demonstrated a significant association with presence of N2/N3 stage (N2/N3 vs N0/N1: Odds Ratio (OR): 5.45) and elevated LDH (OR: 5.30). At median follow-up of 91.1 months (mon), median OS was 122.3 mon (95% confidence interval 67.2-159.2 mon). In subset analyses, Black race (p=0.001) and SS (p=0.0001) were associated with worse OS outcomes.

Conclusion: We present initial data from our prospective LEO-MER cohort, a large US-based multicenter consortia. Our findings demonstrate variability in both diagnostic staging and treatment approaches for MF/SS patients. The cohort demonstrated worse outcomes with high-risk disease and Black race/ethnicity. These findings warrant further study on the impact of underlying social determinant factors, given the variability noted in this population.

Link to Abstract abs25-10345

Abstract Number: abs25-10558

Cytotoxic lymphoma assessment response (CLyAR): A harmonized, compartment-based consensus response assessment framework for cytotoxic T-cell lymphomas

Presenter: Swami Iyer
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Background: Cytotoxic T-cell lymphomas (CTLs) are rare, comprising only 3–5% of all Mature T-cell lymphomas and have very poor outcomes. While sharing key biological features, including frequent expression of CD8, or NK-associated cytotoxic markers, and CD94 as a common molecular target, they present with wide clinical variability across anatomical compartments—cutaneous, intestinal, hepatosplenic, nodal, and leukemic. Current response criteria based on anatomic involvement have challenges in endpoint objectivity, response determination, cross-study interpretation, and regulatory approval. Objectives: Objectives: The CLyAR (Cytotoxic Lymphoma Assessment of Response) initiative aimed to harmonize response assessment by integrating existing validated criteria into a single, compartment-based framework for CTL subtypes. The goal was to improve consistency in therapeutic response evaluation and support broader patient inclusion in clinical trials for this underserved population.

Methods: An international expert panel and patient advocates convened to develop a harmonized response assessment framework for CTLs, drawing from current practices across trials and institutions. In preparation for the workshop, panelists reviewed the full spectrum of CTL histologies and provided structured evaluations of the appropriateness of existing response tools—Lugano, Olsen, and modified T-PLL—for each subtype and disease compartment. Using a structured matrix, experts rated the suitability of each modality (e.g., PET, CT, skin scoring, marrow assessment) as “Yes,” “No,” or “Maybe” based on their clinical experience. These pre-meeting assessments were developed to identify areas of consensus and divergence. During the workshop, the panel systematically revisited each histology and compartment, deliberating on discrepancies and refining criteria recommendations.

Results: The harmonized CLyAR framework applies to the heterogeneous set of cytotoxic T-cell lymphoma subtypes, including ENKTL (nasal type), EATL, MEITL, HSTCL, SPTCL, PCγδTCL, ET-CTCL, ANKL, HVLPD, PTCL-NOS, and cutaneous PTCL-NOS. The panel concluded that no single response criterion is adequate across all subtypes. Instead, they were grouped into four compartments: (1) nodal/systemic diseases. (2) leukemic or marrow-based diseases with or without organomegaly, (3) cutaneous/subcutaneous presentations, and (4) gastrointestinal (GI) presentations. The following conclusions were reached: Nodal cytotoxic PTCLs are best evaluated using Lugano criteria with PET/CT. ENKTL, while using Lugano criteria, still requires MRI of the sino-nasal area for treatment planning, serial EBV PCR, and bone marrow evaluation. For leukemic presentations and HSTCL, modified T-PLL criteria were adapted, combining disease-specific parameters with hematologic recovery markers. A complete response (CR) requires normalization across all areas including the bone marrow; partial response (PR) requires improvement in at least two disease- specific and one hematologic criterion. For cutaneous and subcutaneous variants (SPTCL and PCγδTCL), a global approach is necessary for response assessment. The primary evaluation method for quantifiable cutaneous disease is the Olsen criteria, with a strong emphasis on mSWAT scoring and serial photography. PET imaging is recommended for evaluating deeper lesions. Due to false-negative results (microscopic disease) and false-positive results (inflammatory changes), gastrointestinal lymphomas require careful PET interpretation and endoscopic confirmation. The panel emphasized that dominant anatomical presentation, measurable sites, and imaging features should be the basis for assigning response criteria. For non-standard presentations, a decision-tree algorithm was developed to direct the assignment of criteria. This adaptable, compartment-driven model takes into account the clinical diversity of CTLs while enabling harmonized assessment.

Conclusions: The CLyAR framework offers a single, compartment-based response that encompasses the diverse CTL presentations. It provides a way forward for standardized evaluation in real-world registries as well as prospective trials. Key priorities include patient-centered outcomes, coordinating response benchmarks with regulatory authorities, and engaging biopharma sponsors to use the framework in the trial design of novel treatments. The consensus details will be forthcoming at ASH 2025.

Link to Abstract abs25-10558

Abstract Number: abs25-10662

Prognostic significance of post-treatment EBV clearance and relapse patterns in localized extranodal NK/T-cell lymphoma treated with low-dose radiotherapy: A single-center analysis of 155 patients

Presenter: Yoon Sang Eun
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Background: Localized extranodal NK/T-cell lymphoma (ENKTL), nasal type, is commonly treated with radiotherapy (RT) and L-asparaginase (L-ASP) based chemotherapy. While international protocols often adopt RT doses of 50-56Gy, our center utilizes a low-dose RT strategy (40Gy in 20 fractions) with concurrent weekly cisplatin, followed by chemotherapy. This study aimed to evaluate long-term outcomes, relapse patterns, and the prognostic significance of EBV clearance in these patients under our protocol.

Methods: We retrospectively reviewed 155 patients with localized ENKTL treated between 1996 and 2022. All patients received RT (200cGy/day ⅹ 20 fractions) with concurrent cisplatin (30mg/m2 weekly). Among them, 141 (91.0%) received subsequent chemotherapy (CCRT-CTX), and 14 (9.0%) received CCRT alone. Chemotherapy regimens included L-ASP-containing or non-L-ASP-based protocols. Outcomes were analyzed according to EBV status, treatment response, and relapse patterns. The incidence of secondary primary malignancies was also recorded.

Results: The median age was 50 (range, 15-82), and 64.5% were male. Most patients(65.2%) had stage IE, and 89.0% had involvement of the nasal cavity. 69.0% of patients were classified as PINK 0, and 85.8% as PINK-E 0-1. Of 141 (91.0%) patients who received CCRT-CTX, 85.8% presented CR. In the 14 patients treated with CCRT alone, 57.1% maintained CR. With a median follow-up of 73 months (range 62-83), the PFS was 142 months, and the OS had not been reached. Patients treated with CCRT-CTX had significantly longer PFS than those treated with CCRT alone (p=0.004). PFS and OS did not significantly differ by the type of chemotherapy regimen (VI DL, VIPD, MIDL, GDP) or L-ASP use. Post-treatment EBV DNA negativity was associated with a favorable trend toward improved PFS (p=0.092). However, when combined with treatment response, patients who achieved CR and EBV negativity had significantly better PFS (p<0.001) and OS (p=0.061) than those with non-CR or EBV positivity. Of the 155 patients, 54 (34.8%) experienced relapse, including 29 at the primary site and 25 at distant sites. The primary site control rate was 81.3% (n=126/155) despite the use of low-dose RT (40Gy). Regarding long-term toxicity, the incidence of secondary malignancies was low (3 cases: breast cancer, melanoma, bladder cancer), suggesting that the limited RT field and low-dose strategy may reduce the risk of second cancers.

Conclusion: In localized ENKTL, a low-dose and limited RT approach with concurrent cisplatin showed favorable long-term outcomes with a low incidence of secondary malignancies. Additional chemotherapy after CCRT significantly improved survival. Post-treatment EBV negativity combined with CR was associated with a better prognosis and may serve as a practical prognostic marker. The outcome is relatively favorable compared to prior studies using high-dose RT, suggesting that RT dose de-escalation may be feasible in selected patients.

Link to Abstract abs25-10662

Abstract Number: abs25-10826

Upregulation of extracellular matrix remodeling gene set drives progression and poor prognosis in angioimmunoblastic T-cell lymphoma.

Presenter: Jieyu Xu
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Introduction: Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive and heterogeneous peripheral T-cell lymphoma derived from follicular helper T cells (Tfh cells). Despite conventional chemotherapy, patient outcomes remain dismal, with a 5-year overall survival rate of only from 44% to 52% and progression-free survival of 32% [1]. Mounting evidence implicates the complex tumor microenvironment (TME) as a key driver of AITL pathogenesis and clinical heterogeneity. While interactions between immune cells within the tumor microenvironment have been elucidated, the role of extracellular matrix (ECM) remodeling in AITL pathogenesis remains unexplored [2]. To address this, we performed bulk and single-cell RNA sequencing on an AITL patient cohort, identifying an extracellular matrix (ECM) remodeling-associated gene signature with prognostic relevance in AITL. Method Method This study included frozen tumor tissues from 10 treatment-naïve AITL patients and fresh lymph node tissues from 3 additional treatment-naïve AITL patients, all diagnosed according to the 2022 World Health Organization criteria. Bulk RNA sequencing and single-cell transcriptome sequencing were employed to analyze these tissue samples to obtain prognostically relevant microenvironment characteristics and mechanisms of cell-cell communication. The comparative RNA sequencing dataset (GSE250050) was obtained from the Gene Expression Omnibus database. The comparative sc-RNA sequencing dataset was sourced from the study by Vitalii et al (https://doi.org/10.1101/2020.11.15.378125). Result Result Through Multi-omics analysis, this study revealed significant enrichment of ECM remodeling genes in AITL, correlating with poor prognosis. Single-cell RNA sequencing identified a unique tumor-associated stromal cell (TASC) population characterized by high expression of ECM remodeling-related genes. Compared to normal stroma, TASCs exhibited upregulated MMP2/9 (facilitating basement membrane degradation and metastasis, log2FC = 3.32/1.33), LAMA2/LAMB3 (potentially promoting extranodal extension, log2FC = 4.71/3.31), and COL1A1/2, TIMP1/2 (driving synthesis and stabilization of immunosuppressive type I collagen, log2FC = 8.72/7.66 and log2FC = 2.25/1.57), while downregulating COL4A1/2 (synthesizing type IV collagen, log2FC = -1.77/-1.22) and MMP1 (degrading type I collagen). Cell communication analysis revealed robust TASC-TFH cell interactions mediated by FN1-ITGA4 and COL1A2- CD44 pairs, potentially activating oncogenic PI3K/AKT and FAK/ERK pathways. These coordinated alterations demonstrate TASCs actively reshape the AITL ECM to create an immune-suppressive microenvironment conducive to invasion, and immune evasion.The strong association of TASC-derived ECM regulators such as MMP2 and COL1A2 with poor prognosis highlights their biomarker potential for risk stratification. While this study implicates TASCs as key orchestrators of the pathogenic AITL microenvironment and suggests targeting stromal-mediated ECM remodeling, further validation with larger cohorts and in vivo/in vitro experiments is needed. Conclusions Conclusions This study identifies a unique tumor-associated stromal cell subpopulation, TASC, within the AITL microenvironment that drives ECM remodeling and engages in specific ligand-receptor interactions with Tfh cells. These findings establish TASCs as a critical mediator of AITL progression and poor prognosis, providing a novel prognostic biomarker and potential therapeutic target. References References [1] Ricard, L., Cervera, P., Stocker, N., Corre, E., Van de Wyngaert, Z., Banet, A., Marjanovic, Z., Dulery, R., Bravetti, C., Joly, A.-C., et al. (2024). A combination of 5-azacytidine and nivolumab is a potentially effective rescue therapy in relapsed/refractory AITL. Front. Immunol. 15, 1410638. [2] Zhu, M., Li, N., Fan, L., Wu, R., Cao, L., Ren, Y., Lu, C., Zhang, L., Cai, Y., Shi, Y., et al. (2024). Single-cell transcriptomic and spatial analysis reveal the immunosuppressive microenvironment in relapsed/refractory angioimmunoblastic T-cell lymphoma. Blood Cancer J. 14, 1–18.

Link to Abstract abs25-10826

Abstract Number: abs25-10860

A Phase 2, multicenter, open-label, single-arm study assessing a 4-weekly dosing schedule for mogamulizumab in patients with mycosis fungoides/Sézary syndrome (MOGA-2MG-Q4W)

Presenter: Julia Scarisbrick
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Introduction: Mogamulizumab (moga), a monoclonal antibody targeting chemokine receptor 4 (CCR4), is approved for relapsed/refractory mycosis fungoides/Sézary syndrome (MF/SS) after ≥1 prior systemic therapy with a dosing schedule of 1.0 mg/kg weekly (Q1W) in cycle (C) 1 (28 days) then every 2 weeks (Q2W) until disease progression (PD). A lower-frequency dosing schedule option could benefit some patients (pts) by reducing the number of clinic/infusion center visits. Safety and efficacy of a 2.0 mg/kg every 4 weeks (Q4W) dosing schedule was assessed in a phase 2 study in stage IB–IV MF/SS after ≥1 prior systemic therapy (NCT04745234).

Methods: The primary objective was to assess the safety and tolerability of a 1.0 mg/kg Q1W in C1 followed by a 2.0 mg/kg Q4W dosing regimen. Secondary objectives included pharmacokinetics/pharmacodynamics evaluation and efficacy evaluation by MF/SS consensus response criteria: overall response rate (ORR: global complete response [CR]/partial response lasting ≥4 weeks), duration of response (DOR), disease compartmental response, time to global response (TTR), and progression-free survival (PFS). Exploratory objectives included characterizing immunophenotypic, gene expression, and mutational profiles, and identifying specific genetic alterations in lesional skin and blood samples, pre- and post-moga treatment, which are associated with clinical response, resistance, or drug eruption. Descriptive statistics for continuous variables, frequency, and percentages for discrete variables were used.

Results: As of the April 18, 2025 data cut, study enrollment and follow-up are completed in 34 pts (median age 64.0 years; 64.7% male) in the United States (US) and Europe. At baseline (BL): 28 pts (82%) presented with MF at stages IB–IIA (n=8, 24%), IIB (n=12, 35%), IIIA–IIIB (n=7, 21%), and IVB (n=1, 3%), and 6 pts (18%) with SS at stages IIIA (n=1, 3%) and IVA1 (n=5, 15%). Median follow-up (min, max) was 21.1 (2.8, 35.2) months (mo). Treatment-emergent adverse events (TEAEs) occurred in all 34 pts. Serious adverse events occurred in 26.5% of pts, with 17.6% deemed drug-related. Drug-related TEAEs occurred in 76.5% of pts (majority Grades 1/2), most frequently drug eruption (38.2%), infusion-related reaction (23.5%), diarrhea, and fatigue (both 14.7%). Thirteen pts (38.2%) discontinued due to TEAEs; 11 [32.3%] due to drug-related TEAEs. Five pts completed the 2-year protocol-prescribed treatment. There were no drug-related deaths. The efficacy-evaluable set comprised 32 pts who completed C1 and received at least one 2.0 mg/kg dose in C2. ORR was 37.5% for all pts (12/32; CR: 2 pts), 30.8% for pts with MF (8/26; CR: 0 pts), and 66.7% for pts with SS (4/6; CR: 2 pts). For compartmental responses, ORR was 40.6% in skin (13/32 pts; CR: 2 pts), 100.0% in blood (9/9 pts; CR: 8 pts) and 0.0% in viscera (0/1 pts; CR: 0 pts). Median (min, max) TTR was 1.8 (1.0, 3.7) mo, median (min, max) DOR 13.4 (2.8, 22.7) mo, and median (min, max) PFS was 6.3 (1.7,23.6) mo (not Kaplan–Meier adjusted). Drug eruption occurred in 13 pts (38.2%), 7 (53.8%) of whom were responders. Moga concentration increased with repeated doses, reaching a steady state by C3 (mean±SD concentration on C3 Day 1: 17,005.4±8,077.4 ng/mL). Flow cytometry showed a strong, sustained reduction in circulating malignant T cells and almost complete depletion of CCR4 + T cells. Evaluation of blood CCR4 + T-cell counts of US pts showed B1/B2 pts had a higher BL count compared to B0 pts, which correlated with better moga treatment response; however, correlation between response and BL CCR4 expression in tumor, skin, and disease stage was not seen. Integrated genomic analysis of gene expression and mutational changes, including single-nucleotide polymorphisms in skin and/or blood at BL and post-treatment revealed distinct immune regulatory and skin-homing profiles associated with treatment response and drug eruptions. Conclusions Conclusions Results show a similar safety profile for the Q4W dosing schedule relative to the 1.0 mg/kg Q2W dosing schedule in a patient population that included a higher proportion of pts with MF vs the pivotal MAVORIC study (Kim 2018, Lancet Oncol). Although an increased rate of drug eruption relative to other trials was seen, this may have resulted from improved investigator experience discerning rash from PD since initial trials. Exploratory data on mutational profiles and immune response may allow for optimizing patient selection and management.

Link to Abstract abs25-10860

Abstract Number: abs25-13103

Efficacy and safety of mitoxantrone hydrochloride liposome in peripheral T-cell lymphoma: A multicenter, non-interventional, ambispective cohort real-world study

Presenter: Donglu Zhao
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Background: Peripheral T-cell lymphoma (PTCL) represents a heterogeneous group of aggressive lymphomas, accounting for 25%–30% of non-Hodgkin lymphomas (NHL) in China. The CHOP regimen remains the standard first-line treatment for PTCL, yet its long-term efficacy requires improvement. Relapsed or refractory (R/R) PTCL is highly aggressive with extremely poor survival outcomes, exhibiting a 3-year overall survival (OS) rate of less than 30%. This MOMENT study demonstrated promising efficacy and safety of the mitoxantrone hydrochloride liposome (Lipo-MIT)-based regimen in PTCL (J Leuk Lymphoma, 2023, 32(8): 457-464). Nevertheless, additional data are warranted to establish further validation. We previously reported updated real-world evidence for Lipo-MIT in treatment-naïve (TN) PTCL (2025 EHA, #PF949), showing a complete response (CR) rate of 48.2% and objective response rate (ORR) of 83.6%. Herein, we present updated survival outcomes for Lipo-MIT in TN-PTCL and provide the most recent real-world evidence regarding Lipo-MIT in R/R PTCL.

Methods: This multicenter, non-interventional, ambispective cohort real-world study was registered at www.chictr.org.cn (ChiCTR2200062067). It enrolled adult patients diagnosed with TN or R/R PTCL. The primary endpoint was ORR. Secondary endpoints included CR rate, progression-free survival (PFS), OS, and safety.

Results: As of February 8, 2025, 609 patients were enrolled, comprising 494 with relapsed/refractory PTCL (R/R PTCL) and 115 with treatment-naïve PTCL (TN-PTCL). The R/R cohort had a median age of 56 years (range: 19–86) with 62.1% males; subtypes included angioimmunoblastic T-cell lymphoma (AITL, 30.0%), extranodal NK/T-cell lymphoma (NKTCL, 25.9%), PTCL not otherwise specified (PTCL-NOS, 24.9%), ALK- negative anaplastic large cell lymphoma (ALCL, ALK-, 5.9%), ALK-positive ALCL (ALCL, ALK+, 2.8%), and other subtypes (10.5%). Advanced-stage (III–IV) disease was present in 67.0% pts, 27.9% had International prognostic index (IPI) scores 3–5, and 21.1% exhibited B symptoms. Prior therapy exposure included: ≥1 lines in all patients (50.4% first-line, 21.3% second-line, 28.3% ≥third-line), with 74.9% previously receiving anthracyclines. Patients received Lipo-MIT-containing regimens for a median of 3 cycles (range: 1–11), with median Lipo-MIT doses of 17.7 mg/m² (monotherapy: range 11.2–20.3 mg/m²; combination: range 5.4–23.3 mg/m²). Among 456 efficacy-evaluable R/R patients, the overall response rate (ORR) was 62.1% (283/456) and complete response (CR) rate was 29.2% (133/456), with ORR varying by subtype: AITL 68.6% (96/140), NKTCL 60.8% (73/120), PTCL-NOS 57.5% (65/113), ALCL ALK- 51.9% (14/27), and ALCL ALK+ 61.5% (8/13). Response rates decreased with prior lines: 68.1% (160/235) after first-line, 61.6% (61/99) after second-line, and 50.8% (62/122) after ≥third-line therapy. With a median follow-up of 6.5 months, median progression-free survival (PFS) was 9.9 months (95% CI: 7.1–12.7) and median overall survival (OS) was not reached. In the TN cohort (n=115), median follow-up was 11.6 months with median PFS of 14.6 months (95% CI: 10.8–18.3); 1-year PFS rates was 58.6%. Median OS was not reached, with 1-year OS rates of 88.0%. Safety analysis of the full cohort (n=609) revealed treatment-related adverse events (TRAEs) in 89.0% (542/609), with grade ≥3 TRAEs in 66.0%. Predominant hematologic toxicities included neutropenia (46.6%), leukopenia (42.2%), lymphopenia (34.5%), anemia (22.5%), and thrombocytopenia (23.0%). Non- hematologic TRAEs were primarily grade 1–2; no unexpected or serious adverse events were observed.

Conclusion: Lipo-MIT-based regimens demonstrated favorable clinical efficacy and tolerability in both TN- PTCL and R/R PTCL, representing a promising therapeutic option. Continued follow-up for survival outcomes is ongoing, with additional results forthcoming.

Link to Abstract abs25-13103

Abstract Number: abs25-13809

Efficacy and safety of duvelisib combined with chidamide as first-line treatment for angioimmunoblastic T-cell lymphoma (AITL)

Presenter: Liling Zhang
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Background: Background: : : Angioimmunoblastic T-cell lymphoma (AITL), an aggressive peripheral T-cell lymphoma (PTCL) subtype, demonstrates limited responsiveness to conventional chemotherapy, with a 5-year overall survival (OS) of 44% and progression-free survival (PFS) of 32%. Duvelisib (DUV), an oral dual inhibitor of phosphatidylinositol 3-kinase (PI3K)- δ / γ isoforms, has shown promising efficacy and tolerability in relapsed/refractory PTCL. This study evaluates the efficacy and safety of combining duvelisib with chidamide as first-line therapy for AITL to explore optimized treatment strategies.

Methods: This study was a prospective, single arm study (NCT05976997) that enrolled newly diagnosed AITL patients aged ≥ 18 years. All patients received duvelisib plus chidamide combined with CHOP chemotherapy of 6 cycles (Q3W). The dosing schedule is as follows:duvelisib 25mg (bid) for 10 days, and chidamide 20mg (biw).The primary endpoint was safety after induction. Secondary endpoints included duration of response (DoR), overall response rate (ORR), complete response (CR),progression-free survival (PFS), and overall survival (OS). Adverse events were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Results: From November 3, 2022 to June 11, 2024, a total of 12 newly diagnosed AITL were enrolled. The median age of all patients was 63 years (range 47-69), 58.3% were male. Among all patients, 91.7% were advanced stages disease with stage IV and 8 (66.7%) patients had IPI scores of 3 – 4. And 6 patients (50%) presented with B symptoms. As of the data cutoff, 12 patients were evaluated for efficacy,the ORR was 75% (9/12) and the CR rate was 66.7% (8/12).With a median follow-up of 16.54 months (range 7.20 – 24.93), the median PFS and OS have not yet been reached. the 1-year PFS and OS rates were 90% and 100%,respectively.The common grade 3/4 treatment-related adverse events (TRAEs) (incidence ≥ 10%) were mainly hematological toxicity, including leucopenia (41.7%)and neutropenia (41.7%), as well as infections including lung infections 33.3% .

Conclusions: The preliminary results of the study indicate that the combination of targeted therapy using DUV and chidamide and chemotherapy shows good efficacy and manageable safety. profile in newly diagnosed AITL, warranting further exploration.

Link to Abstract abs25-13809

Abstract Number: abs25-14290

Detection of intratumoral microorganisms in CTCL and patients symptoms and outcomes.

Presenter: Paola Ghione
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Detection of Intratumoral microorganisms in CTCL and patients symptoms and outcomes. Detection of Intratumoral microorganisms in CTCL and patients symptoms and outcomes. Introduction: In CTCL the tumor microenvironment (TME) is a critical component of lymphoma biology and impacts patient outcomes. Intratumoral microorganisms (IMS) constitute a part of the TME in solid tumors and tend to localize in specific niches, influencing response to therapy and outcomes. We hypothesized that IMS may impact presentation and outcomes of patients with CTCL.

Methods: Targeted next-generation sequencing (NGS) was performed on CTCL biopsy samples from 93 patients (pts) followed at our institution with the Memorial Sloan Kettering-Integrated Mutational Profiling of Actionable Cancer Targets (MSK-IMPACT). The control group comprised 177 melanoma biopsies, 49 systemic T-cell lymphoma (TCL) non-cutaneous biopsies and 66 normal lymph nodes. Microbial reads from regions that do not align with the human reference genome were analyzed (Elkrief JCO 2024). Several databases were referenced to exclude contaminations, and IMS were deemed positive if a minimal number of 2 reads was present, and with a higher individualized read threshold for potential contaminants based on the literature. These results were coupled with data on biopsy type (shave vs punch vs excision) lesion characteristics (tumor, plaque, patch), ulceration, pruritus, systemic antibiotics use, ethnicity, and outcomes from our clinical database. Ancestral annotation was inferred using the same MSK-IMPACT NGS platform. We compared variables with Fisher’s exact test, the t-test, and LogRank for each IMS present in more than 10% of the samples. ROC curve was used to estimate the AUC and best cut-off value for the IMS/sample.

Results: Median age at diagnosis in the 92 pts was 56 (20 – 90) years, 57 pts were male (52%), 55 pts had limited (IA, IB, IIA) stage CTCL (60%), 33 pts (36%) presented with patches, 41 (45%) with plaques, 13 (14%) with tumors, and 5 (5%) with erythroderma. Twenty-two (24%) were of African American descent, 6 (7%) Asian, 1 (1%) Hawaiian, 53 (58%) white and 10 (11%) had mixed ancestry. Compared to controls, CTCL samples had a similar number of IMS per sample compared to melanoma and systemic TCL, and a significantly higher number of IMS/sample compared to normal lymph nodes. Detection of Escherichia, Erythrobacter, Bordetella, Melothermus Bacillus and Prevotella was typical of melanoma but not found in CTCL samples, while Aquabacterium (p=.0005) and Helicobacter (p=.01) were more prevalent in CTCL. The presence of <9 IMS per sample was associated with worse overall survival (OS), p=.052. The ROC curve demonstrated an AUC of 0.8 for the relation of IMS/sample and OS. Median number of IMS/sample was 13 (3-62) in African American patients and 21 (1-124) in white patients. IMS <9 was associated with non- Caucasian ethnicity (p=.03). Systemic antibiotic use (20 pts, 18%) was associated with worse OS (p=.006) and advanced stage, and with a relative abundance of Prevotella, Streptomyces, Klebsiella . Detection of Staphylococcus was not associated with stage, type of lesion, pruritus or survival. Pruritus was experienced by 48 patients (52%) and was more prevalent in pts with plaques, erythroderma and tumors lesions and localized in the trunk. Acquabacterium detection was associated with less pruritus (p=.002).

Conclusions: Similar to previous findings in solid tumors, our study of IMS in CTCL suggests an increased incidence of intratumoral microbiota detection compared to normal LN, but similar to melanoma and systemic TCL. High number of IMS per sample was associated with improved OS and with Caucasian ethnicity. Further studies in larger independent cohorts are needed to confirm these results and evaluate the interactions of IMS with the lymphoma TME.

Link to Abstract abs25-14290

Abstract Number: abs25-9653

Trial in progress: A phase I/ib dose-finding study of ropeginterferon alfa-2b (P1101) in patients with cutaneous T-cell lymphoma (CTCL)

Presenter: Yumeng Zhang
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster I

Abstract: Background: and Significance: Background: and Significance: Cutaneous T-cell lymphoma (CTCL) is a rare, incurable non-Hodgkin lymphoma characterized by progressive Th2 immune skewing, loss of tumor surveillance, and chronic skin inflammation. Interferon- alpha (IFN-α) has long demonstrated immunomodulatory and antitumor effects in CTCL, with historical response rates between 30–80%, but is limited by short half-life, frequent dosing, and dose-limiting toxicities (DLTs). Pegylated IFN-α2a (Pegasys) has become a mainstay for systemic treatment in CTCL due to improved tolerability and biweekly administration; however, recent supply shortages in the U.S. have limited access, creating a significant treatment gap. Ropeginterferon alfa-2b (P1101) is a monopegylated IFN-α-2b with a longer half-life, reduced dosing frequency, and improved pharmacokinetics. It is FDA- approved for polycythemia vera and may permit sustained IFN exposure at higher doses. No studies have evaluated P1101 in CTCL. This trial seeks to define the recommended Phase 2 dose (RP2D) of P1101 in CTCL patients who have failed skin-directed therapies and to explore associated immune biomarkers. Study Design and Methods: Study Design and Methods: This is a Phase I/Ib, open-label, single-center, investigator-initiated trial (ClinicalTrials.gov: NCT07047885) conducted at Moffitt Cancer Center (Tampa, FL, USA). Eligible patients have stage IA–IIIB CTCL (WHO- EORTC criteria), including Mycosis Fungoides, Lymphomatoid Papulosis, and other rare variants, with no evidence of large cell transformation at screening. Patients with stage IA–IB must have an inadequate response to ≥2 lines of skin-directed therapy, where "inadequate response" is defined as any of the following: a. persistent clinically significant lesions or symptoms, b. Unacceptable toxicity, or c. Disease progression. Those with stage IIA–IIIB must have less than a complete response after phototherapy, extracorporeal photopheresis (ECP), or total skin electron beam therapy (TSET). Patients must have adequate organ function and no uncontrolled psychiatric, infectious, ophthalmic, or autoimmune comorbidities. The Phase I dose-escalation cohort will enroll up to 18 patients using a Bayesian Optimal Interval (BOIN) design with three target dose levels: 250 mcg, 350 mcg, and 500 mcg P1101 administered subcutaneously every 2 weeks. Intra-patient dose titration is allowed. DLTs are defined as grade ≥3 non-hematologic or grade ≥4 hematologic adverse events (CTCAE v5.0) within 6 weeks or 14 days after reaching the target dose. A Bayesian continuous toxicity monitoring algorithm halts accrual if the posterior probability of exceeding the 25% DLT threshold surpasses 80%. The expansion phase will enroll up to 20 additional patients at the RP2D. RP2D selection will integrate safety (DLTs, AE profile), preliminary efficacy signals (mSWAT, time to response, patient-reported outcomes), and immunologic biomarker trends. An interim futility analysis will occur after 10 patients in the expansion cohort have completed ≥24 weeks of therapy. Biomarker studies include serial blood and optional skin biopsies to analyze treatment-related changes in circulating T cells, NK cells, LGLs, and cytokines. Whole blood, PBMC, and plasma samples will be collected at baseline, during therapy, and at progression. Gene expression and immune profiling will explore predictors of response. This is the first prospective study of Ropeginterferon alfa-2b in CTCL in U.S. It aims to define a biologically active, immunomodulatory dose with sufficient tolerability for extended administration.

Link to Abstract abs25-9653

Abstract Number: abs25-8332

AI-based diagnosis of cutaneous lymphoma and lymphoproliferative disorders via H&E morphology and LLM-assisted cohort curation

Presenter: Ali Kamali
Session: 803. Emerging Tools, Techniques, and Artificial Intelligence in Hematology: Poster I

Abstract: Background: Cutaneous T-cell lymphomas (CTCLs) and cutaneous lymphoproliferative disorders (CLPD) are diagnostically challenging clonal lymphoproliferations that clinically and pathologically masquerade as inflammatory dermatoses such as eczema, psoriasis and drug reactions. Accurate diagnosis requires expert dermatopathologists to integrate clinical, histopathologic, immunophenotypic, and molecular features. However clinical and ancillary pathologic data is often unavailable, and overall exposure to CTCL/CLPD in training is poor, contributing to uncertain diagnosis and inconsistent patient management, particularly in early stage disease.

Methods: We developed a weakly supervised, end-to-end AI system for the classification of CTCL/CLPD using routinely stained hematoxylin and eosin (H&E) slides. The system combines a pretrained pathology foundation model with gated attention-based multiple instance learning to analyze whole-slide images and identify regions most predictive of a CTCL/CLPD diagnosis. To generate large-scale training data, we applied a large language model (LLM; GPT-4o) to 2,803 pathology reports from Memorial Sloan Kettering Cancer Center, which were preselected based on the presence of relevant keywords. The LLM parsed free-text diagnoses, extracted slide-level associations, and assigned case-level labels as positive or negative for CTCL/CLPD. This process identified 1,011 positive and 1,482 negative cases, corresponding to 2,493 whole-slide images used for model training (47% female; mean patient age: 61 ± 15 years). The feature extractor model extracted 1,024-dimensional embeddings from 256x256 patches at 20x magnification using the UNI pathology foundation encoder. These embeddings were aggregated via gated attention multiple instance learning (MIL) for binary classification. For evaluation, a balanced, held- out test set of 50 slides (25 positive, 25 negative) was randomly selected from the LLM-labeled dataset. A dermatopathologist independently reviewed these cases to confirm label fidelity and provide a pathologist-verified benchmark. Subsequently, one case initially labeled as CTCL by the LLM was excluded from the test set due to an inconclusive diagnosis in the report.

Results: Our model demonstrated strong performance in distinguishing cutaneous lymphoproliferative disorders from reactive mimics using H&E morphology alone. It achieved an area under the ROC curve (AUROC) of 0.96, overall accuracy of 0.84, sensitivity of 66.7%, and specificity of 100%. Precision was 1.00, indicating perfect positive predictive value. This performance suggests the model is highly reliable for confirming disease presence, though with moderate sensitivity. The attention maps revealed strong localization to perivascular and lichenoid infiltrates, intraepidermal/epidermotropic regions, and adnexal structures, highlighting clinically relevant features learned without explicit supervision.

Conclusion: This study demonstrates the synergistic application of large language models for automated cohort curation and advanced computer vision techniques to train high-performing models for challenging histopathologic diagnoses. Using this approach, we developed a model that achieved highly accurate diagnosis of cutaneous lymphoproliferative disorders based on H&E morphology. Our AI-based approach to CTCL shows promise for reducing diagnostic variability, improving triage, and guiding ancillary testing. The model’s interpretable outputs support integration into dermatopathology workflows, offering decision support in an area marked by high clinical ambiguity.

Link to Abstract abs25-8332

Abstract Number: abs25-8484

Development of a machine learning model to predict overall survival in patients with peripheral T-cell lymphoma in a minority enriched population

Presenter: Kimberly Seymour
Session: 803. Emerging Tools, Techniques, and Artificial Intelligence in Hematology: Poster I

Abstract: Introduction: Peripheral T-cell lymphomas (PTCL) are a group of heterogeneous lymphomas that arise from mature T- cells and comprise about 10% of all non-Hodgkin lymphomas. While diverse clinically and pathologically, these lymphomas often present at advanced stages and have a poor prognosis. Accurate prognostication for these patients is critical to inform clinical decision making and treatment strategies. Traditional tools to estimate overall survival (OS) can fall short when it comes to handling complex clinical data. Established indices such as the International Prognostic Index (IPI), Prognostic Index of PTCL-NOS (PIT), modified PIT, and others typically include factors such as age, disease stage, performance status, and lactate dehydrogenase (LDH), but may not capture the full spectrum of clinical and laboratory data in individual patient cases. In this study we aimed to develop and validate a machine learning (ML) model to predict OS using comprehensive demographic, clinical, and laboratory data from diagnosis.

Methods: We identified 97 patients with PTCL diagnosed at Montefiore Medical Center between January 1 st , 2010 and December 31 st , 2022. Data was collected via manual chart review. Inclusion criteria included a diagnosis of PTCL, age >18, and complete data at diagnosis. Patients with incomplete data were excluded. Data processing and modeling was performed in Python using libraries such as scikit-learn, scikit-survival, and pandas. A random forest survival model was used for model development. Model performance was evaluated using concordance index (C-index) to assess discriminatory ability and Brier scores were calculated at different time points (30, 365, 730, and 1095 days) to assess calibration. Permutation feature importance (PFI) was used to evaluate individual variable contribution, and partial dependence plots were used to interpret model behavior.

Results: Among the 97 patients with PTCL, 42% were diagnosed with Adult T-cell Leukemia/Lymphoma (ATLL), 28% with Peripheral T-cell Lymphoma not otherwise specified (PTCL-NOS), 8.2% with Extranodal NK/T-cell Lymphoma, Nasal Type (ENKTCL), 7.2% with Angioimmunoblastic T-cell Lymphoma (AITL), and 13.4% with other PTCL subtypes. The cohort was 54.6% male and 45.4% female. 49.6% were Black, 36.1% were categorized as Other, 9.2% were White, 4.1% were Unknown, and 1% was Asian. 38% were of Hispanic ethnicity. The average age at diagnosis was 60 years. During the study period, 57.7% of patients died and 25.8% were lost to follow-up. The average time from diagnosis to death or censorship was 760 days. Our ML model demonstrated predictive performance in the full dataset with a C-index of 0.86, suggesting strong overall discriminative performance, though on the validation set the C-index decreased to 0.68. Brier scores at 30, 365, 730, and 1095 days were 0.07, 0.21, 0.21, and 0.19, respectively, indicating good calibration over time. The most predictive features for the full data set included baseline LDH, ECOG at diagnosis, Charlson Comorbidity Index score, ejection fraction (EF), absolute neutrophil count (ANC), hemoglobin, and if the patient received a transplant after first- or second-line therapy (PFI of 0.03, 0.02, 0.02, 0.02, 0.02, 0.01, and 0.01 respectively). Creatinine (PFI= 0.009), number of extranodal sites (VI=0.009), Medicaid coverage (PFI= 0.007), and GFR (PFI= 0.007) had the next highest feature importance scores. Baseline LFTs and bilirubin did not significantly contribute, and neither did age >60. Partial dependence plots were suggestive of shorter predicted survival among patients of Hispanic ethnicity and those with Medicaid.

Conclusions: Our machine learning model demonstrated predictive capacity for OS in our full cohort. The discrepancy in the C-index in the full cohort and validation sets is likely reflective of the impact of limited sample size and indicates potential overfitting in our model. This emphasizes the need for further model refinement and validation on independent data. Overall, these findings do support the feasibility of machine learning in generating survival prediction models in PTCL but again highlight the importance of external validation and a larger sample size to improve model robustness and possibility for clinical use. Future work will focus on refining the model, incorporating further molecular and genetic data, and validation in multi- institutional cohorts.

Link to Abstract abs25-8484

Abstract Number: abs25-9174

Diagnosing mycosis fungoides using AI powered histologic analysis

Presenter: Mohamed Sharaf
Session: 803. Emerging Tools, Techniques, and Artificial Intelligence in Hematology: Poster I

Abstract: Background: Background: Mycosis Fungoides (MF) is the most common type of cutaneous T-cell lymphoma. Unfortunately, the diagnosis of MF is challenging due to its shared histological features with benign inflammatory conditions such as dermatitis, psoriasis, and eczema. Typically, MF diagnosis requires integration of clinical, histopathologic, immunohistochemical, and/or molecular evaluation, which can be time-consuming, subjective, and error prone, leading to significant delays in diagnosis and treatment, negatively impacting patient outcomes. We sought to determine if machine learning approaches may enhance MF diagnostic accuracy using skin biopsy whole slide images (WSI’s). Design Design We employed a self-supervised learning model, Histomorphological Phenotype Learning (HPL), with the BarlowTwins algorithm to autonomously extract distinctive features from skin biopsy hematoxylin and eosin (H&E) stained slide images scanned at 20x magnification and tiled into 224px sections. Our training dataset was comprised of 300 sections from 50 patients diagnosed with early-stage MF, and 300 sections from 50 patients with non-MF inflammatory skin conditions (spongiotic and eczematous dermatitis) sourced from NYU Langone Health (2021–2024). The images were split into 70% training, 10% validation, and 20% testing. External validation was performed using an independent dataset from the University of Minnesota using 50 MF and 50 non-MF cases. Attention heatmaps were applied on the slide level to evaluate the spatial distribution of the highly diagnostic image tiles. Result Result Our model identified seven enriched, and four depleted image tile clusters in MF vs non-MF cases. In the NYU test set, the model achieved 96% accuracy, 94% specificity, 98% sensitivity, an F1 score of 0.96, and an AUC of 96% for slide-level classification. Application of the model to the second dataset without any additional fine-tuning resulted in a nearly identical performance: 98% accuracy, 96% specificity, 100% sensitivity, an F1 score of 0.98 (precision ≈ 0.96, recall = 1.0), and an AUC of 95.5%. Heatmaps demonstrated distinct patterns of diagnostic patches, with subsets of cases showing predictive clusters predominantly in the dermis, while others were predominantly in the epidermis or epidermal-dermal junction.

Conclusion: Our studies demonstrate that self-supervised learning can detect features in skin biopsies that can accurately diagnose MF solely based on H&E stained images. Attention heatmaps highlighted three patterns of diagnostic feature enrichment – predominantly epidermal, dermal, or at the epidermal- dermal junction, compatible with biological diversity characterized by distinct patterns of neoplastic cell infiltration. Overall, these studies demonstrate that AI-trained models can accurately diagnose MF. Such models have the potential to increase the speed and accuracy of diagnosis, as well as minimize the use of resource-intensive ancillary testing in MF, leading to improve patient outcomes.

Link to Abstract abs25-9174

Abstract Number: abs25-11618

Therapeutic targeting of sphingosine-1-phosphate receptor 1 (S1PR1) in angioimmunoblastic T-cell lymphoma.

Presenter: Ruth Alonso Alonso
Session: 621. Lymphomas: Translational – Molecular and Genetic - Decoding Lymphomagenesis through Multiomics

Abstract: Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphoma (PTCL) derived from malignant transformation of T follicular helper (TFH) cells. AITL, which represents 20– 30% of PTCLs, is associated with autoimmune features, poor response to conventional chemotherapy, and dismal prognosis. The molecular landscape of AITL is characterized by frequent genomic alterations in epigenetic regulators, including TET2, DNMT3A, and IDH2 , as well as components of the T-cell receptor (TCR) signaling pathway. Among the latter, the RHOA G17V mutation has been recognized as a genetic hallmark uniquely associated with TFH-derived lymphomas. Previous work from our group demonstrated that the RHOA G17V mutation induces TFH speciﬁcation and, in cooperation with the loss of Tet2, promotes lymphomagenesis. Recent data from our laboratory has shown that expression of RHOA G17V regulates the sphingosine-1- phosphate (S1P) receptor 1 (S1PR1), a key mediator of lymphocyte traﬃcking and immune activation. Expression of RHOA G17V in CD4⁺ T cells antagonizes S1PR1 internalization, leading to increased activation of S1PR1 downstream signaling. Interestingly, deletion of S1pr1 in CD4⁺ T cells in a murine Rhoa G17V conditional model partially rescues the thymic phenotype and peripheral systemic inﬂammation characteristic of RHOA G17V-expressing mice, suggesting a contribution of S1PR1 to the aberrant function of RHOA G17V . This, together with our observation of increased S1PR1 expression in human RHOA G17V⁺ AITL tumor samples, identiﬁes S1PR1 deregulation as a potentially relevant eﬀector of the oncogenic effects of RHOA G17V in TFH cells. S1P receptor inhibitors, such as fingolimod (FTY720) and next-generation, more selective modulators such as ozanimod, siponimod, and ponesimod, are FDA-approved for the treatment of multiple sclerosis and other autoimmune diseases. These agents function by inhibiting S1P receptors, thereby sequestering lymphocytes in lymphoid tissues and reducing pathogenic immune cell trafficking. Their established safety and immunomodulatory effects make them attractive candidates for repurposing as targeted therapies in AITL, where S1PR1 signaling seems to be implicated in disease pathogenesis. However, their mechanistic effects in T-cell lymphoma cells remain to be characterized. To dissect the effects of S1PR1 inhibition, we used fingolimod (a pan-S1PR modulator) and ozanimod (a more specific S1PR1 and S1PR5 modulator), in murine preclinical models of AITL in vitro . Both compounds significantly reduced viability and induced apoptosis in the murine AITL cell line. In parallel, migration assays with ex vivo primary murine lymphoma cells revealed potent inhibition of both spontaneous and S1P-induced migration. We performed RNAseq in a Tet2 ⁻ / ⁻ RHOA G17V -expressing murine lymphoma line treated with ﬁngolimod or ozanimod for 24 h. GSEA analysis revealed robust downregulation of IL6-JAK-STAT3, TNFA- NF κ B, and apoptosis pathways (FDR < 0.25), supporting the existence of a proinﬂammatory transcriptional program sustained by S1PR1 signaling. To functionally validate the contribution of STAT3 to this circuit, we treated cells with stattic, a selective inhibitor of STAT3 phosphorylation. Stattic partially recapitulated the anti-lymphoma eﬀects of ﬁngolimod, suppressing migration and inducing apoptosis in vitro. Importantly, in vivo treatment with either ﬁngolimod or stattic led to reduced tumor burden and systemic dissemination and was associated with decreased STAT3 phosphorylation. These ﬁndings deﬁne an S1PR1–STAT3 inﬂammatory loop that promotes survival and dissemination in RHOA G17V -driven AITL and identify this axis as a therapeutically actionable vulnerability. In summary, our preliminary data establish a mechanistic link between oncogenic RHOA signaling and S1PR1-mediated membrane receptor signaling, highlighting a previously unrecognized pathway in AITL pathogenesis. The demonstration that clinically approved S1P receptor modulators suppress lymphoma growth and dissemination provides a strong rationale for repurposing these agents as targeted therapies for AITL, encouraging future translational studies and clinical investigation.

Link to Abstract abs25-11618

Abstract Number: abs25-9456

Distinct blood endothelial cells shape spatial niches in angioimmunoblastic T-cell lymphoma

Presenter: Yuki Shimizu
Session: 621. Lymphomas: Translational – Molecular and Genetic - Decoding Lymphomagenesis through Multiomics

Abstract: Background: Background: Angioimmunoblastic T cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma with a poor prognosis. Pathologically, AITL is characterized by the proliferation of diverse stromal cells (SCs), including blood endothelial cells (BECs) and follicular dendritic cells (FDCs). However, the tumor histology exhibits considerable heterogeneity, both between and within patients. It is hypothesized that these SCs form a supportive tumor microenvironment, and their histological heterogeneity may influence the clinical course. We previously reported that single-cell RNA sequencing (scRNA-seq) of SCs in lymph nodes (LNs) identified 30 distinct SC subclusters (Nat Cell Biol, 2022). However, the specific SC subclusters involved in AITL tumorigenesis remain undefined. Aims Aims We aimed to characterize the SC heterogeneity in AITL microenvironments by employing scRNA-seq and spatial multi-omics at single-cell resolution.

Methods: Non-hematopoietic cells were isolated from 10 AITL and 5 normal LNs using magnetic- and fluorescence- activated cell sorting, followed by scRNA-seq. Based on the scRNA-seq data of SCs and immune cells, we designed a 289-gene panel for spatial transcriptomics (ST) using Xenium in situ, and a 50-protein panel for spatial proteomics (SP) using PhenoCycler fusion targeting immune cell and SC subclusters. These assays were applied to 27 formalin-fixed paraffin-embedded AITL samples. Whole exome sequencing (WES) was successfully performed on 26 of the 27 samples. We analyzed a bulk RNA-seq dataset of 97 AITL to validate the prognostic potential of gene expression patterns.

Results: First, we analyzed scRNA-seq data from 49,363 stroma cells and identified 30 SC subclusters consistent with our prior findings. Notably, transitional BECs between capillary BECs and activated h igh endothelial venules (C-aHEVs) expressed markers of both capillary BECs and HEVs, and were further subdivided into C-aHEV1 and C-aHEV2. Both tip cells, which contribute to angiogenesis, and C-aHEV2 were increased in AITL samples. Differentially expressed genes analysis revealed that both C-aHEV1 and C-aHEV2 highly expressed ACKR1 . Notably, C-aHEV1 exhibited high expression of chemokines such as CXCL10 and CXCL12 , whereas C-aHEV2 expressed genes encoding extracellular matrix proteins. Interaction analysis revealed that the CCL5-ACKR1 axis, which is known as a regulator of leukocyte migration, was activated between CD8-positive T cells and C-aHEVs. Furthermore, the COL15A1-integrin and SPARC-ENG axis, both of which have been reported to promote angiogenesis, were specifically enriched between C-aHEV2 and other HEVs. ST analysis of 2,020,192 cells identified 10 BEC subclusters, 5 non-endothelial SC subclusters, and 12 immune/tumor cell subclusters. Spatial proximity measurement revealed that C-aHEV1 was the BEC subcluster most closely associated with tumor cells. Spatial niche analysis revealed that C-aHEV1, together with FDCs, formed a distinct tumor-associated niche (CFT niche). On the other hand, C-aHEV2 was localized farther from the tumor than C-aHEV1, and formed a niche in conjunction with other HEV subclusters (HEV niche). The CFT niche-dense area and the HEV niche-dense area were often in close proximity, and the densities of CXCR4 , encoding a receptor for CXCL12 , and LAG3 and CXCR6 , serving as T-cell exhaustion markers, were high in the CFT niche. SP analysis detected 6,172,072 cells and identified SCs containing 5 BEC components (artery, capillary, C- aHEV, HEV, and vein), tumor cells, and immune cell subtypes. C-aHEVs tended to be located closer to tumor cells than other BECs and formed a unified vascular niche in conjunction with HEV. WES analysis revealed the recurrent G17V RHOA mutations in 19 samples. Notably, samples harboring G17V RHOA mutations exhibited significantly higher densities of C-aHEV2 cells. Bulk RNA-seq analysis revealed that patients with high expression of C-aHEVs and other HEV-related signature exhibited poorer survival outcomes. Summary/ Conclusion Summary/ Conclusion By integrating scRNA-seq and spatial data, we identified C-aHEVs as key components in shaping the AITL microenvironment through the recruitment of immune cells. As the gene expression level, C-aHEVs can be subdivided into C-aHEV1 and C-aHEV2, which exhibited distinct properties. Further investigation is needed to validate the mechanisms by which these BEC clusters interact with tumor cells and contribute to tumorigenesis.

Link to Abstract abs25-9456

Abstract Number: abs25-13595

Implementation of a patient-reported outcome assessment during radiotherapy for mycosis fungoides and other cutaneous lymphomas

Presenter: Kaitlyn Lapen
Session: 902. Health Services and Quality Improvement: Lymphoid Malignancies: Redefining supportive care: Development of novel safety, patient engagement, and delivery models in hematologic oncology

Abstract: Introduction: Radiotherapy (RT) is often used to manage disease burden and symptoms in patients with cutaneous lymphomas. However, patient-reported outcomes (PRO) related to symptoms and treatment-related toxicity are not often collected in routine clinical practice. Therefore, we developed and implemented a prospective PRO assessment to monitor symptoms, toxicity, and quality of life during and after RT for mycosis fungoides (MF) and other cutaneous lymphomas.

Methods: We developed a novel 30-item patient-reported outcome (PRO) assessment by combining the Skindex-16 (S16) instrument with selected validated items from the PRO-CTCAE and EORTC QLQ-C30 tools. The assessment was incorporated into routine care for all patients receiving RT for cutaneous lymphoma, and all patients at two specialized hematologic radiation clinics were invited to participate in the pilot. The assessment was administered at the initial consultation, weekly during RT, and monthly post-RT, either in paper form during clinic visits or electronically via REDCap. Descriptive statistics were used to summarize patient and treatment characteristics. Wilcoxon rank-sum tests were used to compare S16 scores between groups. A change of ≥10 points in the S16 composite or subscale scores was considered clinically meaningful, based on previously established thresholds.

Results: Between November 2024 and July 2025, 63 patients treated for cutaneous lymphoma completed at least one PRO assessment during 75 RT courses, yielding a total of 248 assessments (47% response rate). Most patients had MF (n = 41; 65%) or cutaneous indolent B-cell lymphoma (n = 12; 19%). Median age was 60.0 years (IQR: 47.5–70.0 years). Treatment included total skin electron beam therapy (TSEBT) in 36% of courses and focal RT in 64%, most commonly targeting the face/head (33%), trunk (24%), groin (18%), or extremities (18%). Overall, 67% (n = 50) of courses were delivered using electron beam therapy, and 33% (n = 25) with photon therapy. Baseline assessments were available for 56 patients, with a median S16 composite score of 46.8 (IQR: 24.6–64.7), where higher scores indicate worse quality of life. Baseline scores were higher among patients with MF compared to those with other histologies (51.1 vs. 29.4; p = 0.005), but did not differ significantly between patients treated with TSEBT and focal RT (52.1 vs. 42.9; p = 0.147). Clinically meaningful improvements in composite S16 scores were observed by one month post-RT and sustained through six months. For the full cohort, median S16 scores were 19.6 (IQR: 7.9–39.9), 25.0 (IQR: 7.7–35.9), and 30.2 (IQR: 6.8–34.7) at one, three, and six months post-RT, respectively. Improvements were more pronounced in patients receiving TSEBT than those treated with focal RT. At one month, median scores declined by 69% in the TSEBT group (from 52.1 [IQR: 30.7–72.8] to 16.5 [IQR: 8.2–33.1]) and by 48% in the focal RT group (from 42.9 [IQR: 21.0–54.8] to 22.4 [IQR: 6.9–39.9]). Subscale analysis showed parallel improvements across symptom, emotional, and functional domains following RT. Median pre-treatment scores were 37.5 (IQR: 24.0–56.3) for symptoms, 66.7 (IQR: 39.9–83.3) for emotional well-being, and 30.0 (IQR: 9.2–53.3) for function. By one month post-RT, scores improved to 14.6 (IQR: 5.2–38.5), 34.5 (IQR: 10.7–58.3), and 8.3 (IQR: 0.0–32.5), respectively. During RT, PRO-CTCAE responses indicated moderate to very severe fatigue in 59% of patients, skin dryness in 52%, insomnia in 41%, and skin burns in 25%. By one month post-RT, these rates declined to 36% for both fatigue and skin dryness, 33% for insomnia, and 19% for skin burns.

Conclusions: Routine implementation of a structured PRO assessment in patients undergoing RT for cutaneous lymphoma is both feasible and informative. Our findings demonstrate that both focal RT and total skin electron beam therapy (TSEBT) are associated with clinically meaningful improvements in symptoms, emotional well-being, and functional status. These pilot results support broader PRO integration into routine clinical practice and highlight the important palliative role of RT in this population. Ongoing follow-up is needed to evaluate long-term toxicity and the relationship between PRO responses and disease control. Future research should aim to validate the assessment, evaluate its clinical utility, and enhance response rates and patient engagement.

Link to Abstract abs25-13595

Abstract Number: abs25-3912

CDK7 enables adaptive gene transcription required by stromal cells to support distinct T-cell lymphoma phenotypes and represents a novel microenvironment-directed therapeutic target

Presenter: Khouloud Kouidri
Session: 622. Lymphomas: Translational - Non-Genetic: T cell interactions in the lymphoma microenvironment - the good and the bad

Abstract: Over 75% of PTCL-NOS patients fail to achieve long-term control with current therapies, highlighting the need for novel therapeutic targets . . Genetic and non-genetic drivers in cancer cells require external cues from other cancer cells and from the lymphoma microenvironment (LME), which enable cancer cell adaptation to metabolic stress, immune mediated stress and treatment exposure. The resulting signaling crosstalk propels the co-evolution of cancer and LME cells with emergence of diverse cancer-supporting cell states. Identifying these and their maintenance mechanisms may therefore reveal novel therapeutic targets. We characterized the LME of PTCL using transcriptional signature deconvolution and multiparametric imaging in 845 patient samples. We identiﬁed four biologically and clinically distinct categories named Depleted (DP), B-cell rich (BR), Mesenchymal (MS) and Inﬂammatory (IN) based on the proportion of diﬀerent LME cells. RNA-seq analysis showed that SMA+ cancer associated ﬁbroblasts (CAF) are present in DP, MS and IN LMEs each with distinct phenotypes. To functionally analyze the contribution of CAFs to PTCL maintenance, we established multiple patient-derived tumor xenografts (PDXs) that retain the same LME categories of primary tumors. We then tested lymphoma cell survival in co-cultures of CAFs and PTCL cells from matched (e.g., IN-CAF + IN-PTCL) and unmatched PDXs (e.g., IN-CAF + DP-PTCL). Matched co-cultures sustained lymphoma cell proliferation to a higher extent than unmatched, independently of LME subtype. This suggests that CAF are distinctly reprogrammed within each LME. We hypothesize that pro-tumoral CAF phenotypes require adaptive gene expression in coordination with lymphoma cells' phenotypes. RNA-Seq of matched IN-CAF co-cultured with IN-PTCL revealed activation of pathways like “Transcription”, “DNA replication” and “Translation” including the upregulation of CDK7. Although CDK7 plays a minor role in cell cycle progression, its phosphorylation of the RNA polymerase II as part of the TFIIH complex is critical in activating and coordinating "cell state"-defining transcription. To assess CDK7’s role in establishing lymphoma-supportive CAF states, IN-PTCL PDX mice were treated with the covalent selective CDK7 inhibitor YKL-5-124 for 12 h followed by transcriptomic and proteomic proﬁling of IN-PTCL and IN-CAFs. In IN-CAFs, CDK7 inhibition altered gene and protein expression of several collagens and cytokines, including COL1A1, COL1A2, MMP8, and CXCL12. Ligand-receptor analysis identiﬁed CXCL12-CXCR4 as the key CDK7-dependent interaction between IN-CAFs and IN-PTCL cells. IN-PTCL cells showed activation of DNA damage repair pathways, including upregulation of ALYREF and EIF4E, likely as compensatory mechanisms for decreased CDK7-dependent transcription. Since these may represent acquired therapeutic vulnerabilities, we conducted viability screenings in co-cultures of IN-PTCL and IN-CAF isolated from YKL-5-124 (and vehicle) tretated PDX mice. Cells were subsequently exposed for 48 h, individually and in co-culture s , to a drug library containing 40 clinical-phase compounds. This approach led to the identiﬁcation of 14 compounds with synergistic anti-lymphoma eﬀects. Among these, ten drugs including the XPO1 inhibitor Selinexor, the HSP90 inhibitor PU-H71 and the translation inhibitor Omacetaxine exhibited enhanced anti-lymphoma activity speciﬁcally in the co- culture setting, whereas four compounds showed reduced eﬃcacy. This was not seen in mismatched co- cultures and indicates a potential protective role of CAFs and, importantly, that this mechanism is CDK7 dependent. To address the limitations of PDX models established in immunodeﬁcient mice with limited ability to capture the immune-mediated eﬀects of drug treatments, we developed an IN-PTCL syngeneic model by intrasplenic implantation of the murine T-cell lymphoma cell line EL4. Treatment with YKL-5-124 signiﬁcantly reduced the tumor burden compared to vehicles. Cytokine proﬁling (immunoblotting array) and ELISA of culture medium of YKL-5-124 treated EL4-CAFs showed reduced levels of pro-inﬂammatory cytokines such as CXCL12, IL6, CCL2, ICAM-1, and CXCL1 indicating that CDK7 is necessary in establishing pro-lymphomagenic IN-CAF phenotypes. In conclusion, CDK7 activity is required to sustain speciﬁc pro-tumoral crosstalk interactions of matched CAFs and PTCL cells, which can be exploited therapeutically.

Link to Abstract abs25-3912

Abstract Number: abs25-764

Integrative profiling of t-follicular helper cells heterogeneity and tumor microenvironment signatures in angioimmunoblastic T cell lymphoma

Presenter: Tania Sainz
Session: 622. Lymphomas: Translational - Non-Genetic: T cell interactions in the lymphoma microenvironment - the good and the bad

Abstract: Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of mature T-cell lymphoma (TCL) that arises from T follicular helper (TFH) cells and is characterized by distinct clinicopathologic features, poor prognosis, and resistance to current treatments. A hallmark of AITL is its complex lymphoma microenvironment (LME), in which neoplastic TFH cells typically comprise only 10–30% of the infiltrate, complicating diagnosis. The heterogeneous cellular composition of the LME, along with subtle morphological features and frequent overlap with other reactive lymphoid processes or classic Hodgkin lymphoma, often results in delayed diagnosis or misdiagnosis. This persistent diagnostic challenge, together with poor therapeutic responses, underscores the need to further define the transcriptional and spatial programs of neoplastic TFH cells and their environment. To address this, we performed single-cell RNA sequencing on five AITL lymph node specimens. After quality filtering, cells expressing 200–10,000 genes with fewer than 10% mitochondrial transcripts were retained. Seurat-based integration was used to mitigate batch effects and cluster cells by transcriptional similarity. Malignant TFH cells were identified by co-expression of ten canonical TFH genes ( CD3E , CD4 , BCL6 , ICOS , PDCD1 , CXCR5 , CXCL13 , IL21 , CTLA4 and CD40LG ) alongside monoclonal T-cell receptor expansions via scRepertoire. Gene set enrichment revealed consistent upregulation of oxidative phosphorylation signatures, implicating altered mitochondrial metabolism, and expression of central memory-associated transcripts. Notably, a subset of malignant TFH cells expressed FOXP3, a hallmark of regulatory T cells, suggesting phenotypic plasticity and context-dependent adoption of regulatory programs. Immunofluorescence validation confirmed FOXP3 expression in neoplastic cells. To study the LME, we performed sequential forty ‑ plex immunofluorescence (COMET Lunaphore) in 14 AITL and 3 reactive lymph nodes. In AITL we identified two distinct microenvironmental archetypes. Both niches exhibited marked CD40 upregulation relative to controls, but with distinct cellular localizations: in the M1 ‑ skewed archetype CD40 was confined primarily to macrophages, whereas in the M2 ‑ skewed niche it was predominantly B ‑ cells. CD40 single immunostaining was conducted in 200 additional cases, including other T-cell lymphomas and autoimmune disorders, and confirmed that while CD40-driven immune activation is a hallmark of AITL, elevated CD40 expression was also observed in a subset of other T-cell lymphomas. In our AITL PDX models using NSG mice, CD40 expression persisted in tumor- infiltrating B cells (patient derived), reinforcing the potential role of the CD40-CD40L axis in tumor– microenvironment crosstalk (PMID: 35921527). Altogether, our data indicates that neoplastic TFH cells in AITL possess phenotypic plasticity, adopting both Treg ‑ like and central memory expression programs. These cells reside within two distinguishable microenvironmental archetypes which may underlie aspects of diagnostic complexity and variable clinical behavior. The consistent overexpression of CD40 across these niches suggests it could serve as a biomarker for stratifying microenvironmental contexts and monitoring therapeutic responses. While these findings provide preliminary insight into the cellular and spatial heterogeneity of AITL, further studies in larger patient cohorts are necessary to confirm these observations and to explore the feasibility of targeting the CD40-CD40L axis or related pathways as part of future therapeutic strategies.

Link to Abstract abs25-764

Abstract Number: abs25-11509

A new prognostic index (CLIPI) stratifies risk in advanced cutaneous lymphomas: Associations with treatment pathways, quality of life and survival

Presenter: Julia Scarisbrick
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Fresh insight for Cutaneous and Virus-associated TCLs

Abstract: Advanced-stage mycosis fungoides (MF) and Sézary Syndrome (SS) are primary cutaneous T-cell lymphomas (CTCL) have a high symptom and emotional burden and a poor prognosis with overall survival <5 years. Treatment selection is particularly challenging in these patients who have high clinical needs. Studies have also found the current clinical staging (IA-IVB) inadequate for risk stratification with worse survival in IIB than stage III. Developing a prognostic index in MF/SS will identify patients with poor outcomes and may allow better management decisions, improve HRQoL and ultimately survival. The PROCLIPI (PROspective Cutaneous Lymphoma International Prognostic Index) Study was launched in 2015 at 46 international expert CTCL Centers, prospectively collecting pre-defined datasets in newly diagnosed MF/SS patients to determine a cutaneous lymphoma IPI (CLIPI), which included treatment selection and HRQoL measures using Skindex-29 at diagnosis. 552 advanced-stage MF/SS patients were recruited. The 5-year overall survival (OS) is IIB=50.0%, IIIA=64.8%, IIIB=43.9%, IVA1=50.8%, IVA2=25.9%, IVB=36.9%. Factors at diagnosis associated with a significantly worse survival were lymphomatous nodes (N3 status) (p<0.001); age>60years (p<0.001), raised serum lactate dehydrogenase (p=0.005); and large-cell transformation in skin (p=0.006). These 4 independent prognostic factors were modelled into prognostic index (CLIPI) risk groups, where patients with 0-1 prognostic factors were low-risk, 2 were intermediate-risk, and 3-4 factors were high-risk. CLIPI stratification by risk group found there was a significantly worse OS in high versus low-risk (p<0.001), high-versus intermediate-risk (p=0.002), as well as intermediate-versus low-risk (p=0.010) with 5-Year OS in low-risk=63.3%, intermediate-risk=44.7% and high-risk=18.3%. Analysis of first-line treatment selection in these risk-groups found that most received systemic therapies however 23.5% of low-risk patients, 25.0% of intermediate-risk and 13.2% of high-risk patients received skin-directed therapies (SDTs) only, with no significant difference between groups (low-versus intermediate-risk p=0.121, intermediate-versus high-risk p=0.10, low vs high-risk p=0.799). In all patients given subsequent systemic treatments, the median time to next systemic treatment (TTNT) trended downward; low-risk=6.3mnths (Interquartile range (IQR):4.3,14.5), intermediate-risk patient=5.7mnths (IQR:3.5,8.1), and high-risk=4.7 months (IQR:3.3-7). The median number of total treatment lines was 4 (IQR:2,5) in low-risk, 2 (IQR:2,5) in intermediate-risk and 3 (IQR:2,5) in high-risk patients, with a significant difference between intermediate-versus low-risk patients (p=0.0211). HRQoL measured using Skindex-29 found median global scores (symptom+emotion+function domains) were low-risk=36.6 (23.0,50.8), intermediate-risk=42 (29.5,62.3) and high-risk=45.6 (34.9,58.1) with a trend towards worse HRQoL in high-risk which didn’t reach statistical significance. The median symptom domain scores were low-risk=42.9 (25,58.9), intermediate-risk=53.6 (39.3,67.9) and high-risk=58.9 (51.8,69.6) respectively, with a significant difference between low versus high-risk (p=0.003) and low versus intermediate-risk (p=0.008) groups. Median functioning scores also trended downward at low- risk=21.9 (8.3,52.1), intermediate-risk=33.3 (14.6,54.2) and high-risk=41.7 (20.8,59.4) whilst median emotions domain scores were similar across the groups with low-risk=43.8 (26.3,63.4), intermediate- risk=42.5 (25,62.5) and high-risk=41.3 (33.8,50). The CLIPI stratifies advanced-stage MF/SS into low, intermediate and high-risk groups with significantly worse 5-year survival rate. Most MF/SS treatments are associated with low response rates and duration of response. Treatment patterns emerged between the risk-groups with SDTs more commonly used in low and intermediate-risk and shorter TTNT in the high-risk group. HRQoL using Sindex-29 found significantly worse symptom burden in intermediate and high-risk groups. Emotional scores were similar in risk groups reflecting the negative effect of MF/SS on patients well-being. Our data shows that CLIPI can stratify patients into precise low, intermediate, and high-risk prognostic groups and emphasizes the potential to be utilized in optimizing treatment selection to improve patient quality of life and outcomes.

Link to Abstract abs25-11509

Abstract Number: abs25-12629

Clinical features and outcomes of patients with non-erythrodermic mycosis fungoides with high blood tumor burden

Presenter: Colin Thomas
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Fresh insight for Cutaneous and Virus-associated TCLs

Abstract: Introduction: : Sézary Syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma involving diffuse erythroderma (T4) and leukemic disease (B2). Prognosis is poor, with 5-year overall survival ranging from 30-50%. A unique cohort of patients diagnosed with B2 (high blood tumor burden) leukemic disease without erythroderma has previously been described. However, little is known about these patients’ clinical features and prognosis.

Methods: : A retrospective study of SS patients diagnosed after 1/1/2010 was conducted at the University of Pennsylvania. Patients with B2 disease with or without T4 disease at diagnosis were identified. B2 disease was defined as positive blood T-cell receptor clonality and Sézary cell count ≥1,000 cells/µl by flow cytometry (CD4+/CD7- or CD4+/CD26-). T4 was defined as erythroderma involving ≥80% body surface area (BSA). Fisher’s exact test and Wilcoxon rank-sum test were used for statistical significance. Patients with HTLV-I/II and B2 disease utilizing only percentages of lymphocytes/elevated CD4:CD8 ratio criteria were excluded as per modified ISCLC/USCLC/EORTC criteria. T0/B2 patients were diagnosed based on Sézary immunophenotype and were ruled out for other diagnoses (e.g. T-PLL, T-LGLL, ATLL).

Results: : Two cohorts of patients with B2 disease were identified: 21 patients without erythroderma (non- erythrodermic SS, neSS) and 79 classic SS patients (T4/B2 stage at diagnosis, cSS). There were no significant differences in age (70 and 71.5 years), race (76% and 74% white, 24% and 25% black) or absolute Sézary cell count at diagnosis (2,225 vs 2,812 cells/µl) for neSS versus cSS, respectively. A significantly greater proportion of neSS patients were female (76.2% vs 44.3%, p = 0.0034), but significantly fewer had N2/3 nodal disease (4.8% vs 43.4%, p=0.0002). One neSS patient had visceral disease pathologically confirmed in the liver (M1) at diagnosis. This did not occur in the cSS patient cohort. Of the neSS patients, 3 had no skin involvement (T0), 6 had patch/plaque disease <10% BSA (T1a/b), and 13 had patch/plaque disease >10% BSA (T2a/b). Pruritus was reported in 55% (11/20) of patients at diagnosis. With a median follow-up of 5 years, 3 patients later developed erythroderma (T4). Among these patients, the median time to T4 disease was 1.9 years after B2 diagnosis. Median follow-up for the 18 patients who never developed erythroderma was 4.5 years. Interrogation of 9 neSS patient samples for cancer-associated mutations showed known disease-associated variants in TP53 (n=3), PTEN (n=1), DNMT3A (n=1) and EGR2 (n=1). The median number of systemic treatments for neSS patients was similar to cSS patients (3.5 vs 3). Among the neSS patient cohort, systemic treatments included extracorporeal photopheresis (ECP)(n=16), bexarotene (n=11), interferon (IFN)(n=8), mogamulizumab (n=8), romidepsin (n=4), brentuximab vedotin (BV)(n=3), pembrolizumab (n=3), chemotherapy (n=1), methotrexate (n=1) and clinical trial (n=1). None underwent hematopoietic stem cell transplant. Four underwent surveillance/topical-only treatment without systemic therapy. Radiation was commonly used, with 4 patients receiving localized radiation, 4 receiving total skin electron beam therapy, and 4 receiving narrow-band UV phototherapy. ECP was the most common first-line therapy. Of the 3 patients who later developed erythroderma, treatments prior to developing T4 disease included ECP (n=3), IFN (n=3), bexarotene (n=3), BV (n=2) and mogamulizumab (n=1). When compared to the cSS patients, outcomes were significantly better for neSS patients. 2-year overall survival (OS) for neSS vs cSS was 100% (18/18) versus 74% (54/73) (p = 0.0275). 5-year OS was 100% (11/11) versus 34.5% (19/55) (p<0.0001). Conclusions Conclusions : Non-erythrodermic patients with B2 disease (T0-2/B2, neSS) had a significantly better prognosis compared to classic SS patients with erythroderma (T4/B2, cSS). neSS patients received multiple systemic treatments; however, 4 patients with minimal skin disease were managed with surveillance or skin-directed therapy alone. Only 3 neSS patients (9.6%) later developed erythroderma. Although neSS patients were more often women and less likely to have nodal disease at diagnosis, other clinical characteristics including age, race and Sézary cell count at diagnosis were similar to cSS patients. Further exploration into mechanisms driving these clinical differences and the optimal management of this unique cohort of patients is needed.

Link to Abstract abs25-12629

Abstract Number: abs25-2858

Liquid-biopsy mutation landscape and its concordance with skin biopsies in cutaneous T-cell lymphoma

Presenter: Yoni Sacknovitz
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Fresh insight for Cutaneous and Virus-associated TCLs

Abstract: Introduction: Liquid biopsy (LBx) is widely utilized for clinical evaluation and therapeutic monitoring in solid and hematologic malignancies (Talotta et al. Frontiers in Oncology 2023; Huang et al. Molecular Cancer 2024). Analyzing circulating cell-free DNA (cfDNA) and RNA (cfRNA) through LBx can offer minimally invasive insights into tumor burden and disease dissemination (Huang et al. Molecular Cancer 2024). Given that diagnosing CTCL is challenging both clinically and histologically, employing liquid biopsy as a diagnostic tool could enable the detection of disease, potentially reducing reliance on skin biopsies. LBx application in CTCL is complicated by overlapping somatic mutations found in clonal hematopoiesis of indeterminate potential (CHIP) and other hematologic malignancies (Marnell et al. Journal of Molecular and Cellular Cardiology 2021). CHIP-associated mutations in genes like TET2 and DNMT3A closely resemble those in myeloid and T-cell neoplasms, complicating LBx interpretation (Kusne et al. Leukemia Research 2022). In CTCL, mutations commonly affect pathways critical for T-cell receptor signaling, cytokine activation, cell-cycle regulation, apoptosis, and epigenetic regulation. Notably, epigenetic regulators ( TET2, DNMT3A, ASXL1, ARID1A , histone-modifying enzymes) are commonly mutated in CTCL and myeloid neoplasms (Choi et al. Nature Genetics 2015). In our study, we analyzed cfDNA and cfRNA from patients with CTCL, comparing LBx, skin biopsies (SBx), and paired LBx-SBx samples to characterize the mutations present in LBx associated with CTCL. Our goal is to enable accurate interpretation of LBx data and supports its potential role in identification in CTCL. Methods: Using hybrid capture and next generation sequencing (NGS), we performed targeted sequencing of DNA (302 gene) and RNA (1600 genes) extracted from SBx, and cfDNA and cfRNA extracted from peripheral blood plasma. B and T cell clonality in cfRNA was confirmed by evaluating heavy and light chain immunoglobulin and TCRs, respectively. For B and T cell repertoire analysis, sequences were mapped and assembled into clonotypes using MiXCR software. Results: In the SBx cohort (n=200), 263 unique genetic mutations were identified. The most frequently mutated genes included DNMT3A (25.3%), KMT2C (16.4%), TET2 (15.1%), TP53 (15.1%), KMT2D (13.0%), NOTCH1 (13.0%), STAT3 (9.59%), NOTCH3 (7.53%), ATM (6.85%), and CHEK2 (6.85%). These mutations are predominantly involved in epigenetic regulation, DNA repair, cell-cycle control, and key signaling pathways essential for T-cell proliferation and survival. In the LBx cohort (n=41), 66 unique genetic mutations were identified. The 10 most frequent mutations were found in DNMT3A (38.7%), KMT2C (29.0%), TET2 (19.4%), PPM1D (12.9%), ARID1A (9.68%), EPHA5 (9.68%), JAK2 (9.68%), AKT1 (6.45%), ASXL1 (6.45%), and ATM (6.45%). Notably, there was overlap between LBx and SBx, with 4 out of the top 10 mutated genes ( TET2 , DNMT3A , KMT2C , and ATM ) detected in both sample types. Clonotype-naive TCR clonality analysis of cfRNA in 32 LBx samples identified clonality in 6 samples (19%). These clonally expanded samples exhibited a distinct mutation profile, with notable involvement of genes such as DNMT3A, TET2, EZH2, JAK2, BRAF, and NOTCH3 , likely reflecting more tumor cfDNA and cfRNA in circulation. Non-clonal samples generally lacked these specific mutation signatures or presented them at markedly lower frequencies. Higher sensitivity in demonstrating TCR clonality is expected if testing was clonotype-informed. Among 16 paired LBx and SBx samples, mutations were detectable in 81% of LBx and 75% of SBx samples. Within 12 pairs where mutations were present, 92% showed concordance in at least one mutation. A total of 63 mutations were identified, with 34 variants (54%) being concordant across LBx and Bx. High concordance was observed in mutations of key genes involved in epigenetic regulation ( DNMT3A, TET2), NOTCH /T-cell receptor signaling ( NOTCH2, NOTCH3, BTK ), and the PI3K–mTOR signaling pathway ( MTOR, BRAF ), representing 72% of the shared variants. Conclusions: These results indicate that LBx has potential clinical utility as a non-invasive tool for identifying key driver mutations in CTCL, thus aiding diagnosis and possibly reducing reliance on skin biopsies. Additional studies and clinical trials are needed to evaluate its prognostic value.

Link to Abstract abs25-2858

Abstract Number: abs25-4328

Thyroid hormones enhance the responsiveness of T-cell lymphomas to romidepsin

Presenter: María Debernardi
Session: 622. Lymphomas: Translational – Non-Genetic: Poster II

Abstract: T-cell lymphomas (TCL) are aggressive and clinically heterogeneous malignancies originating from mature or immature T cells. Standard combination chemotherapy protocols, yield limited long-term benefit, and most patients experience relapse or refractory disease. In recent years, histone deacetylase inhibitors (HDACi) , have emerged as promising alternatives. Although HDACi are FDA-approved for select TCL subtypes, their clinical benefit remains limited, with overall response rates—comprising complete and partial responses—typically ranging from 20% to 40%, depending on the disease subtype and treatment context. Chromatin regulation, including its accessibility state, is increasingly recognized as a critical factor influencing the therapeutic response to HDACi. However, the upstream regulators of chromatin architecture in TCL are not fully understood. In this sense, thyroid hormones (THs) have been implicated in chromatin remodeling and oncogenic signaling in other cancers. Our most recent work demonstrated that THs promote TCL cell proliferation, survival, and angiogenesis via activation of the integrin αvβ3– JAK/STAT signaling pathway. The role of THs in regulating the epigenetic landscape and affecting HDACi therapy response in these hematologic malignancies has not been previously explored. We investigated the impact of THs on romidepsin-induced anti-tumoral effects and epigenetic modulation in TCL models. In vitro assays were performed using TCL cell lines representing immature (EL-4 and CUTLL-1) and mature (HuT78, OCI-Ly13.2, OCI-Ly12 and Karpas299) subtypes. Cells were treated with vehicle, physiological concentrations of THs (T3: 1 nM; T4: 100 nM), romidepsin, or their combination. After 48 hours, cell viability and apoptosis (via caspase 3/7 activity) were assessed. Histone acetylation (H3K27 and H4K16) was analyzed by Western blot after 24 hours, and global HDAC activity was measured at 6 and 24 hours using a luminescence-based assay. In vivo , we employed a syngeneic EL4 TCL model in C57BL/6 mice with euthyroid or hypothyroid status. Hypothyroidism was induced by administering propylthiouracil (PTU, 0.5 mg/mL in drinking water) for 14 days. We first evaluated the in vitro activity of romidepsin across our panel of TCL cell lines under standard culture conditions. Romidepsin induced a dose-dependent reduction in cell viability, with IC 50 values ranging from 4.5 to 17 nM, confirming its potent anti-tumoral effect across all TCL subtypes tested. To specifically assess the role of THs, we performed subsequent experiments in TH-depleted culture conditions to minimize Background: hormonal effects. We found that physiological concentrations of THs significantly increased the anti-tumoral activity of romidepsin in all TCL cell lines, with Karpas299 cells representing the only exception. The observed increase in romidepsin efficacy caused a 30–60% greater decrease in cell viability and a 25–70% increase in apoptosis, depending on the TCL subtype (p < 0.05). Mechanistically, this enhanced effect was accompanied by epigenetic alterations, with acetylation levels of histone marks H3K27ac and H4K16ac increasing significantly by approximately 30% and 50%, respectively, both indicative of open chromatin and active transcriptional states (p < 0.05). Additionally, global HDAC activity decreased by 20 to 50% depending on the TCL subtype (p < 0.05), supporting the notion that THs potentiate romidepsin’s inhibitory action on HDACs. To assess the in vivo relevance of these findings, we employed a syngeneic TCL murine model with euthyroid or hypothyroid status. Mice were subcutaneously injected with 3×10⁵ EL-4 cells, and once tumors reached a palpable size, animals were randomized to receive daily intraperitoneal injections of either (i) vehicle or (ii) romidepsin (0.5 mg/kg). Romidepsin treatment significantly reduced tumor size in both groups (p < 0.05 vs. vehicle). Notably, the magnitude of tumor growth inhibition was significantly greater in euthyroid mice compared to hypothyroid counterparts, suggesting that systemic thyroid status may play a key role in influencing treatment HDACi response in TCL patients. All together, our findings highlight the importance of thyroid status as a modulator of romidepsin efficacy in patients with TCL and provide a strong basis for further study of TH-regulated epigenetic mechanisms during HDAC inhibitor treatment, which may contribute to improved therapies and identification of novel targets.

Link to Abstract abs25-4328

Abstract Number: abs25-8099

Single-cell profiling of natural killer T-cell lymphoma reveals stratified immune features and therapeutic strategies

Presenter: Yi Cao
Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster II

Abstract: Background: Background: : : Natural killer T-cell lymphoma (NKTCL) is a rare subtype of non-Hodgkin lymphoma (NHL) characterized by rapid progression and poor prognosis. The cornerstone of treatment for NKTCL patients is L-asparaginase-based chemotherapy, which exploit the metabolic vulnerability of NKTCL resulting from its dependence on extracellular asparagine for tumor growth. Similar to many other hematologic malignancies, immune checkpoint inhibitors (ICIs) are increasingly used to treat advanced NKTCL in the first-line setting. However, approximately 40% of patients are resistant to ICIs. Given the molecular heterogeneity among patients, stratified targeted therapies are essential to improve treatment efficacy and clinical outcomes. In the current study, we performed the scRNA-seq analysis on 63 samples and identified four subgroups in NKTCL, each associated with distinct immune-related TME characteristics, e.g., immune exhaustion, immune desert, immune exclusion, and tertiary lymphoid structures (TLSs) enrichment.

Methods: : : For the scRNA-seq analysis, we included a total of 63 samples from 53 individuals, comprising five normal nasal mucosa samples from healthy controls and 58 NKTCL patient samples. Among the 58 NKTCL samples, 10 were obtained from publicly available datasets, while 48 were self-collected from our institution. The remaining two datasets were obtained from the GEO and GSA database under accession number GSE203663 and HRA000772, respectively. Xenium in situ expression analysis was conducted in 14 treatment-naive samples from 14 patients.

Results: Four distinct subgroups (MP1-MP4) were identified, each linked to specific molecular and immune features with varying clinical outcomes. MP1 was characterized by an immune-exhausted TME and high PD-L1 expression, suggesting a potential response to immune checkpoint blockade. MP2 was characterized by an immune-desert phenotype with elevated HDAC2 and MKI67 expression, indicating a role for epigenetic regulation in tumor proliferation. MP3 was characterized by a myeloid-dominant TME and upregulated inflammatory pathways, association with JAK/STAT pathway activation, hemophagocytic lymphohistiocytosis (HLH), and an aggressive clinical course. MP4 was characterized by tertiary lymphoid structures (TLS) and enhanced amino acid metabolism, and favorable prognosis and high sensitivity to asparaginase-based regimens. Based on these findings, We propose tailored therapeutic strategies for each MP, including combination therapies targeting immune checkpoints, epigenetic regulators, or inflammatory pathways, currently under clinical investigation. We are currently conducting a series of clinical trials investigating these proposed therapeutic strategies. These trials, including PD-1 blockade combined with anti-LAG3-antibody (NCT06649656), HDAC inhibitor (NCT04994210) or JAK1 blockade (NCT06733051), and asparaginase-based regimens (NCT06583083), aim to translate our molecular findings into tailored treatment approaches for NKTCL.

Conclusion: In this study, we performed a comprehensive analysis of the molecular and immune landscapes of NKTCL at the single-cell level. We identified four MP subgroups distinguished by specific tumor-intrinsic and immune features, with varying clinical outcomes and associations with potential biomarkers and therapeutic strategies. These findings were further validated by spatial transcriptomics, bulk RNA sequencing, metabolomics, proteomics, as well as by in vitro and in vivo functional experiments. Our classification reveals tumor heterogeneity in NKTCL and lays the groundwork for precision treatment strategies.

Link to Abstract abs25-8099

Abstract Number: abs25-9982

IFN-γ-induced CD4+ CADM1+ T cells emerged as malignancy-progressive biomarkers in EBV NK/T lymphoproliferative disorders and potential drivers of malignant expansion in AITL

Presenter: Qinhuan Luo
Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster II

Abstract: Objective Objective Epstein-Barr virus (EBV) infection of T and NK cells leads to EBV-associated NK/T-cell lymphoproliferative disorders (EBV NK/T LPDs), a spectrum of aggressive and poorly understood diseases that range from chronic inflammation to fulminant hemophagocytic lymphohistiocytosis. Accurate diagnosis remains challenging due to disease heterogeneity and technical barriers. Although immunostaining and PCR of biopsies are commonly used, obtaining biopsies is invasive and risky, and PCR of sorted cells often yields ambiguous results. Compared to EBV-associated B-cell neoplasms, which benefit from targeted therapies such as rituximab, EBV NK/T LPDs lack effective molecular therapies and respond poorly to chemotherapy. These diagnostic and therapeutic challenges are compounded by our limited understanding of pathogenesis and molecular mechanisms underlying the EBV NK/T LPDs. This study aims to characterize the immune and molecular landscape of EBV NK/T LPDs and to identify novel diagnostic biomarkers and therapeutic targets to improve patient outcomes.

Methods: We collected and analyzed single-cell RNA-sequencing (scRNA-seq) and TCR-sequencing (scTCR-seq) data of peripheral blood mononuclear cells (PBMCs) from 15 patients: 2 with infectious mononucleosis (IM), 8 with chronic active EBV (CAEBV) at various grades, 2 with EBV (+) angioimmunoblastic T-cell lymphoma (AITL), 2 with EBV (+) peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), and 1 with EBV (+) nodular-type NK/T-cell lymphoma. EBER determined EBV positivity in situ hybridization on pathological tissue sections: EBV (+) AITL cases showed scattered EBER (+) cells, while EBV (+) PTCL-NOS cases exhibited diffuse EBER (+). Flow cytometry, multiplex immunofluorescence (mIF), and cytometric bead array (CBA) were employed to profile immune cell populations and cytokine levels. In vitro functional assays were conducted to investigate transcriptional regulation and phenotypic plasticity of candidate cell types.

Results: Using scRNA-seq data, we first identified a population of CD4⁺ CADM1⁺ T cells as a malignancy- progressive signature in EBV NK/T LPDs, their frequency increased significantly with disease progression, peaking in CAEBV grade 3 and EBV (+) NK/T non-Hodgkin lymphomas (NK/T NHL) (R² = 0.48, p = 0.0058). Combining with published scRNA-seq datasets, we also found that these cells were scarcely detected in healthy controls or EBV (−) NK/T NHL. Flow cytometry further verified that CD4⁺ CADM1⁺ T cells were significantly more abundant in EBV (+) NK/T NHL (n=5) compared to EBV (−) NK/T NHL (n=6, p = 0.0015), and also significantly elevated in CAEBV (n=4, p = 0.0166) relative to EBV (−) NK/T NHL. Notably, the EBV (−) NK/T NHL group included AITL cases with EBER (-) (n = 2), PTCL-NOS cases with EBER (-) (n = 3), and one PTCL-NOS case with scattered EBER (+) (n = 1). Moreover, mIF also demonstrated significantly greater infiltration of CD4⁺ CADM1⁺ T cells in tissue sections from EBV (+) NK/T-NHL compared to EBV (−) cases. We further observed significantly elevated plasma IFN-γ levels in EBV NK/T LPDs (n=13) compared to healthy controls via CBA assay (n=20, p = 0.0165), suggesting a cytokine milieu consistent with Th1-type inflammation. IFN-γ aligns with the emergence of CD4⁺ CADM1⁺ T cells, which exhibit a Th1-like transcriptional profile and may contribute to disease pathogenesis. Functional experiments also revealed that IFN-γ upregulates CADM1 expression in H9 cells via IRF2, promoting a Th1-like phenotypic shift. In AITL, CD4⁺ CADM1⁺ T cells exhibited clonal TCR expansion, suggesting malignant potential. Notably, mIF analysis of AITL tissues revealed substantial spatial colocalization between CADM1 and PD-1, an established marker of neoplastic T follicular helper cells. This histopathological finding provides strong evidence that CD4⁺ CADM1⁺ T cells represent malignant components within AITL lesions. Conclusions Conclusions Our study reveals CD4⁺ CADM1⁺ T cells as a distinct immunophenotypic and molecular hallmark of EBV NK/T LPDs, correlating with disease progression. These cells may serve as a minimally invasive diagnostic biomarker and a potential therapeutic target. These insights enhance our understanding of EBV NK/T LPDs and may facilitate the development of novel strategies for early detection and treatment of this aggressive disease group.

Link to Abstract abs25-9982

Abstract Number: abs25-14585

Title first‑in‑human Phase 1 dose‑finding study (VIPER 101) of dual‑population autologous CD5‑deleted anti-CD5 CAR‑T (Senza5 CART5) cells in Relapsed/Refractory T‑cell lymphomas

Presenter: Stefan Barta
Session: 704. Cellular Immunotherapies: Early Phase Clinical Trials and Toxicities: Poster II

Abstract: Background. T‑cell lymphomas carry a very poor prognosis and lack eﬀective treatments. Despite the transformative success of chimeric antigen receptor (CAR) T‑cell therapies in B‑cell malignancies, translation to T‑cell malignancies has been impeded by target antigen overlap that causes CAR T‑cell fratricide and on‑target T‑cell aplasia. Senza5 CART5 is an autologous, gene-edited, dual-population, rapidly manufactured (5-day) CAR T‑cell (CART) product comprised of both a CD5-deleted (CRISPR- Cas9) CAR‑expressing (lentivirus transduced) T cell population (CD5 ⁻ CAR ⁺ ) and a CD5-deleted, non- transduced T‑cell population (CD5 ⁻ CAR ⁻ ). This dual population is designed to enhance both potency and safety as CD5 deletion removes a negative regulator of T‑cell eﬀector function ( Patel R., Science Immunology, 2024 ), while the companion CD5 ⁻ CAR ⁻ cells are intended to mitigate on-target T‑cell aplasia during immune reconstitution. Methods. In this open‑label, dose‑ﬁnding Phase1 trial, adults with histologically conﬁrmed relapsed/refractory (r/r) CD5+ T‑cell lymphoma after ≥1 prior therapy receive lymphodepletion (ﬂudarabine 25mg/m² + cyclophosphamide 250mg/m² x 3 days or bendamustine 90mg/m² x 2 days) followed by a single IV infusion of Senza5 CART5 at doses ranging from 3x10 6 to 1.25x10 8 CAR+ cells. Primary endpoints are safety and recommended Phase2 dose (RP2D); secondary/exploratory endpoints include manufacturing feasibility, invivo expansion, tissue traﬃcking, T‑cell aplasia mitigation, overall response rate (ORR), and complete response (CR) rate per Lugano criteria. The Viper 101 trial is ongoing ( NCT06420089) . Results. As of August5,2025, 6 patients were manufactured and 5 patients (pts) were treated (1 at a ﬂat dose of 1x10 7 CAR+ cells and 4 at a ﬂat dose of 3x10 6 CAR+ cells) with 4 pts evaluable for dose limiting toxicities (safety) and 3 pts evaluable for eﬃcacy. Median age was 65years (range 55–75); histologies included PTCL‑NOS (n=2), TFHL (n=1), AITL (n=1), and MF (n=1). Pts had a median of 3 prior lines (range 2–5), and 2 had prior autologous stem cell transplant. Manufacturing success was 100% (6/6). Treatment-related adverse events (TRAEs) included cytokine-release syndrome (CRS) (Grade1–2) in 100% of safety-evaluable pts (4/4) that resolved with standard care; no neurotoxicities or hemophagocytic lymphohistiocytosis syndrome were reported. All pts experienced Grade3–4 transient cytopenias and Grade 1-2 TRAEs of the skin, mouth, and gastrointestinal tract. Infections were observed in 3/4 pts . One pt treated at the 1x10 7 CAR+ dose experienced a Grade5 severe AE (infection) on Day54 while presenting with multineage cytopenias that were considered unrelated to the investigational product. No pts experienced clinical EBV or CMV infections. All safety-evaluable pts (n=4) experienced robust in vivo CART cell expansion (median peak in peripheral blood (PB): 33,664copies/µg gDNA). On-treatment biopsies conﬁrmed CART traﬃcking to disease sites, including lymph nodes, skin, and marrow. Of note, no detectable CD5+ cells (normal or malignant) were detected in these biopsies. CART cells persisted and were still detected in the PB at last follow-up (median 1,426copies/µg gDNA). Due to the risk of on-target T-cell toxicity, immune reconstitution was also monitored. By Day28, all evaluable pts demonstrated reconstitution of a CD5‑negative, CAR‑negative (CD5- CAR-) T‑cell compartment (both CD4+ and CD8+ subsets). Among eﬃcacy‑evaluable pts (n=3), overall response rate (ORR) was 100% (3/3) with all three pts achieving a complete response (CR) at a median follow‑up of 4.0 months (range 1.9–5.5). 2/3 pts had FDG-avid lesions on the Day 30 scan, which, upon biopsy, were negative for the original lymphoma, and became PET negative by Day 90. No patients have relapsed at last follow up. Updated clinical outcomes and correlative data for all pts treated will be presented at the meeting. Conclusions. Early results suggest that Senza5 CART5 has manageable toxicities, potent antitumor activity, robust and durable CART expansion, and T‑cell reconstitution at low doses of CART cells (3x10 6 CAR+ cells). While follow-up is limited, these data support further development of Senza5 CART5 for r/r T‑cell lymphomas. Moreover, these results underscore the potential for CD5 deletion as a platform to broadly enhance the efficacy of engineered T-cell therapies for additional indications.

Link to Abstract abs25-14585

Abstract Number: abs25-3879

Real-world barriers to treatment access in T-cell lymphoma

Presenter: Christina Poh
Session: 906. Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster II

Abstract: Introduction: T-cell lymphomas (TCL) are associated with limited therapeutic options and poor outcomes. Identifying real-world barriers to treatment is essential to inform strategies that optimize care delivery and improve outcomes in this underserved population.

Methods: We conducted a retrospective review of patients with a primary diagnosis of TCL who were seen at the Fred Hutchinson Cancer Center/University of Washington. Clinical and demographic data were extracted from electronic medical records. Associations between patient characteristics and type of treatment received were analyzed using Wilcoxon rank sum tests for continuous variables and Pearson’s Chi- squared or Fisher’s exact tests for categorical variables, as appropriate.

Results: Between 2014 and 2024, 400 patients were identified. Males comprised 61% of patients. The majority of patients (69%) were non-Hispanic whites, with Asians/Pacific Islanders, Hispanics/Latinos, and African Americans comprising 13%, 8.4%, and 7.2%, respectively. The most common TCL subtypes were peripheral TCL not otherwise specified (PTCL-NOS; 28%), large granular lymphocytic leukemia (LGL; 17%), nodal T follicular helper (TFH) lymphoma (17%), anaplastic large cell lymphoma (ALCL; 16%), and primary cutaneous TCL (CTCL; 8%), with other subtypes comprising 15%. Eighty-nine percent of patients had insurance coverage: 32% were enrolled in commercial PPO plans, 29% in Medicare, 15% in Medicaid, and 7.8% in commercial HMO plans; 11% of patients were uninsured. The median number of treatment lines was 2 (range, 0–11); 5.8% of patients received an autologous stem cell transplant (SCT), 17% an allogeneic SCT, and 77% neither as part of their treatment course. Fifty-six percent of patients received at least one novel agent during their treatment, while 27% received only conventional chemotherapy. Seven percent participated in at least one clinical trial. Among patients with CD30+ disease, 36% were treated with a brentuximab vedotin (BV)-containing regimen. Treatment patterns varied significantly by TCL subtype (p < 0.001). Patients with ALCL and nodal TFH lymphoma were most likely to receive at least one novel or experimental agent (77% and 59%, respectively). In contrast, those with LGL and CTCL more often received therapies outside of conventional chemotherapy or novel agent–based regimens (51% and 50%, respectively). Patients with PTCL-NOS demonstrated a more even distribution, with 36% receiving only conventional chemotherapy and 36% receiving at least one novel agent. Among patients with CD30+ disease, receipt of BV was significantly associated with insurance status (p = 0.001); only 4.8% of uninsured patients received BV compared to 41% of insured patients. Insured patients were 6.4 times more likely to receive BV as part of first-line therapy than uninsured patients (32% vs 5%, respectively, p = 0.013). Clinical trial participation varied significantly by both insurance status and TCL subtype. While 7.8% of insured patients enrolled in at least one clinical trial, no uninsured patients participated. The highest enrollment was observed among patients with commercial HMO insurance (19%), followed by commercial PPO, Medicare, and Medicaid(9.3%, 6.0%, 5.1%, respectively, p = 0.025). Participation differed by diagnosis (p = 0.029), with ALCL patients showing the highest enrollment (14%) and PTCL-NOS the lowest (1.8%).

Conclusion: Real-world treatment patterns in TCL vary significantly by histologic subtype and insurance status, with notable disparities in access to novel therapies, BV, and clinical trial participation. These findings highlight the need for targeted efforts to address structural barriers in care delivery and ensure equitable access to emerging therapies in this patient population.

Link to Abstract abs25-3879

Abstract Number: abs25-10821

Real-world monotherapy and combination usage of mogamulizumab among patients with mycosis fungoides or Sézary syndrome in the United States

Presenter: Bradley Haverkos
Session: 906. Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster II

Abstract: Introduction: Mogamulizumab is approved in the United States (US) for the treatment of adults with relapsed/refractory (r/r) mycosis fungoides/Sézary syndrome (MF/SS) following ≥1 prior systemic treatment. This retrospective, observational cohort study investigated adult patients (pts) treated with mogamulizumab as monotherapy (MT) or combination therapy (CT) in the US.

Methods: ConcertAI de-identified electronic medical records from academic and community oncology practices were analyzed. Eligible pts were diagnosed with r/r MF/SS and had initiated mogamulizumab treatment between 10/1/2018–08/12/2022. CT was defined as mogamulizumab usage concomitant with another systemic or skin-directed treatment (excluding topical steroids) for ≥28 days. Duration was calculated from the start of mogamulizumab until the last treatment (+14 days). Response was assessed after Day 27 of treatment until the start of the next systemic treatment or the last available medical record (response assessment period). Time to next treatment (TTNT) and progression-free survival (PFS) were estimated by Kaplan-Meier methods. Selected safety events (infusion reactions, rash, severe skin reactions, infection, immune-related reactions, and cardiac events) were also extracted.

Results: We identified 110 pts with MF/SS treated with mogamulizumab; 6 with <28 days of treatment were excluded from efficacy analyses. Seventy-five (72.1%) and 29 (27.9%) pts had MT and CT, respectively. Median (Q1, Q3) time from diagnosis to mogamulizumab treatment was 26.6 (10.3, 80.1) months (mo) in the MT group and 53.3 (18.0, 86.1) mo in the CT group. Mogamulizumab was used in MF and SS as MT in 64.0% and 79.6%; and CT in 36.0% and 20.4% of pts, respectively. Stage at diagnosis in the MT vs CT group included: 18.7% vs 20.7% I-IIA; 4.0% vs 17.2% IIB; 14.7% vs 10.3% III, and 22.7% vs 17.2% IV. Thirty- two pts (30.8%) were diagnosed with blood involvement (data missing for 60 pts); 24 had MT and 8 had CT. Mogamulizumab was given as MT in 45.3% and 46.7% of pts and CT in 58.6% and 37.9% of pts in academic and community settings, respectively. Fourteen CT pts (48.3%) had mogamulizumab added to pre-existing treatment, 8 (27.6%) had another treatment added to mogamulizumab, and 7 (24.1%) initiated mogamulizumab concurrently with CT. The most common systemic CT options were bexarotene (8 pts [27.6%]), extracorporeal photopheresis ([ECP] 7 pts [24.1%]), and methotrexate (5 pts [17.2%]) with some differences between MF and SS. Of 99 pts with results in the response assessment period, physician-reported response was documented in 47/70 pts (67.1%) on MT and 21/29 pts (72.4%) on CT. Median (Q1, Q3) time from initiation to initial response was 1.5 (0.9, 2.5) mo for MT and 2.3 (1.8, 4.7) mo for CT. Overall response rate for pts with ≤3 and >3 prior therapies, respectively, was 75.0% and 53.8% in MT (n=70), and 73.9% and 66.7% in CT (n=29). Median (95% CI) PFS was 8.3 mo (4.4, 13.5) for MT and 9.2 mo (2.8, 14.8) for CT. Median (95% CI) TTNT was 12.3 mo (7.2, 22.3) (MT: 10.7 mo [6.5, 22.6]; CT: 12.3 mo [5.6, 23.8]). In 110 pts in the safety analysis, 72/81 pts (88.9%) on MT and 22/29 pts (75.9%) on CT had ≥1 safety event. Infections included cellulitis (MT: 7 pts [8.6%], CT: 1 pt [3.4%]), pneumonia (MT: 4 pts [4.9%], CT: 0 pts), and sepsis (MT: 2 pts [2.6%], CT: 0 pts). Infusion reactions occurred in 23 pts (28.4%) on MT and 5 (17.2%) on CT. Skin conditions (due to disease or adverse events) were reported by 60 pts (74.1%) on MT and 19 (65.5%) on CT, most commonly pruritus (MT: 47 pts [58.0%]; CT: 16 pts [55.2%]) and rash (MT: 39 pts [48.1%]; CT: 11 pts [37.9%]). Rash was documented before mogamulizumab in 65/110 pts (59.1%). In the 45/110 pts (40.9%) without a history of rash, 13/32 pts (40.6%) on MT and 5/13 pts (38.5%) on CT reported treatment-emergent rash after mogamulizumab. Conclusions Conclusions These data show relatively frequent CT with mogamulizumab, most often with ECP, bexarotene, or methotrexate with mogamulizumab, often added to another systemic treatment for CTCL. In this cohort, the risk of selected safety events was not significantly different with mogamulizumab CT. Response rate, TTNT, and PFS were numerically higher with CT. Study limitations include potential for incomplete or incorrect documentation in medical records and lack of standardized response assessment criteria; however, this analysis demonstrates safety and a potential benefit of mogamulizumab in CT for pts with MF/SS.

Link to Abstract abs25-10821

Abstract Number: abs25-11387

Racial and socioeconomic disparities in clinical trial participation and outcomes in systemic peripheral T-cell lymphoma (PTCL): A multicenter retrospective Study

Presenter: Alexander Sanjurjo
Session: 906. Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster II

Abstract: Background: Background: : Peripheral T-cell Lymphoma (PTCL) is an aggressive and heterogenous disease with known survival disparities across racial and ethnic groups (Adams et al . 2016). The causes remain incompletely understood but may include differences in socioeconomic status (SES), access to care, clinical trial participation, and disease biology. In this retrospective study, the primary aim is to investigate disparities in trial participation and outcomes by race and SES in systemic PTCL, and examine how clinical trial enrollment m ay mitigate these differences.

Methods: : We conducted a multicenter retrospective study of adults diagnosed with systemic PTCL between 2010-2022 across 10 academic centers in the U.S. SES was measured using 2019 zip code–linked census data to assign income quintiles and Social Deprivation Index (SDI); High SDI (above the US median) indicates greater socioeconomic disadvantage. O verall survival (OS) was defined from diagnosis to death or last follow-up. Survival dif ference was tested by log-rank and Cox proportional hazards analysis. All multivariable models included age, sex, race/ethnicity, stage, ECOG, Charlson Comorbidity Index (CCI), treatment center, first line ( 1L ) complete remission (CR), histology, and trial enrollment. Trial enrollment differences were tested by logistic regression. Trial eligibility was approximated using ECHELON-2 criteria.

Results: : Among 621 patients, median age was 62 (IQR 51-71); 52% were non-Hispanic White (NHW), 25% non-Hispanic Black (NHB), 18% Hispanic, and 5% Asian. Subtypes included PTCL-NOS (35%), AITL (31%), ALCL (18%; 12% ALK−, 6% ALK+), and ATLL (15%), with ATLL found exclu sively in NHB (46%) and Hispanic (21%) patients . Most (78%) had stage III/IV disease; 43% had IPI ≥3, and 44% had CCI ≥3. With a median follow up of 66 months (m), t he median OS for this cohort was 68m ; 121m among those enrolled on a 1L trial vs. 61m among those not enrolled ( p=.03 ). By univari able analysis , NHB, age, stage, ECOG, CCI ≥ 3, ATLL, and high SDI were associated with lower OS while higher number of 1L treatment cycles, 1L CR, and trial enrollment were associated with higher OS. In multi vari able analysis , increased age, stage, ECOG, and ATLL remained associated with worse OS, while 1L CR (HR 0.40, p<.001 ) and trial enrollment (HR 0.66, p=.04 ) remained associated with better OS. After excluding ATLL , 1L CR and trial enrollment continued to predict better OS in multivariable analysis. Significant disparities were o bserved across race /ethnicity and SES: Trial participation 1L was lower in NHB compared to NHW patients (7.1% vs. 16%; p=.02 ), and by multivariable analysis , NHB patients were less likely to enroll on a trial (OR 0.32, p=.01 ). After excluding ATLL, NHB patients continued to be less likely to enroll on a trial (OR 0.29, p=.01 ). T rial eligibility differed by race /ethnicity as only 35 % of NHB patients and 4 3 % of Hispanic patients met baseline lab and performance stat us criteria, compared to 63% of NHW patients ( p < .0 01 ). T rial eligibility differences by race were driven by ECOG ( p=.0 04 ) , absolute neutrophil count ( p<.0 0 1 ) , and creatinine ( p=.0 2 ) . These differences remained significant ( p <.05 ) when excluding patients with ATLL. NHB patients were less likely to receive novel agents compared to NHW patients (19% vs. 33%; p<.01 ) and had lower CR rates than NHW patients (39% vs. 62%, p=.001 ) . NHB and Hispanic patients were more likely to reside in lower income quintiles ( p<.001 ) and high SDI areas ( p<.001 ). Patients with higher SDI had significantly worse OS ( p=.002 ); among these patients, trial enrollment trended toward improved OS (HR 0.62, p=.08 ).

Conclusion: : In this large multicenter cohort with systemic PTCL, racial and SES disparities were evident with significantly lower trial participation in NHB patients and differences in clinical trial eligibility by race/ethnicity . These disparities persisted even when excluding ATLL , an aggressive subtype of PTCL that was found exclusively in NHB and Hispanic patients. Importantly, however, t rial enrollment was consistently associated with longer survival and appeared to mitigate differences in survival for patients from high SDI neighborhoods . Future efforts should prioritize expand ing equitable trial access , r efining eligibility criteria, and delineating system-level barri er s t o trial participation.

Link to Abstract abs25-11387

Abstract Number: abs25-11443

Impact of angiotensin converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARB) on tumor lysis syndrome, acute kidney injury, and rasburicase use in patients undergoing chemotherapy for hematologic malignancies

Presenter: Haris Sohail
Session: 906. Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster II

Abstract: Introduction: Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are widely used in patients with cardiovascular disease, diabetes, and hypertension, with well- established mortality benefits. However, concerns remain about their potential to worsen kidney function. In patients with hematologic malignancies undergoing treatment, the risk of tumor lysis syndrome (TLS) and acute kidney injury (AKI) is already elevated. This study examines the impact of concurrent ACEi/ARB use on the incidence of TLS, AKI, and rasburicase utilization in this high-risk population. Methods The TriNetX Research Network was used to identify patients aged 18 years or older with hematologic malignancies who initiated chemotherapy between 2015 and 2024. The following malignancies were included due to their established risk for TLS: Burkitt lymphoma, acute lymphoblastic leukemia, acute myeloblastic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, adult T-cell lymphoma/leukemia, lymphoblastic lymphoma, and peripheral T-cell lymphoma. Patients were divided into those who received an ACEi or ARB within 30-days of chemotherapy initiation, and those who did not. Propensity score matching was conducted using 1:1 nearest-neighbor matching based on age, sex, race, comorbidities, baseline laboratory values, and history of nephrotoxic medication use. TLS, AKI, and rasburicase use were assessed within the first month following chemotherapy initiation. Analyses were performed within the TriNetX platform using the measures of association function to estimate risk differences, relative risk (RR), and 95% confidence intervals (CIs). Results A total of 17,583 patients receiving ACEi/ARBs within 30 days of chemotherapy initiation were identified, compared to 111,600 patients who were not. After propensity matching, both cohorts included 17,583 patients. After removing patients with a prior history of TLS, AKI, or rasburicase use from each respective analysis, 1.9% of patients in the ACEi/ARB group developed TLS, compared to 1.3% in the control group, with a risk difference of 0.6% and a RR of 1.5 (95% CI: 1.5–1.8; p < 0.001). The incidence of AKI was also higher in the ACEi/ARB group (7.8%) compared to the control group (5.0%), with an RR of 1.6 (95% CI: 1.4–1.7; p < 0.001). Similarly, rasburicase use was greater in the ACEi/ARB group (3.1%) versus the control group (2.2%), with an RR of 1.4 (95% CI: 1.2–1.6; p < 0.001). Conclusion This study highlights the clinical impact of ACEi/ARB use in patients with hematologic malignancies undergoing treatment. Although TLS is relatively uncommon, it can be life- threatening, and its incidence is significantly increased with concurrent ACEi/ARB use. This has important implications not only for patient outcomes but also for the financial burden related to supportive care, including rasburicase use. Clinicians should carefully consider the risks and benefits of continuing ACEis/ARBs during the acute treatment phase, particularly when the risk of TLS is highest.

Link to Abstract abs25-11443

Abstract Number: abs25-12337

Real-world survival outcomes following allogeneic hematopoietic cell transplantation in peripheral T-cell lymphomas: A Florida multi-institutional cohort study

Presenter: Fatima Tuz Zahra
Session: 906. Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster II

Abstract: Introduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of aggressive lymphoid malignancies characterized by high relapse and mortality rates. Allogeneic hematopoietic cell transplantation (allo-HCT) is recommended upfront for high-risk subtypes—including NK/T-cell lymphoma, hepatosplenic T-cell lymphoma (HSTCL), and adult T-cell leukemia/lymphoma (ATLL)—and recommended for relapsed or refractory nodal PTCL, including PTCL-not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL). This study aims to evaluate real-world survival outcomes and prognostic factors in a Florida multi-institutional PTCL cohort treated with allo-HCT.

Methods: Patients with a diagnosis of PTCL undergoing allo-HCT at Moffitt Cancer Center (MCC) and University of Miami (UM) between February 14, 2002, and April 30, 2025, were included, excluding those with cutaneous T-cell lymphoma or cord blood grafts. Data were collected through chart review and analyzed using SAS 15.3. Overall survival (OS) and progression free survival (PFS) were estimated by the Kaplan-Meier method; cumulative incidences of relapse and non-relapse mortality (NRM) by competing risks analysis. Cox proportional hazards models and Fine-Gray regression models were used to assess factors influencing survival, relapse, and NRM.

Results: We identified 99 patients who received allo-HCT for PTCL at the two centers between February 2002 and April 2025. Median age at transplant was 54 (range 23–72) years; 61% were male. 71% of patients received allo-HCT at MCC and 28 patients at UM. The histology included PTCL-NOS (43%), followed by AITL (21%), anaplastic large cell lymphoma (ALCL) (13%), NK/T-cell lymphoma (9%), ATLL (6%), and other subtypes (7%). Ninety-two (93%) patients had Ann Arbor stage III–IV and 56 (57%) had primary chemo-refractory disease. 24% of patients had received an autologous stem cell transplant prior to allo- HCT. Median number of lines of therapy prior to allo-HCT was 2 (range: 1 – 8). 48 patients (48.5%) had received ≥3 prior lines of therapy. Prior to allo-HCT, 57% were in CR, 35% PR, and 8% had SD/PD. Majority (58%) received reduced-intensity conditioning (RIC). The day +30 cumulative incidence of neutrophil and platelet engraftment was 94% and 78%, respectively. Day +100 cumulative incidence of Grade II–IV acute GVHD was 44.3% (95% CI: 34.2 – 53.9). The 1-year cumulative incidence of chronic GVHD (mild–severe) was 39% [95% CI: 29%–48%] (moderate–severe 24%) Median follow-up for survivors was 59.2 months (range: 0.4–217.5). The 3-year cumulative incidence of relapse and NRM was 28% (95% CI: 20%–38%) and 25% (95% CI: 17%–34%). Median OS was 7.9 years (95% CI: 2.7 – 10.9). Median PFS was 2.5 years (95% CI: 0.7–7.9). Estimated 3- and 5-year OS was 59% (95% CI: 48%–68%) and 56% (95% CI: 45%–65%); PFS at 3 and 5 years was 47% (95% CI: 36%–56%) and 45% (95% CI: 35%–55%). On the multivariate analysis, disease status prior to transplant showed a strong association with the risk of relapse (less than CR; HR 3.8; 95% CI 1.6–9.1, p= 0.003 ). Compared to PTCL-NOS, relapse risk was significantly higher for ATLL (p=0.0003); no significant differences were observed for extranodal NK/T-cell leukemia/lymphoma (p=0.30). On the univariate analysis for OS and PFS, no significant association was observed for age, sex, race, ECOG status at transplant, or donor type. PFS and OS with RIC were not inferior to MAC (PFS HR 0.65 [95% CI, 0.38–1.11]; OS HR 0.58 [95% CI, 0.33–1.05]). Less than CR prior to transplant was associated with worse PFS (HR 1.84, 95% CI 1.09–3.1, p= .02 ). Factors associated with higher risk for NRM in multivariate analysis included ECOG status ≥1 at transplant (HR 2.61, 95% CI 1.19–5.70, p= 0.016 ). Primary chemo-refractory disease was associated with a lower risk of NRM (HR 0.42, 95% CI 0.19–0.92, p= 0.029 ).

Conclusions: Our study shows that disease status prior to allo-HCT and the lymphoma subtype are key prognostic factors for relapse after transplant. Limited performance status at transplant is predictive of worse NRM. Allo-HCT remains the primary potentially curative therapy offering long-term survival and remission for high-risk and relapsed/refractory PTCL, although significant unmet needs remain for patients with ATLL who exhibit substantially higher relapse risks.

Link to Abstract abs25-12337

Abstract Number: abs25-450

Chidamide-BEAM conditioning plus autologous stem cell transplantation forperipheral t-cell lymphoma: A single-arm, single-center, phase 2 trial

Presenter: Meng-Meng Ji
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Chidamide-BEAM Conditioning plus Autologous Stem Cell Transplantation for Peripheral T- Chidamide-BEAM Conditioning plus Autologous Stem Cell Transplantation for Peripheral T- cell Lymphoma: A single-arm, single-center, phase 2 trial cell Lymphoma: A single-arm, single-center, phase 2 trial Importance: Considering the therapeutic effect of Chidamide in T-cell lymphoma (TCL), adding Chidamide to the pre-treatment and maintenance regimen of ASCT may have a better therapeutic efficacy. Therefore, this study aimed to evaluate the effect and safety of the Chidamide-BEAM regimen, followed by frontline ASCT and Chidamide maintenance, in TCL patients. Objective: Objective: To compare the efficacy and safety of Chidamide-BEAM regimen, followed by frontline ASCT and Chidamide maintenance, in PTCL patients. Design, Setting, and Participants: Design, Setting, and Participants: Between June 15, 2022 and June 15, 2023, 26 TCL patients were screened and enrolled. Eligible patients were aged 18–65 years; histologically diagnosed as PTCL excluding IPI 0-1 ALK+ anaplastic lymphoma, with CR or PR after frontline chemotherapy. Interventions: Interventions: All patients received chidamide combined with BEAM followed by ASCT. D0 is the day of reinfusion of stem cells. Main Outcomes and Measures: Main Outcomes and Measures: The primary endpoint was the 2-year progression-free survival (PFS). The secondary endpoints include 2-year overall survival (OS), complete remission rate, the time of hematopoietic reconstruction, and transplantation-related adverse events

Results: Between June 15, 2022 and June 15, 2023, 26 patients were enrolled. 2 were excluded for withdrawing consent and 1 for mobilization failure. Of all the 23 patients, 100% were alive at the time of analysis. The median follow-up of surviving patients was 24.6 months (range, 18.2 to 38.7 months). The 2- year PFS and OS for the ITTP were 95.7% (95% CI, 72.9% to 99.4%) and 100.0% (95% CI, 100.0% to 100.0%), respectively. The grade 3-4 non-haematological adverse events included infection (13.0%), hepatic toxicities(8.7%), vomiting (4.3%) and mucositis (4.3%). Conclusions and Relevance: Conclusions and Relevance: Chi-BEAM might be an effective conditioning regimen of ASCT for PTCL and shows a good safety profile. Trial Registration: Trial Registration: ClinicalTrials.gov identifier: NCT05367856

Link to Abstract abs25-450

Abstract Number: abs25-1658

Prognostic value of interim PET in patients with extranodal natural killer/T-cell lymphoma treated with non-anthracycline containing l-asparaginase based regimen

Presenter: Sojin Kim
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Background: Background: Extranodal natural killer/T-cell lymphoma (ENKTL) is a rare subtype of non-Hodgkin lymphoma predominantly involving the nasal cavity and nasopharynx. Despite advances with L- asparaginase-based regimens, rapid disease progression remains common, underscoring the need for enhanced risk stratification. While baseline Prognostic Index for Natural Killer cell lymphoma (PINK) and PINK with Epstein-Barr virus DNA (PINK-E) scoring provide initial risk assessment, it lacks dynamic evaluation during treatment. Therefore, we evaluated the prognostic value of interim positron emission tomography (PET) and its integration with the PINK-E scoring system to enable longitudinal risk assessment and improve prognostic accuracy.

Methods: We retrospectively analyzed 48 patients with ENKTL treated with L-asparaginase-based regimens and underwent interim PET analysis between May 2009 and May 2020. Patients with progressive disease on interim PET were excluded. PET images were evaluated using the Deauville score (DS) and the percentage decrease in maximum standardized uptake value (%ΔSUVmax). Patients were categorized by interim DS (iDS1-3 vs iDS4-5) and by %∆SUVmax (>61% vs ≤61%) using the first quartile cut-off (Q1=61%). The primary endpoint was overall survival (OS) and secondary endpoint was progression-free survival (PFS).

Results: A total of 48 patients were included (median age, 54 years; 60.4% male) with a median follow-up of 50.9 months. Four patients were excluded from %ΔSUVmax analysis due to missing baseline PET data. In multivariable analysis, %ΔSUVmax≤Q1 (n=11, 25.0%) independently predicted poor outcomes for both OS (adjusted HR, 6.32; p <0.001) and PFS (adjusted HR, 5.51; p <0.001), while iDS 4–5 (n=24, 50.0%) showed a trend toward significance for OS (adjusted HR, 2.20; p =0.076) but not for PFS. Among patients with iDS 4–5, %ΔSUVmax>Q1 (n=11) was associated with longer OS (median, 54.87 vs. 5.19 months; p =0.100) and PFS (median, 63.12 vs. 2.89 months; p =0.061) compared to ≤Q1 (n=11), though not statistically significant. Combining PINK-E and %ΔSUVmax stratified patients into three prognostic groups: low-risk (PINK-E low/intermediate + %ΔSUVmax>Q1, n=10), intermediate-risk (PINK-E low/intermediate + %ΔSUVmax≤Q1 or PINK-E high + %ΔSUVmax>Q1, n=27), and high-risk (PINK-E high + %ΔSUVmax≤Q1, n=7). Pairwise comparisons revealed significant differences in OS: low vs. intermediate ( p =0.039), low vs. high ( p <0.001), and intermediate vs. high ( p =0.002). For PFS, differences were significant between low vs. high ( p <0.001) and intermediate vs. high ( p <0.001), with a trend toward significance between low and intermediate groups ( p =0.069).

Conclusion: Interim PET response measured by %ΔSUVmax offered significant prognostic value in ENKTL patients treated with L-asparaginase-based therapy. Integrating interim PET results with the PINK-E score enhanced risk stratification, enabling identification of high-risk patients who may benefit from intensified or alternative strategies.

Link to Abstract abs25-1658

Abstract Number: abs25-1813

BI-1808, a tumor necrosis factor receptor 2 (TNFR2) blocker/depleter, showing promising efficacy in T cell lymphoma patients

Presenter: Stefan Barta
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Background: T-cell lymphomas (TCL) make up about 10-15% of all Non-Hodgkin’s Lymphomas (NHLs), with peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) being the main types. PTCLs are nodal or systemic T-cell lymphomas, whereas CTCL originates in the skin and includes mycosis fungoides (MF) and Sézary syndrome (SS). Survival is poor in PTCL, advanced MF as well in SS, with a 5-year survival range of 20–60%. TNFR2 is a potential oncogene in TCL, characterized by recurrent point mutations and gain of function alterations, leading to its abnormal expression on CD4+CD26- tumor cells 1 . BI-1808 is an IgG1 monoclonal antibody that targets TNFR2. It inhibits TNFR2 interaction with the ligand TNF-α, enabling FcγR-dependent depletion of regulatory T cells (Treg), and promoting the expansion of intratumoral CD8+ T cells. BI-1808 has shown single agent activity in CTCL, PTCL, and solid tumor patients. Consequently, targeting TNFR2 constitutes a promising and innovative cancer treatment for patients.

Methods: Safety and preliminary efficacy of BI-1808 as single agent is currently investigated in patients with T-cell lymphomas in a sub-cohort of the ongoing Phase 2a clinical trial 19-BI-1808-01. The study is designed to enroll 20 patients at signal seeking dose, whereafter a dose optimization phase will open.

Results: We report here the outcome of the signal seeking portion of the study. As of August 4 2025 the signal- seeking portion of the study has been fully enrolled. 19 patients with CTCL and 2 patients with PTCL received BI-1808 as single-agent Q3W. 6 female and 15 male patients, with a median age of 69,5 y (28-77), received a median of four cycles administered (range 1-19). In CTCL, 11 classified as MF (stage IIIA/IIB) and 8 as SS (stage IV), with a median of 5 (2-10) prior systemic treatments. All treatment related adverse events were classified as mild or moderate with no potentially related Gr3+ AE reported. Disease “flares” characterized by increased skin peeling, erythema, and pruritis) were observed during the first weeks of treatment in several cases, considered related to immune activation associated with depletion of T reg and influx of CD8+ T cells. Immunofluorescence multiplex staining of skin biopsies showed evidence of significant increase in CD8+ infiltration and accompanying granzyme B elevation at 5 weeks after start of treatment. Out of 9 CTCL evaluable cases, 1 SS patient exhibited complete response (CR) 4 participants (3 MF, 1 SS) exhibited partial response (PR) as best clinical response; the remaining 4 participants showed stable disease (SD). Out of 2 evaluable PTCL patients (both stage IV), 1 patient showed SD as best clinical response, while the other patient exhibited a substantial PR at first assessment. More complete data will be disclosed in poster

Conclusions: Current data from the signal seeking cohort of BI-1808 in TCL show promising efficacy associated with strong immune activation in patients with advanced CTCL, leading to an objective response rate of 46% and a 100% disease control rate in the evaluable population, warranting the study to proceed to next stage of dose optimization. 1 Ungewickell et al Nat Genet. 2015

Link to Abstract abs25-1813

Abstract Number: abs25-1886

Duvelisib in patients with relapsed/refractory peripheral T-cell lymphoma: Final results from the phase 2 PRIMO trial - impact of prior therapy and expanded safety analysis

Presenter: Pier Luigi Zinzani
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Introduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of aggressive lymphomas that have a poor prognosis, with a median overall survival (mOS) of <6 months (mos) for relapsed/refractory (R/R) disease. Current single agent therapies deliver modest overall response rates (ORR), typically <30% (except brentuximab vedotin [BV] in anaplastic large cell lymphoma; ALCL). Duvelisib is an oral dual inhibitor of phosphatidylinositol 3-kinase (PI3K)-δ and PI3K-γ isoforms approved in the US for treatment of R/R chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after ≥2 prior systemic therapies. The PRIMO trial (NCT03372057; sponsor: Secura Bio, Inc.) was a phase 2, open-label, single- arm trial evaluating duvelisib monotherapy in R/R PTCL. Methods PRIMO enrolled patients (pts) with R/R PTCL after ≥1 standard regimen. After a dose optimization phase, the recommended dose for the expansion phase (PRIMO-EP) was duvelisib 75 mg BID for 2 cycles to maximize early disease control, followed by 25 mg BID to mitigate late toxicities, continued until progressive disease or unacceptable toxicity. Primary endpoint of the PRIMO-EP was ORR by Independent Review Committee (Lugano 2014). Here we report the impact of prior treatments and expanded safety analyses from the PRIMO-EP. Results PRIMO-EP included 123 pts with median age 65 (21-92) years and 2 (1-9) prior lines of therapy. The most common baseline histologies were PTCL-NOS (n=53), angioimmunoblastic TCL (AITL) (n=37), and ALCL (n=20). Median follow-up time was 11.5 mos; median treatment duration was 8.3 weeks. Efficacy outcomes were ORR 48%, complete response rate (CRR) 33%, median duration of response (mDOR) 7.9 mos, median progression free survival (mPFS) 3.4 mos, and mOS 12.4 mos. AITL subgroup outcomes were ORR 62%, CRR 51%, mDOR 11.7 mos, mPFS 8.3 mos, and mOS 18.1 mos. Thirty-four pts (28%) had 1, 29 (24%) had 2, and 59 (48%) had ≥3 prior lines of therapy (AITL subgroup only: 20.6% had 1, 48.3% had 2, and 27.1% had ≥3 prior lines). In the total population, there was no consistent impact on efficacy outcomes by number of prior lines, with ORR: 29%, 66%, 49%; CRR: 18%, 52%, 32%; mDOR: 6.5, 11.7, 7.9 mos; mPFS: 1.9, 9.0, 3.0 mos, and mOS: 30.2, 22.7, 7.3 mos in pts with 1, 2, and ≥3 prior lines of therapy, respectively. Eighty-three pts (68%) received prior CHOP-based therapy, 43 (35%) had salvage chemotherapy, 25 (20%) had autologous stem cell transplant (SCT), 21 (17%) had HDAC inhibitor (HDACi), and 47 (38%) had BV. For the AITL subgroup, prior therapies included: CHOP-based (70%), salvage therapy (35%), SCT (16%), HDACi (19%), and BV (32%). Considering that this regimen included 2 cycles of 75 mg BID, we also analyzed safety according to number of cycles; 123 pts received ≤2 cycles, 63 pts (51%) received >2 to 6 cycles, and 25 pts (20%) received >6 cycles. Adverse events (AEs) in ≥20% of pts by treatment duration category (cycles ≤2/cycles >2-6/ cycles >6) included: neutropenia (29%/22%/16%), aspartate aminotransferase (AST) increased (29%/29%/4%), alanine aminotransferase (ALT) increased (25%/35%/4%), thrombocytopenia (19%/13%/28%), fatigue (15%/13%/24%), and diarrhea (20%/25%/32%). Grade ≥3 AEs in ≥5% of pts by treatment duration category included: neutropenia (14%/13%/12%), ALT increased (13%/22%/0%), AST increased (12%/13%/4%), thrombocytopenia (4%/8%/8%), lymphopenia (4%/8%/4%), maculopapular rash (6%/6%/0%), diarrhea (3%/8%/20%), hypokalemia (1%/0%/12%), and hypoxia (1%/0/8%). Conclusions In a heavily treated, R/R population, duvelisib efficacy outcomes did not show a consistent pattern based on prior lines of therapy; notably, pts with more heavily pretreated disease (where unmet need may be the greatest) demonstrated numerically favorable outcomes. For R/R PTCL, a 75 mg BID dose was administered for the first 2 cycles (in CLL/SLL, the indicated dose is 25 mg BID). Despite the higher initial dose, generally there was no consistent pattern of higher rates of persisting or emerging AEs with longer treatment duration. Rates of diarrhea showed a modest trend of increase, but there was no increase in rates of colitis. These data support the tolerability of this regimen in R/R PTCL despite a higher starting dose. Efficacy in the AITL group stands out; based on these results, the sponsor has initiated a randomized phase 3 study to investigate duvelisib in a homogeneous population of R/R nodal T-follicular helper cell lymphoma (NCT06522737; TERZO™).

Link to Abstract abs25-1886

Abstract Number: abs25-2337

Patterns of care in second line management of nodal peripheral T-cell lymphoma from the lymphoma epidemiology of outcomes (LEO) and molecular epidemiology resource (MER) prospective cohort Study

Presenter: N. Nora Bennani
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Background: Background: Nodal peripheral T-cell lymphomas (nPTCLs) are a challenging group of non-Hodgkin lymphomas that frequently recur after or are refractory to first line (1L) treatment. Chemotherapy options in the relapsed or refractory (R/R) setting are limited. The incorporation of non-cytotoxic agents including antibody drug conjugates, immune checkpoint inhibitors, epigenetic modifiers, and phosphatidylinositol 3-kinase inhibitors offers new therapeutic potential and possibly better outcomes. We report on outcomes for patients (pts) with R/R nPTCL enrolled in the multi-center LEO-MER prospective cohort study (NCT02736357) who received second line (2L) therapy.

Methods: Six hundred and three adult pts with newly diagnosed nPTCL were prospectively enrolled in the University of Iowa/Mayo Clinic MER observational cohort (2002-2015) or the expanded LEO cohort (2015- 2020). Secondary overall survival (sOS) was calculated from date of 2L treatment initiation to date of death or last follow-up. Secondary event-free survival (sEFS) was calculated from date of 2Ltreatment initiation to disease progression, initiation of 3rd line therapy, or death from any cause. sEFS and sOS were evaluated using Cox model and Kaplan-Meier estimator. Log-rank test was used to test the significance of difference between groups. Pts with concomitant B-cell lymphomas were excluded from this analysis.

Results: Thus far, 169 pts with nPTCL initiating 2L therapy were evaluated. Of these, 75 (44.4%) had PTCL-NOS, 63 (37.3%) had angioimmunoblastic T-cell lymphoma (AITL, inclusive of nodal T-follicular helper cell lymphoma), 20 (11.8%) had ALK-negative anaplastic large cell lymphoma (ALCL), and 11 (6.5%) had ALK- positive ALCL. At 2L treatment initiation, the median age was 64 with 86.1% of pts having advanced stage disease. Of the 108 pts with available international prognostic index (IPI) scoring, 46.3% had an IPI of ≥3. Thirty-four (20.1%) pts had received a consolidative autologous stem cell transplant (ASCT) in the 1L. A total of 86 pts (50.1%) had primary refractory disease (partial response, stable or progressive disease as best response to 1L therapy), 45 (26.6%) experienced early relapsing disease within 6 months of 1L therapy, and 38 (22.5%) had relapsed disease >6 months from 1L therapy. After a median follow-up of 7.1 years (yrs), median sOS was 1.52 yrs, and sEFS was 3.2 months (mos). There was no difference in sOS or sEFS regardless of timing of relapse. In keeping with other studies, ALK-positive ALCL pts had the best 5-year OS (70.1%) compared to other subgroups (ALK-negative ALCL 45.0%, AITL 30.4%; PTCL-NOS 21.3%). Lymphoma was the leading cause of death following 2L therapy, with a 2-year cumulative incidence of 49.2%. Eighty pts (47.3%) received only cytotoxic chemotherapy as second line (2L) therapy; ICE (41 (51.3%)) and gemcitabine-containing regimens were most common (14 (17.5%)). Seventy-five pts (44.4%) were treated with non-cytotoxic agents given as monotherapy or in combination with chemotherapy. The most common non-cytotoxic therapies were brentuximab vedotin (33 (44.0%)), romidepsin (17 (22.7%)) and immune checkpoint inhibitors (9 (12.0%)). Fourteen pts (8.3%) underwent palliative interventions involving radiation, steroids, or cyclosporine alone. Intent to proceed to transplant in the 2L was known in 158 pts (101 (63.9%) not intended, 57 (36.1% intended)). Following 2L treatment, 18 (10.7%) pts proceeded to consolidative ASCT and 10 (5.9%) to allogeneic transplant. Only 21 (12.9%) were treated on a clinical trial. Pts who received a non-cytotoxic agent had superior outcomes compared to pts receiving only chemotherapy; the median sOS was 30.4 mos (95% confidence interval [CI] 15.3, 53.52 mos) vs 11.7 mos ((95% CI 7.95,19.58); p=0.04; HR 0.67) and the median sEFS was 4.83 mos (95% CI 3.38, 10.09) vs 2.33 mos ((95% CI 1.71,3.02); p=0.02; HR=0.65). Conclusions Conclusions We report here one of the largest prospective cohorts in R/R nPTCL. The LEO-MER cohort, despite its association with academic centers, shows poor outcomes regardless of refractory or relapsed disease, frequent inability to proceed to intended consolidative transplant, and low clinical trial participation in 2L, which corroborates findings from other registries (Jain 2025, Stuver 2019). Outcomes improved for pts treated with non-cytotoxic agents. Updated data including additional pts and subgroup analyses will be reported at the meeting.

Link to Abstract abs25-2337

Abstract Number: abs25-4687

CHOP combined with linperlisib or chidamide may decrease the risk of mortality of monomorphic epitheliotropic intestinal T-cell lymphoma: A single-center cohort study

Presenter: Ning Su
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Background: Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is an extremely rare and highly aggressive subtype of peripheral T-cell lymphoma that primarily arises in the intestine. MEITL exhibits a high resistance to conventional chemotherapy and a strong tendency for relapse, resulting in a dismal prognosis. The median overall survival is only about seven months, with most patients succumbing to gastrointestinal complications such as perforation, obstruction, or bleeding. In recent years, advances in molecular biology have highlighted the increasingly important role of genetic testing in the diagnosis and treatment of MEITL. This approach not only facilitates the identification of molecular characteristics of the tumor but also supports the development of individualized treatment strategies. To further elucidate the clinical and genetic features of this disease, we conducted a retrospective analysis of 11 MEITL patients treated at our center. Methods: Patients diagnosed with MEITL between July 16, 2023 and December 15, 2024 were enrolled in the analysis. Cut-off date for follow-up was July 24, 2025. Clinical data were collected using the electronic medical record system, including age, sex, disease stage, presenting symptoms, and laboratory findings. Heatmaps were drawn to visualize the results of genetic testing, treatment modalities, and patient outcomes. Survival outcomes between different subtypes were compared using Kaplan-Meier curves. Results: The mean age of the patients was 56.6 years (SD = 12.6), and 9 patients (81.8%) were male. Eight patients (72.7%) were classified as Ann Arbor stage IV and Lugano stage IV. The most frequently involved site was the ileum (n = 6). Most cases expressed CD3 (100%), TIA1 (100%), CD56 (81.8%), and CD7 (72.7%), but were negative for CD30, CD20, CD103, and EBER (all 0%). The most frequently mutated genes were STAT5B (72.7%), SETD2 (63.6%), and JAK3 (45.5%). The median overall survival was 3.0 months (95 % CI 2.0–4.0); Seven patients (63.6%) underwent surgery, and nine (81.8%) received chemotherapy. The complete response (CR) rate was 18.1%. Although the optimal management of MEITL remains unclear, surgery combined with chemotherapy may help improve patient prognosis. Two patients underwent CHOP combined with histone deacetylase (HDAC) or PI3Kδ inhibitors as their frontline regimen, and both of them were survival until follow-up cutoff date. Conclusion: Based on present data, the most frequently mutated pathways in MEITL patients was JAK- STAT pathway. Surgery combined with chemotherapy may prolong their overall survival. And CHOP combined with HDAC or PI3Kδ inhibitors may decrease risk of mortality of them. However, the relationship between patient prognosis and gene mutations in MEITL should be further investigated.

Link to Abstract abs25-4687

Abstract Number: abs25-7214

Facility-level variation in hepatosplenic T-cell lymphoma care: Comparative outcomes from academic and community cancer centers

Presenter: Daniel Rosas
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Background: Background: Hepatosplenic T-cell lymphoma (HSTCL) is a rare, aggressive peripheral T-cell lymphoma subtype with poor outcomes and limited standard treatment [ Transplantation and Cellular Therapy PMID: 38431075, World Journal of Surgical Oncology PMID: PMID: 39696449 ] Due to its rarity, disparities in survival and treatment access based on facility type remain poorly described. This study utilizes the National Cancer Database (NCDB) to compare demographic, treatment, and survival outcomes in patients treated at Academic Cancer Programs (ACPs) versus Community Cancer Programs (CCPs).

Methods: We performed a retrospective analysis of patients diagnosed with HSTCL in the United States between 2004 and 2022 using the NCDB. Demographic, clinical, and outcome data were compared between patients treated at ACPs and CCPs. ACPs included academic and research programs, including NCI- designated comprehensive cancer centers. CCPs comprised community, comprehensive community, and integrated network cancer programs. Kaplan-Meier and Cox proportional hazards models were used to compare overall survival (OS), adjusting for age, race/ethnicity, insurance status, comorbidity score (Charlson-Deyo), and distance from treating facility.

Results: A total of 518 patients with HSTCL were identified, with 265 (51%) treated at ACPs and 89 (17%) at CCPs; facility type was not available for 164 (31.6%) patients. ACPs cared for a younger population compared to CCPs, with a median age of 56 years vs. 63, and a greater proportion of people younger than 60 years of age (60% vs. 42%, p<0.001). Race distribution showed that the two most affected races across facilities were white (65%) and black (28%), with a higher proportion of white patients being cared for at CCP (75% vs. 65%), and black patients at ACPs (28% vs. 18%). However, the difference was not statistically significant (p= 0.2). Stage IV disease was prevalent in both groups but more common in ACPs (77% vs. 69%). Patients treated at CCPs were more likely to be Medicare-insured (48% vs. 29%, p<0.001), whereas patients treated at ACPs were more likely to have private insurance (52% vs. 35%, p<0.001). Treatment was more often administered at ACPs (76% vs. 64%, p = 0.005). The median time to chemotherapy was similar across facilities (20 days in ACPs and 18 days in CCPs, p = 0.52). Survival analysis showed poor adjusted median OS in both settings: 0.91 years for ACPs and 0.73 years for CCPs. KM survival estimates at 2, 5, and 10 years remained under 25% for both groups. While not statistically significant, trends favored slightly better OS in ACPs. At 2 years, survival was 31% for ACPs vs. 24% for CCPs. At 10 years, OS was 11% and 17%, respectively (p>0.3). Notably, 30-day mortality was higher in CCPs (5.6% vs. 0.4%, p = 0.012).

Conclusion: HSTCL carries a dismal prognosis across all facility types, with a modest survival advantage observed in patients treated at academic centers. While the rarity of HSTCL limits statistical power, trends suggest earlier diagnosis, better access to therapy, and reduced early mortality in ACPs. These findings underscore the importance of timely referral to specialized centers and ongoing efforts to develop optimal therapeutic strategies for this aggressive lymphoma.

Link to Abstract abs25-7214

Abstract Number: abs25-8010

Autologous stem cell transplantation and real-world outcomes in angioimmunoblastic T-cell lymphoma: A national cohort study

Presenter: Yu Tao
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Background: Background: The benefit of high-dose chemotherapy and autologous stem cell transplantation (ASCT) as a consolidation strategy after initial chemotherapy in peripheral T-cell lymphoma (PTCL) is currently unclear, and a randomized trial (EA4232/PTCL-STAT) to answer this question is currently underway. Angioimmunoblastic T-cell lymphoma (AITL) is a rare, aggressive subtype of nodal PTCL with poor prognosis and unique features. Here, we report a large-scale, real-world evidence on the role of ASCT in frontline AITL management.

Methods: We analyzed a national cohort of 5,827 patients diagnosed with AITL between 2004 and 2020 from the National Cancer Database (NCDB). Baseline demographic, clinical, and socioeconomic characteristics were assessed. Treatment modalities included chemotherapy alone, chemotherapy with ASCT, and no treatment. Overall survival (OS) was evaluated using Kaplan-Meier method and multivariable Cox proportional hazards regression. Propensity score matching (PSM) was performed to validate ASCT's treatment effect.

Results: Among patients with complete treatment information (n = 5,224), the median age at diagnosis was 68 years (range 20–90). Frontline treatments included chemotherapy alone (68.6%, n = 3,584), chemotherapy with ASCT (14.6%, n = 761), and no treatment (16.8%, n = 879). Compared with patients who did not receive ASCT, those who underwent ASCT were significantly younger (median 60.0 vs 68.0 years), more frequently treated at academic centers (81.5% vs 57.9%, p < 0.001), and more likely to reside in areas with higher educational attainment (p < 0.001). They exhibited lower Charlson-Deyo comorbidity scores (CDS), with a higher proportion having a score of 0 (82.8% vs 73.6%, p < 0.001), and were more likely to have advanced-stage disease (93.0% vs 86.9%, p < 0.001). Furthermore, a higher proportion of patients who received ASCT were diagnosed in more recent years (p < 0.001). Sex, race, and IPI score distribution showed no significant baseline differences. Median follow-up time was 81.1 months (95% CI: 77.4–84.9), and the median OS was 23.3 months (95% CI: 21.3–25.2) for the entire cohort. For patients receiving chemotherapy with ASCT, the median OS was 139.2 months (95% CI: 104.2–174.2). In comparison, chemotherapy alone yielded a median OS of 23.6 months (95% CI: 21.4–25.8), while patients who received no treatment had a median OS of 4.0 months (95% CI: 2.7–5.2); overall p < 0.001. Median OS also significantly improved with more recent diagnosis eras: 20.1 months for patients diagnosed in 2004–2009 (95% CI: 16.8–23.4), 23.9 months for those diagnosed in 2010–2015 (95% CI: 21.0–26.7), and 26.7 months for patients diagnosed in 2016–2020 (95% CI: 23.1–30.4) (p < 0.001). Analyses consistently demonstrated longer median OS in female patients (27.5 vs. 20.7 months in males, p <0.001), and in patients treated at academic centers (27.5 vs. 16.4 months at non-academic centers, p < 0.001). Median OS varied by race (White: 24.0 months vs. Black: 15.2 months vs. Others: 30.3 months; p = 0.017). Patients with higher household income and higher educational attainment experienced significantly improved survival (p = 0.005 and p = 0.017, respectively). Patients with early-stage disease, lower IPI scores, and lower CDS also showed significantly longer survival (p < 0.001 for all comparisons). Multivariate Cox regression showed that chemotherapy with ASCT significantly reduced mortality risk compared to chemotherapy alone (HR = 0.438, 95% CI: 0.364–0.527, p < 0.001). No treatment significantly increased mortality risk (HR = 1.941, 95% CI: 1.634–2.305, p < 0.001). PSM analysis further validated that chemotherapy with ASCT significantly lowered mortality risk compared to chemotherapy alone (HR = 0.608, 95% CI: 0.503–0.736, p < 0.001), after matching for age at diagnosis, sex, race, income, education level, academic center, stage, CDS, and diagnosis era.

Conclusion: This large-scale, real-world analysis suggests that chemotherapy followed by ASCT is associated with significantly improved overall survival in patients with AITL, supported by unadjusted Kaplan-Meier analysis, adjusted multivariate Cox regression, as well as PSM analysis. These data support ASCT as an important consolidation strategy for AITL in real-world practice.

Link to Abstract abs25-8010

Abstract Number: abs25-8852

Frontline chemotherapy for CD30+ non-ALCL peripheral T-cell lymphoma a multi-center retrospective analysis

Presenter: Asaad Trabolsi
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Introduction: The ECHELON-2 trial for newly diagnosed CD30+ peripheral T-cell lymphomas (PTCL) demonstrated superior overall survival with brentuximab vedotin plus chemotherapy (BV-CHP) compared to CHOP. However, total enrollment was restricted to only 30% of patients with non-anaplastic large cell lymphoma (ALCL) histologies and was not powered to analyze survival benefits in this cohort. Thus, the benefit of BV- CHP in non-ALCL patients remains less clear. Adding to this uncertainty, CHOP plus etoposide (CHOEP) remains a standard regimen for many non-ALCL PTCL histologies for patients <60 years of age. Which of these three regimens offers superior outcomes for patients with CD30+ non-ALCL PTCL remains to be determined, is a critical knowledge gap in this area, and could meaningfully inform the management of these patients.

Methods: We conducted a retrospective analysis of chemotherapy-naïve CD30+ (≥1%) PTCL from 7 centers in the United States. Histologies were limited to PTCL-NOS and PTCL with a T follicular helper phenotype (PTCL- TFH). Frontline regimens were defined as BV-based (BV-CHP), etoposide-based (CHOEP/EPOCH), novel- CHOP (CHOP/CHOEP + novel drug on a clinical trial), or CHOP. CD30 was considered positive if any expression was reported, and when available, stratified as ≥10% or <10% of the total lymphocyte population.

Results: The CD30+ PTCL cohort consisted of 194 patients with a median age of 68 years at diagnosis and a male (65%) predominance. Nodal PTCL-TFH (65%) was the most common histology. Most had stage III-IV disease (89%) with a high-intermediate to high-risk IPI score of 3-5 (54%). 18% had an ECOG of ≥2, 45% had ≥2 extranodal sites, and 43% had bone marrow involvement, although biopsies were not performed in all patients. CD30 expression in ≥10% of malignant T cells was observed in 55% of all quantitatively reported cases. Frontline therapy consisted of BV-based (36%), etoposide-based (30%), CHOP (27%), and novel-CHOP (7%). Baseline characteristics and CD30 expression were similar between treatment groups. The ORR was 72% (64% CR, 8% PR), with no differences observed by treatment or histology. On multivariate analysis (MVA), a high LDH was associated with lower CR (OR 2.84, p=0.003). For the patients who demonstrated a CR to frontline therapy, 61% underwent ASCT. With a median follow-up of 26.1 months (IQR 12.3-51.6), the median PFS and OS were 11.4 (9.8-14.2) and 47 (32-60.3) months, respectively. The 2-year PFS and OS were 34.9% (28.1-41.7) and 62% (54.5-68.6), respectively. PFS and OS were similar for PTCL-NOS compared to PTCL-TFH, and AITL fared similarly to non-AITL PTCL-TFH. By treatment, novel-CHOP demonstrated the most favorable PFS (median 41.9 months) and OS (median 68.1 months). Survival curves overlapped continuously with all other treatment regimens and was not statistically significant. For patients <60, PFS and OS were equivocal with BV-based (n=17) compared to etoposide-based (n=26) regimens. On MVA, stage III/IV disease conferred an inferior PFS (HR 2.00, p=0.018) as did an IPI score of 3-5 for OS (HR 2.15, p=0.001). Neither histology nor frontline treatment impacted PFS or OS. The chosen frontline treatment also had no survival impact in key subgroup analyses including patients <60 (n=56) or with CD30-expression ≥10% (n=43). For patients with CR to frontline therapy, ASCT demonstrated a significant PFS benefit (HR 0.59, p=0.028) but no statistically significant difference in OS benefit (HR 0.58, p=0.073).

Conclusion: These data provide valuable insight into the lesser-represented patient population from the pivotal ECHELON-2 trial. In this cohort of CD30+ (≥1%) non-ALCL PTCL, there was no clearly superior standard frontline regimen. The number of patients with quantitively reported CD30 expression was too small for definitive conclusions in the ≥10% CD30+ cohort and retrospective pathology review is ongoing. ASCT for patients in CR offered superior outcomes, supporting this strategy regardless of the frontline regimen, recognizing the limitations of non-randomized, retrospective analyses. Novel-CHOP regimens demonstrated encouraging survival, and clinical trials should maintain priority over standard regimens for patients with CD30+ (1-10%) PTCL-NOS and PTCL-TFH.

Link to Abstract abs25-8852

Abstract Number: abs25-9473

Heterogeneity of circulating CD57+ cytotoxic cell subsets across disease stage and aggressiveness in cutaneous T cell lymphoma

Presenter: Sara Niyazi
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Background: CD57 is a terminal differentiation marker expressed on subsets of T- and NK cells with high cytotoxic potential, and its expansion has been reported in viral infection, autoimmune disease, and aging. We previously reported that clonal CD8⁺CD57⁺CD16 ⁻ large granular lymphocytes (LGLs) are seen in cutaneous T cell lymphoma (CTCL) and associated with favorable outcomes in Sézary syndrome (SS). However, the phenotypic variation of circulating CD57⁺ subsets across disease states, and their relationship to clinical aggressiveness, remain undefined. Cytotoxic CD4⁺CD57⁺ T cells represent a specialized subset of T cells traditionally associated with terminal differentiation or replicative senescence. First identified in humans in the setting of chronic HIV infection, these cells have since been recognized for their ability to exert direct cytotoxicity. Notably, they can target and eliminate MHC class II-expressing tumor cells and have been detected within the tumor microenvironment of various solid malignancies. Here, we assessed the distribution of circulating CD57⁺ subsets in mycosis fungoides (MF) and SS patients, with a particular focus on SS.

Methods: Peripheral blood CD57⁺ T- and NK cell subsets were analyzed from 48 patients with MF (n=8), SS at diagnosis (n=29), and treated SS (n=11). SS at diagnosis was defined as the first available peripheral blood flow cytometry sample at Sézary-stage disease, including MF transformed to SS. Patients with erythroderma and progressive counts near the ≥1,000 Sézary cells/μL threshold were also included to capture evolving SS. Subsets measured by multicolor flow cytometry included CD57⁺CD4⁺ T cells, CD57⁺CD8⁺ T cells, CD57⁺ NK cells (CD57⁺CD56dim⁺CD16⁺), and CD57⁺γδ⁺ T cells. SS patients were further stratified into four clinical subgroups: (1) SS at diagnosis, less aggressive (n=14), (2) SS at diagnosis, aggressive (n=15), (3) treated SS, less aggressive (n=9), and (4) treated SS, aggressive (n=2). Aggressive course was defined as death from disease within two years or progression requiring systemic HDAC inhibitors, chemotherapy, or alemtuzumab after failure of mogamulizumab and extracorporeal photopheresis. Kruskal-Wallis and Mann-Whitney U tests were used for groupwise and pairwise comparisons. Tests were two-sided with p<0.05, and median values, sample sizes, and p-values were reported for each marker comparison.

Results: Median CD57⁺CD4⁺ T cell levels differed significantly across disease states (p=0.0069), with the highest levels in SS at diagnosis (70.96 cells/μL), compared to MF (39.79 cells/μL) and treated SS (29.55 cells/μL). Pairwise comparisons showed significantly higher levels in SS at diagnosis compared to treated SS (p=0.0058) and a borderline difference compared to MF (p=0.0469). CD57⁺ NK cells, CD57⁺CD8⁺ T cells, and CD57⁺γδ⁺ T cells did not differ significantly across disease states. In SS patients stratified by aggressiveness and treatment status, CD57⁺CD4⁺ T cells approached significance across subgroups (p=0.0549). Median levels were 81.24 cells/μL (aggressive SS at diagnosis), 55.90 cells/μL (less aggressive SS at diagnosis), 29.55 cells/μL (less aggressive treated SS), and 136.03 cells/μL (aggressive treated SS; n=2). CD57⁺ NK cells differed significantly across subgroups (p=0.015), with higher levels in aggressive SS at diagnosis (58.78 cells/μL) and less aggressive treated SS (55.36 cells/μL), compared to aggressive treated SS (41.94 cells/μL) and less aggressive SS at diagnosis (18.22 cells/μL). CD57⁺CD8⁺ T cells and CD57⁺γδ⁺ T cells did not differ significantly across subgroups, though intergroup variability was observed.

Conclusion: Circulating CD57⁺ subsets demonstrate significant variation across CTCL disease states and SS subgroups. CD57⁺CD4⁺ T cells were most elevated at SS diagnosis, particularly in aggressive cases, suggesting a potential role in disease onset or progression. CD57⁺ NK cells were increased in both aggressive SS at diagnosis and less aggressive treated SS, indicating a possible immune response from treatment or disease burden rather than aggressiveness alone. These findings underscore the heterogeneity of CD57⁺ immune subsets in SS, implying differential roles in pathogenesis versus immune surveillance. It remains unclear if these proliferations are related to immune response to the disease or an exhausted immune state. Future studies with larger sample sizes, longitudinal characterization, and functional assays are underway.

Link to Abstract abs25-9473

Abstract Number: abs25-10159

Elevated interleukin-10 at diagnosis and during treatment independently predicts adverse outcomes in angioimmunoblastic T-cell lymphoma

Presenter: Yi Zhong
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Introduction: Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphoma (PTCL) with poor survival outcomes. Characterized by a unique inflammatory and immune response, its aggressiveness is highly dependent on the tumor microenvironment (TME). Although cytokines are critical messengers within the TME, their prognostic role in AITL is poorly understood. This study aimed to analyze the relationship between serum cytokine profiles and clinical outcomes in patients with AITL.

Methods: This multicenter, retrospective study enrolled newly diagnosed adult AITL patients between August 2015 and December 2023. Serum levels of seven cytokines were serially analyzed at diagnosis and subsequent timepoints. Optimal cutoff values for overall survival (OS) were determined using maximally selected rank statistics.

Results: The cohort of 267 patients presented with high-risk features, including a median age of 67, a male predominance (57.7%), advanced-stage disease (97.4%), and a majority having poor-risk prognostic scores (IPI ≥ 3: 65.9%; PIT ≥ 2: 73.0%; PIAI ≥ 2: 66.3%). At diagnosis, the median serum cytokine levels were 0.9 pg/mL for interleukin (IL)-2, 0.9 pg/mL for IL-4, 17.5 pg/mL for IL-6, 9.1 pg/mL for IL-10, 1.9 pg/mL for tumor necrosis factor (TNF)-α, 2.4 pg/mL for interferon (IFN)-γ, and 0.1 pg/mL for IL-17A. Elevated levels of IL-6 and IL-10 were both associated with poorer ECOG PS, higher LDH and β2-MG levels, lower albumin, thrombocytopenia, B symptoms, bone marrow involvement, and higher-risk prognostic scores. High IL-10 was also associated with a more advanced disease stage and serous effusion, whereas other cytokines showed limited correlations. Of the seven cytokines analyzed, only IL-6 and IL-10 demonstrated prognostic significance for OS, with optimal cutoffs of 14.6 pg/mL and 16.4 pg/mL, respectively (both p < .001). High baseline IL-6 (n=147) and IL-10 (n=91) were associated with significantly shorter median OS (16.8 vs. 65.1 months and 9.4 vs. 65.1 months, respectively; both p < .001). Concurrent elevation of both cytokines conferred the worst OS ( p < .001). Furthermore, IL-6 and IL-10 levels correlated with the response to first-line chemotherapy. Among 241 evaluable patients, low IL-6 levels were associated with significantly higher complete response (CR) and overall response rates (ORR) (CR: 60.4% vs. 33.8%, p < .001; ORR: 80.2% vs. 66.2%, p = .015). This therapeutic advantage was even more pronounced for patients with low IL-10 levels (CR: 57.2% vs. 21.3%; ORR: 81.3% vs. 53.3%; both p < .001). In univariate analysis, both elevated IL-6 and IL-10 levels significantly predicted worse OS (both p < .001). However, in multivariate analysis adjusted for PIAI score, only high IL-10 (HR, 1.966; p < .001) and low albumin (HR, 1.595; p < 0.05) remained independent prognostic factors for poor OS. We therefore compared the prognostic ability of various dynamic IL-10 metrics (absolute level, absolute change, and relative change). The results showed that only the absolute IL-10 levels after course 1 (cutoff, 23.8 pg/mL) and at the end of treatment (cutoff, 5.1 pg/mL) were independent prognostic indicators. While the end- of-treatment IL-10 model demonstrated a superior statistical fit (AIC: 543.1 vs. 598.9; Harrell's C-statistic: 0.768 vs. 0.761), the absolute IL-10 level after course 1 offered greater clinical utility for early prognostication. In subgroup analyses, this early marker was prognostic regardless of baseline IL-10 status; however, it did not predict early recurrence (≤ 12 months). Additionally, IL-10 levels were significantly higher at relapse compared to post-treatment levels (median: 11.5 vs. 3.4 pg/mL, p < .001), an increase observed in 64.3% (32/39) of patients who had initially responded to therapy (CR/PR). Conclusions Conclusions Serum levels of IL-6 and IL-10 correlate with adverse clinical features, chemoresistance, and poor survival in AITL. An elevated IL-10 level at diagnosis serves as an independent adverse prognostic factor. Dynamic monitoring of IL-10, particularly after the first course of therapy, provides a powerful and clinically valuable tool for early prognostication.

Link to Abstract abs25-10159

Abstract Number: abs25-10824

First evaluation of novel cmoep (Liposomal Mitoxantrone-Based Chemotherapy) in front-line peripheral T-cell lymphoma: The compass Phase II study

Presenter: Jingwei Yu
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous and aggressive group of lymphoma, accounting for 25%~30% of non-Hodgkin lymphomas in China. The standard initial treatments for PTCL are CHOP or CHOEP, but the outcomes remain suboptimal. The Phase I study of mitoxantrone hydrochloride liposome (Lipo-MIT) in combination with cyclophosphamide, vincristine, etoposide and prednisone (CMOEP) regimen was presented at the 2024 ASH (Abstract #PB6403) and published in Frontiers in Immunology (2025 Apr 11;16:1551723.), demonstrating promising efficacy and manageable safety in treatment-naïve (TN) PTCL patients (pts). Based on these findings, a phase II study (NCT06433362) is currently underway, with interim data disclosed at this conference.

Methods: Eligible pts were aged 18-65 years with histologically confirmed TN PTCLs. Pts received Lipo-MIT (18 mg/m 2 ) combined with COEP regimen (cyclophosphamide at 750 mg/m 2 on day 1, vincristine at 1.4 mg/m 2 on day 1, etoposide at 60 mg/m 2 on days 1-3, and prednisone at 100 mg on days 1-5) every 21 days for six cycles. The primary endpoint was the complete response rate (CRR), with key secondary endpoints including the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Adverse events (AEs) were documented according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0.

Results: From June 25, 2024 to March 28, 2025, the study had enrolled 20 pts, including 11 with PTCL-NOS (peripheral T-cell lymphoma not otherwise specified), 5 with AITL (angioimmunoblastic T-cell lymphoma), and 4 with ALCL (anaplastic large cell lymphoma; 2 ALK +, 2 ALK-). The median age was 58 years (Q1-Q3: 40-66), with 10 males (50.0%). Sixteen (80.0%) pts were diagnosed with stage III-IV, and 4 pts had IPI score of 3-5. The median dose of Lipo-MIT was 16.8 mg/m 2 (Q1-Q3: 13.0-17.9), and the median treatment duration were 6 cycles. At data cutoff, 19 pts had undergone at least one efficacy assessment, showing a CRR of 68.4% (13/19) and an ORR of 94.7% (18/19). Among 8 PET/CT-evaluable patients, the CRR was 87.5% (7/8) with ORR 100.0% (8/8). With a median follow-up of 4.2 months, the median PFS and OS were not reached, and the 6-month duration of response (DoR) rate was 100.0%. The most common ≥ grade 3 treatment-related adverse events (TRAEs) with an incidence ≥10% were lymphocytopenia (55.0%), leucopenia (45.0%), neutropenia (45.0%), anemia (15.0%), thrombocytopenia (15.0%), pneumonia (25.0%) and febrile neutropenia (15%).

Conclusion: Building on the completed phase I results, initiation of a phase II trial has demonstrated encouraging efficacy and manageable safety in pts with TN-PTCL. The Phase II trial is currently ongoing.

Link to Abstract abs25-10824

Abstract Number: abs25-11004

Golidocitinib combined with CHOP in treatment-Naïve monomorphic epitheliotropic intestinal T-cell lymphoma: Preliminary results from A phase 2 multicenter, single-arm goal study

Presenter: Yu-Ran Qiu
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Background: Background: Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare and highly aggressive subtype of peripheral T-cell lymphoma (PTCL) with a dismal prognosis and limited therapeutic options. The standard first-line treatment, CHOP (Cyclophosphamide, doxorubicin, vincristine, and prednisone), yields suboptimal outcomes, highlighting a critical unmet need. Pathogenetically, constitutive activation of the JAK/STAT signaling pathway is a key driver of lymphomagenesis in MEITL. Golidocitinib is a potent, selective JAK1 inhibitor with a unique gastrointestinal (GI)-enriched property, making it an ideal candidate for treating intestinal lymphomas. Prior clinical studies have demonstrated golidocitinib’s promising anti- tumor activity and manageable safety in other PTCL subtypes, providing a strong rationale for its investigation in MEITL.

Methods: This multicenter, single-arm, phase 2 study (GOAL; NCT06701344) evaluated golidocitinib plus CHOP in treatment-naïve MEITL patients (pts). Eligible pts received oral golidocitinib at 150 mg once daily, in combination with a standard CHOP regimen every 21 days for 6 cycles. The CHOP regimen consisted of intravenous cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², and vincristine 1.4 mg/m² (capped at 2 mg) on day 1, plus oral prednisone 60 mg/m² on days 1-5. Tumor response was assessed by PET-CT at baseline, after 3 cycles (interim), and at the end of treatment (EOT), according to the Lugano criteria. The primary endpoint was the complete response rate (CRR) at EOT. Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

Results: Between Aug 2, 2024, and Apr 14, 2025, 8 pts were screened for eligibility. One patient withdrew informed consent prior to treatment. A total of 7 treatment-naïve MEITL pts were enrolled and received at least one dose of the study treatment. The median age of the cohort was 60 years (range, 39-73), and 6 pts (85.7%) were male. At baseline, 4 pts (57.1%) had advanced disease (Lugano stage IV). A high proportion of pts (6/7, 85.7%) had a poor performance status (ECOG ≥ 2). The median number of extranodal sites was 1 (range, 1-2), with the gastrointestinal (GI) tract being universally involved. Two pts (28.6%) had elevated lactate dehydrogenase (LDH) levels at baseline. One patient had undergone surgery prior to enrollment. As of the data cutoff on July 31, 2025, with a median follow-up of 6.2 months, all 7 enrolled pts were evaluable for efficacy in an intent-to-treat analysis. The combination demonstrated profound clinical activity. Among 7 evaluable pts, 5 achieved a complete response (CR), 1 achieved a partial response (PR), and 1 had progressive disease (PD), resulting in an overall response rate (ORR) of 85.7% (6/7) and a complete response rate (CRR) of 71.4% (5/7 pts). Correlative biomarker analyses provided strong mechanistic insights. Targeted sequencing on 3 of the 7 pts (2 CR, 1 PR) revealed that all 3 (100%) harbored activating mutations in the JAK/STAT pathway ( JAK3 , n=2; STAT5B , n=1). This was further validated by single-cell RNA sequencing on 4 baseline tumors (2 CR, 1 PR, 1 PD), which identified two key determinants of response. First, at the tumor-intrinsic level, malignant T cells from responders exhibited a significantly stronger baseline JAK/STAT activation signature compared to the non-responder. Second, at the microenvironment level, responders’ tumors displayed a diverse, “hot” TME, rich with infiltrating immune cells, while the non-responder’s tumor was an immune-desert. These data suggest that response to golidocitinib plus CHOP is co-determined by both a tumor’s dependence on the JAK/STAT pathway and a pre-existing, immunocompetent microenvironment. The most common Grade ≥3 treatment-emergent adverse events were hematologic toxicities. Notable non-hematologic events included severe GI events (bleeding/perforation, n=2) and CMV reactivation (n=2). Conclusions Conclusions The combination of golidocitinib and CHOP demonstrates profound clinical activity in treatment-naïve MEITL, representing a significant therapeutic advance over conventional chemotherapy. Preliminary single-cell analysis identifies a baseline JAK/STAT activation signature in malignant cells and a non- immunosuppressive tumor microenvironment as potential biomarkers of response. This regimen represents a highly promising new therapeutic strategy for this aggressive lymphoma.

Link to Abstract abs25-11004

Abstract Number: abs25-11715

Condensed total skin electron beam therapy prior to allogeneic stem cell transplantation in patients with cutaneous T-cell lymphoma/sezary syndrome

Presenter: Jillian Gunther
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Background: Cutaneous T-cell lymphoma (CTCL), including Sezary syndrome (SS), is associated with high relapse rates and poor prognosis, particularly for those with large cell transformation (LCT) and advanced stage disease. Prior to allogeneic stem cell transplantation (SCT), total skin electron beam therapy (TSEBT) is often employed to address any residual cutaneous disease. Standard TSEBT regimens, typically delivered over 8 weeks, may delay transplant timing and compromise systemic disease control. At our institution, we implemented a condensed TSEBT regimen aiming to reduce time to transplant while maintaining efficacy and tolerability.

Methods: We performed a retrospective review of patients with CTCL or SS treated at our institution between 2022- 2025 who were planned for SCT and a condensed TSEBT regimen of 28 Gy in 14 fractions delivered over approximately 5 weeks. Patients were planned for three fractions of standing TSEBT per weeks with supplemental treatments to underdosed areas given on the 4th/5th days starting at week 2. Patient demographics, disease characteristics, treatments, toxicities, and clinical outcomes were collected and analyzed. Toxicity was graded according to CTCAE v5.0 criteria. Skin involvement and response was assessed using body surface area (BSA) and modified severity-weighted assessment tool (mSWAT) scores when available.

Results: Seventeen patients were included (6 female, 35%) with median age 48 years (range 18-65). Patients had mycosis fungoides (MF) (9,52.9%), SS (4,23.5%), MF with other lymphoma (2, 11.8%), or other CTCL (2, 11.8%). Patients had stage I (1,6%), II (5, 29%), and IV (11, 65%) disease with documented LCT (11, 65%), nodal involvement (14, 82%) and blood involvement (9,53%). All patients had 3 or more lines of prior systemic therapy. Ten patients (59%) had prior focal radiation therapy (RT), and 5 patients (29%) had received prior TSEBT courses with 12 Gy. Prior to TSEBT, patients had median BSA (16 available)/MSWAT (13 available) of 5.2/6.4 (range 0-33.5/0-52.5). Twelve patients completed the intended 28 Gy regimen with supplemental treatments over median 31 days (range 27-34); 6 patients (35%) required a dose reduction due to toxicity (median 24 Gy, range 24- 26). Seven patients (41%) received concurrent systemic therapy with ECP/interferon (2), brentuximab vedotin (BV)/bexarotene (2), or BV (2). Patients experienced treatment toxicities including xerosis (16, 94%), pain [grade 1 (7, 41%), grade 2 (3, 18%), grade 3 (2, 12%)], edema (4,24%), blisters (3,18%), erythema (11,65%), hyperpigmentation (5,29%), dry desquamation (10,59%), moist desquamation (3,18%). There was no association between concurrent systemic therapy and edema (p=1.0), Grade 2-3 pain (p=0.60), blisters (p=0.48), or moist desquamation (p=1.0). Of 11 patients with post-TSEBT pre-SCT dermatologic exams, the median BSA/MSWAT was 0/0 (range 0- 0.9/0-1.1). No patients experienced systemic relapse during TSEBT. Most patients (15, 88%) received fludarabine/melphalan with or without 2 Gy total body irradiation as conditioning for SCT. Median time from TSEBT completion to transplant was 25 days (range 13-48). At a median follow-up of 15 months from RT completion, 12 (71%) remained relapse-free. Patients relapsed in the skin (2,12%), skin/lymph nodes (2, 12%) and skin/blood (1,6%). There was no association between reduced TSEBT dose and cutaneous relapse (p=1.0). Three patients (18%) had documented cutaneous graft versus host disease (GVHD) with an additional two patients (12%) with possible GVHD. Fifteen patients (88%) were alive at last follow up; 2 deaths were due to infection/SCT complications.

Conclusions: Our institutional experience suggests that a condensed TSEBT regimen of 28 Gy over ~5 weeks is feasible and generally well-tolerated as a bridging strategy to SCT in patients with CTCL/SS. This approach may facilitate more timely transplantation while maintaining effective skin disease control. Prospective studies are warranted to validate these findings and further optimize pre-transplant conditioning strategies in this high-risk population.

Link to Abstract abs25-11715

Abstract Number: abs25-11856

Performance of radiomics features in patients with peripheral T-cell lymphoma: Data from international prospective T-cell project 2.0

Presenter: Tetiana Skrypets
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Introduction: Peripheral T-cell lymphomas (PTCLs) are a rare, heterogeneous group of hematological malignancies with extremely poor prognosis for nearly all subtypes. FDG-PET using speciﬁc radiomics indexes have showed to be a possible tool for prognostication, treatment response assessment and to extract quantitative features that correlate with the disease’s biological characteristics. However, its usefulness in routine clinical practice for PTCLs is still challenging due to the various subtypes, heterogeneity, and the absence of large prospective trials that include FDG-PET assessment. To address this question, we conducted PET assessment as an ancillary sub-study of the prospective real-world T-Cell Project 2.0 (NCT03964480). Patients and methods: Patients and methods: 138 PTCLs patients from 8 international centers with available PET0 AND/OR a EOT-PET were enrolled in this study. For the further analysis were conﬁrmed eligible 104 patients (PTCL-NOS 35, AITL 17, ALCL ALKneg 19, ALKpos 9, NKTCL 13, ATLL 2, others 9). Anonymized scans underwent a central review on WIDEN platform by a pool of nuclear medicine physicians. Tumor segmentation was performed at baseline with a percentage threshold of SUVmax of 41% in each lesion. Quantitative metrics including SUV max , SUV peak , total lesion glycolysis (TLG) and MTV were deﬁned for each lesion. TMTV and TTLG were deﬁned as the sum of MTV/TLG through all the lesion while SUV max and SUV peak were identiﬁed in the lesion with the highest uptake at baseline. EOT-PET were analyzed using Lugano classiﬁcation with the 5- point Deauville scale. Overall survival (OS) and progression free survival (PFS) were estimated by Kalan-Meier method and the prognostic value was assessed in univariate analysis using log-rank test and estimating the eﬀect as hazard ratio (HR), from Cox PH regression model. All reported p-value were two-sided.

Results: Median follow-up time was 39 months (95%CI 32-45). OS and PFS at 3 years were 55 vs 46%, respectively. Median TMTV was 98 ml (5%-95% 3-1213). A TMTV of 200 ml was chosen as threshold between high and low risk group for OS and PFS. The 3-yr PFS for TMTV41% < 230 was 56% vs 31% for >230 (0.020), TMTV41% < 130 w/o SL was 56% vs 36% for >130 and TMTV41% < 130 w/o SL (p=0.020) and TMTV41% < 130 w/o SL and diﬀ. spleen was 62% vs 39% (p=0.010). In univariate analysis, age>60 yo (p=0.001), LDH>UNL (p=0.014), PS>1 (p=0.008), Hb<12g/dL (p 0.042), albumin<3.5g/dL (p=0.01), PLT<200x10 9 /L (p=0.047), ALC<1x10 9 /L (p=0.031), PIT intermediate (p=0.002) and high (p<0.001), PMR/PMD (p<0.001), DS4-5 (p<0.001), TMTV41%>200ml (p<0.01) were correlated with lower OS. Adverse prognostic features were the same for PFS, except albumin<3.5 g/dL (p=0.06). A DS4-5 in EoT PET demonstrated also to have a strong response assessment value with HR= 4.93 (95%CI 2.40-10.1 in PFS and HR= 3.22 (95%CI 1.48- 7.00) in OS. The prognostic value for baseline TMTV was reinforced when combined to DS EOT. The 3-yr OS for DS 1-3&TMTV41%<200 ml vs DS 1-3 &TMTV41% >200 ml vs DS 4-5 was 89%, 56% and 41% (p<0.001), respectively. At the same time timepoints PFS was 85%, 50% and 21% (p<0,001), respectively. Analysis by subtypes delineated a robust association between histological variants and metabolic activity, with AITL displaying the highest median TMTV 41% of 486.2 ml compared with 141.6 ml for PTCL NOS, 188.8 ml for ALK +, 88 ml ALK – and 77.0 for other rare PTCL subtypes (p=0.033). Besides this empirical observation, there was no statistically signiﬁcant diﬀerence between histological subtypes and metabolic activity (p=0.073).

Conclusion: Our data conﬁrm that TMTV41% appears to be a robust biomarker for diﬀerent histological PTCLs subtypes for development the ﬁrst-line PET-adapted approaches in PTCL. The identiﬁed threshold of TMTV41% >230ml eﬀectively stratiﬁes patients into high and low-risk groups and suits as a more promising tool. Moreover, high TMTV has been associated with poor outcomes independently of clinical prognostic factors. Diﬀerent segmentation methods are being analysed (SUV4). Further analyses is needed to fully understand how the metabolic activity may vary between different PTCLs subtypes.

Link to Abstract abs25-11856

Abstract Number: abs25-12712

Mitoxantrone hydrochloride liposome (Lipo-MIT) combined with azacitidine and Chidamide can be an effective chemotherapy regimen for patients with angioimmunoblastic T-cell lymphoma (AITL)

Presenter: Liping Su
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Background: Background: : : Angioimmunoblastic T-cell lymphoma (AITL) originates from follicular helper T-cell (THF), is the second most common subtype of peripheral T-cell lymphoma (PTCL), accounting for 19% of all T-cell lymphoma cases, which are characterized by a high degree of malignancy, rapid progression and poor prognosis. Currently, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is the most common first-line chemotherapy regimen. But previous studies have reported the 5-year PFS of AITL is 13%-23%, and overall survival (OS) of <40%, effective treatment is urgently needed in the clinic. With the popularization of high-throughput sequencing, AITL epigenetic (DNA methylation modification, histone modification) mutations are prevalent, providing powerful targets for targeted therapy. Previous studies have showed 64% ORR for mitoxantrone hydrochloride liposome (Lipo-MIT) monotherapy in AITL. This study aimed to evaluate the efficacy and safety of mitoxantrone hydrochloride liposome (Lipo-MIT) in combination with azacitidine and chidamide (MAC) in newly diagnosed (ND) and relapsed/refractory AITL (ChiCTR2300075418).

Methods: : : Patients with newly diagnosed and relapsed/refractory AITL were treated with up to 6 cycles of the MAC regimen, administered every 4 weeks. Lipo-MIT was intravenously administered on Day 1 at a dose of 15-20 mg/m 2 in combination with azacitidine (75 mg/day, Days 1-7) and chidamide (20 mg, twice a week). Imaging examinations were performed every two cycles to evaluate therapeutic efficacy. The primary endpoint of the study was the overall response rate (ORR). The secondary endpoints included progression-free survival (PFS), complete response rate (CRR), overall survival (OS), and adverse events (AEs).

Results: : : Between Nov 2022 and June 2025, 8 pts with newly-diagnosed and 9 pts with relapsed/refractory AITL (8 pts were refractory) were enrolled. The median dose of Lipo-MIT in the regimen was 17.3mg/m 2 (range, 11.7-19mg/m 2 ). Among the 9 pts with R/R AITL, 5 (55.6%) pts had received 1st-line chemotherapy, 4 (33.3%) patients had received more than 2nd-line chemotherapy, 1 (11.1%) patient had received 5th-line chemotherapy. The median age was 67 years (range 39-74) and 9 (52.3%) patients were male. All patients had stage III/IV disease, and 13 (76.5%) had IPI score ≥3. All patients completed at least one cycle of the MAC regimen treatment, and 14 pts were evaluable (7 pts were ND AITL and 7 pts were R/R AITL). Among 7 ND pts, the best ORR rate was 100% (7/7) and CRR was 100% (7/7). For the 7 R/R pts, the best ORR rate was 100% (7/7) and CRR was 71.4% (5/7). 10 pts achieved CR within 2 cycles of treatment. Median follow-up of 13 months (3-33) , one year PFS was 100% in ND pts and 85.7% in the R/R pts. Treatment related adverse events (TRAEs) occurred 6 (35.3%) pts. The most prevalent grade 3 or higher treatment-related adverse events included neutropenia (n=6, 35.3%), lymphopenia (n=4, 23.5%), and Infection (n=3, 17.6%). Patients all successfully recoverd from these TRAEs through the implementation of clinical supportive care. There were no treatment-related deaths and adverse cardiac events.

Conclusion: This study showed that the Lipo-MIT combined with azacitidine and chidamide (MAC) regimen is associated with high response rate and manageable toxicity in patients with newly diagnosed and relapsed/refractory AITL. It deserves further large-sample studies to confirm efficacy and safety.

Link to Abstract abs25-12712

Abstract Number: abs25-13707

Clinical significance of blood EBV-DNA in peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and EBV-positive nodal T-cell lymphoma

Presenter: Dok Hyun Yoon
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Background: Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), is a predominantly nodal, diagnosis-of-exclusion entity that encompasses clinically and molecularly heterogeneous lymphomas not meeting WHO criteria for any other specific subtype. A subset previously grouped as PTCL-NOS, characterized by EBV-encoded small RNA in situ hybridization (EBER-ISH) positivity within neoplastic cells, has recently been recognized as EBV-positive nodal T-cell lymphoma (EBV+ nPTCL), a distinct entity with poor prognosis. However, the clinical and prognostic implications of blood EBV-DNA in PTCL-NOS and EBV+ nPTCL remain unclear.

Methods: Patients diagnosed with PTCL-NOS under the 4th edition of the WHO classification of haematolymphoid neoplasms (WHO-HAEM4) who were treated at Asan Medical Center, Seoul, Korea between January 1, 2007, and January 31, 2023, were included. Availability of tumor EBER-ISH and blood EBV-DNA PCR (whole blood or plasma) was required for inclusion. Among EBER-ISH-positive cases, pathology reports were reviewed to reclassify EBV+ nPTCL per contemporary criteria (i.e. WHO-HAEM5); cases with indeterminate reclassification based on report review were excluded. Blood EBV-DNA positivity was defined as detectable EBV-DNA by PCR in either whole blood or plasma. Baseline characteristics and clinical outcomes to first-line chemotherapy were compared by blood EBV-DNA status within the PTCL-NOS and EBV+ nPTCL groups, separately.

Results: A total of 91 patients were included; 14 were reclassified as EBV+ nPTCL and 77 remained PTCL- NOS. Blood EBV-DNA was positive in 31/77 (40.3%) in PTCL-NOS and 11/14 (78.6%) in EBV+ nPTCL. In both groups, baseline characteristics did not differ by EBV-DNA status, except for higher frequency of bone marrow involvement (41.9% vs. 17.4%; P = 0.018) and higher Prognostic Index for T-cell lymphoma (PIT) scores ( P = 0.010) in EBV-DNA-positive patients within PTCL-NOS. The median follow-up duration was 106.3 months (95% CI, 89.5–169.0). Compared with PTCL-NOS, the EBV+ nPTCL group had worse survival outcomes (median PFS, 5.4 vs. 7.3 months; P = 0.138; EFS, 4.9 vs. 5.8 months; P = 0.152; OS, 10.1 vs. 20.4 months; P = 0.012). Within PTCL-NOS, EBV-DNA-positive patients had numerically shorter median PFS (5.4 vs. 8.1 months; P = 0.116), EFS (4.6 vs. 7.3 months; P = 0.125), and OS (17.4 vs. 22.7 months; P = 0.133) than EBV-DNA-negative patients; however, none of these differences reached statistical significance. Within EBV+ nPTCL, survival did not differ significantly by EBV-DNA status (median PFS, 5.3 vs. 8.2 months; P = 0.334; EFS, 4.7 vs. 8.2 months; P = 0.152; OS, 8.6 vs. 11.6 months; P = 0.825).

Conclusions: In PTCL-NOS, blood EBV-DNA positivity was associated with a non-significant trend toward poorer survival outcomes, while no association was observed in EBV+ nPTCL. Further prospective studies in larger, WHO-HAEM5-defined cohorts are warranted.

Link to Abstract abs25-13707

Abstract Number: abs25-13984

Enhanced clinical and systemic response with combination radiation therapy and topical imiquimod in mycosis fungoides: A pilot study

Presenter: Katherine De Jong
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Introduction: Mycosis fungoides (MF), the most prevalent type of cutaneous T-cell lymphoma (CTCL), presents significant therapeutic challenges, particularly due to limited durable systemic responses. Radiation therapy (RT) is a potent, skin-directed treatment for MF lesions, often inducing robust local responses even at low doses. However, systemic or abscopal effects of RT remain rare. Topical imiquimod (IMQ), a toll-like receptor 7 agonist, has demonstrated clinical efficacy as an immunomodulator in early-stage MF. Preclinical evidence suggests IMQ can enhance systemic antitumor immune responses when combined with RT. This study evaluates the clinical safety, efficacy, and potential abscopal effects of combining topical IMQ and RT in patients with MF.

Methods: We conducted a single-arm pilot study enrolling 12 patients with stage IA–IIB MF at Northwestern Memorial Hospital from July 2023 to April 2025. Participants had stable but active disease (>6 months), failed ≥1 prior standard MF therapy, and possessed ≥4 discrete lesions (≥2 lesions with combined surface area ≥50 cm²). At least 2 treated and 2 untreated index lesions were used for Compositive Assessment of Index Lesion Severity (CAILS) assessment. Participants were instructed to apply IMQ 5% cream to designated treated index lesions 3-5 days/week (based on skin tolerability) for 6 weeks. One week after IMQ initiation, localized RT (total dose: 8 Gy over two fractions) was delivered to the treated lesions. Clinical response was assessed using modified Severity-Weighted Assessment Tool (mSWAT), CAILS, and Numerical Rating Scales (NRS) for pruritus and pain. Skin biopsies, swabs, and tape strips were collected pre- and post-treatment (weeks 0 and 8), and histological assessment was performed by dermatopathologists.

Results: Cohort included 8 males (67%) and 4 females (33%) (mean 59 years). Disease staging included 2 patients at stage IA, 7 at IB, and 3 at IIB, with 4 cases of folliculotropic MF. Significant clinical improvements were observed, with mSWAT scores substantially decreasing from baseline to week 8 (mean 38.1 to 17.7, p<0.001). Treated and untreated lesions demonstrated significant CAILS score reductions (mean 23.75 to 9.2, 20.9 to 14.3, both p<0.001, respectively), indicative of a systemic response. Pruritus and pain scores did not significantly change (3.33 to 2.91, p = 0.72; 2.75 to 0.67, p = 0.079). Histological analyses confirmed improvement suggestive of an abscopal effect in 33% of patients. Common adverse events included mild-to-moderate lesion irritation, swelling, dryness, pain and bleeding, without need for early IMQ discontinuation except in one patient.

Conclusion: Preliminary results from this pilot study indicate that topical IMQ combined with RT is generally safe and efficacious for MF, demonstrating significant clinical and histological responses, including evidence of an abscopal effect. Ongoing analyses will further investigate associated proteomic, transcriptomic, and metagenomic changes to enhance our understanding of the underlying immunologic mechanisms.

Link to Abstract abs25-13984

Abstract Number: abs25-15627

Can the development of drug-induced rash after mogamulizumab administration predict survival in mycosis fungoides/sezary syndrome? a trinetx-based analysis

Presenter: Toshali Pandey
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Introduction: Since the Food and Drug Administration approved the anti-CCR4 monoclonal antibody, mogamulizumab, for the treatment of relapsed/refractory MF/SS in 2018, several studies have described an entity called mogamulizumab-associated rash (MAR). In the MAVORIC trial, 24% of patients in the mogamulizumab group developed a “drug eruption”. MAR is thought to be due to excessive immune reaction and has been suggested as a positive predictor of response. However, studies investigating MAR have been limited in their size due to the rarity of MF/SS. We undertook this study to leverage a large real-world database to look for association between emergence of new cutaneous reactions after mogamulizumab administration and overall survival.

Methods: We performed this analysis using data from the TriNetX TM database; a platform for real-world de- identified patient-level data. The cohort of interest was generated using the Research database (155,725,981 patients globally) with a combination of ICD-10-CM codes C84.0 (Mycosis fungoides) or C84.1 (Sezary disease), ICD-0 codes 9700/3 (Mycosis fungoides) or 9701/3 Sezary syndrome. The resulting database of patients was downloaded, and the statistical analysis was carried out using Stata BE 18 (StataCorp LLC). Patients were filtered according to whether they received mogamulizumab using RxNorm codes (2054068, J9204, C9038). The corresponding encounter IDs were used to determine the date of first administration of mogamulizumab. The following ICD-10 codes corresponding to drug- related cutaneous adverse events were used to classify patients: D72.12, L27.0, L27.1, L27.9, L43.2. Patients with a new diagnosis corresponding to this list within 48 months of mogamulizumab administration were included in the MAR+ group while the rest formed the MAR- group. Survival was calculated from the date of first mogamulizumab administration to death due to any cause. Follow up duration was capped at 48 months from mogamulizumab administration.

Results: A total of 24,547 patients in the Research database had a diagnosis of MF/SS. Of these, 342 had received mogamulizumab. The median age of this cohort was 67 years (range 22 to 87). Females comprised 45.6% (156) of the cohort. More than half of the patients, 58.7% (201) had SS while the rest had MF. Of the 343 patients, 57 (16.6%) were placed in the MAR+ group and 285 (83.4%) in the MAR- group. The MAR+ group had a higher proportion of patients with SS (71.9%) compared with the MAR- group (56.1%) and this difference was statistically significant (p-value 0.027). There was no statistically significant difference in the mean age or sex composition between the two groups. The average time from mogamulizumab administration to diagnosis of MAR was 7 months (range 11 days to 43 months). For the 342 patients analyzed, the median follow-up duration was 38 months (95% CI 44.3 to 56.3). There were 84 deaths (24.6%) during this period. Median overall survival (OS) for the whole cohort was not reached. The 4-year OS rate was 69.8% [95% CI 63.4 to 75.2]. There were 75 deaths in the MAR- group and 9 in the MAR+ group. The respective 4-year OS rates were 67.0% [95% CI 60.1 to 73.1] and 78.9 % [95% CI 61.9 to 88.9]. The data did not violate the proportional hazard assumption based on Schoenfeld residuals. Using the Cox proportional hazard model, the univariable hazard ratio for MAR as a predictor returned as 0.55 [p- value 0.048, 95% CI 0.25 to 0.99] favoring the MAR+ group and was statistically significant. Age and sex were not found to be independent predictors of survival on multivariable modelling. The HR for MAR as a predictor on the multivariable model returned as 0.54 (p –value 0.086, 95% CI 0.27 to 1.09). A diagnosis of SS was not found to be a predictive of survival on both univariable (HR 0.85, 95% CI 0.55 to 1.31) and multivariable modelling (HR 0.86, 95% CI 0.54 to 1.37).

Conclusion: We used the TriNetX database to identify surrogate markers for MAR and predict survival in 342 patients with MF/SS. The MAR+ rate stood at 16.6%. The 4-year OS rate was longer in the MAR+ group (78.9% vs 67.0%) and MAR was found to be a positive predictor of survival on univariable regression analysis but not multivariable analysis. A diagnosis of SS was not found to have an influence on survival. A major limitation of this study is the lack of ability to precisely query for MAR using this database as well as the clinical challenge of distinguishing between MAR and disease relapse.

Link to Abstract abs25-15627

Abstract Number: abs25-11050

PlatΤform: A multicenter, multi-arm, academic platform trial evaluating novel agents and combinations in relapsed or refractory peripheral T-cell lymphomas

Presenter: David Sibon
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster II

Abstract: Background: Peripheral T-cell lymphomas (PTCLs) are a heterogeneous and aggressive group of mature T- or NK-cell neoplasms, with poor prognosis and limited therapeutic advances compared to B-cell lymphomas. Drug development in PTCL is hindered by disease heterogeneity and rarity, lack of predictive biomarkers and relevant preclinical models, and limited industry investment. There is an urgent need for ﬂexible trial designs that are biomarker- or histology-driven to identify active therapies and deﬁne optimal patient subsets for future registration strategies. Study Design and Methods: Study Design and Methods: PlaTform (NCT07018752) is a French academic, multicenter, open-label, multi-arm phase 1/2 platform trial evaluating novel agents or combinations in relapsed/refractory (R/R) PTCL using a master protocol framework. Patients will be enrolled and randomly assigned across available sub-studies, unless speciﬁc contraindications apply. Sub-studies may be a phase 1, a phase 1/2 or a phase 2. A shared screening process and centralized pathology review enable harmonized inclusion and integrated translational analyses. In the phase 1 sub-studies, the number of patients will be adapted to the speciﬁc needs of each sub-study. Each phase 2 sub-study will include up to 31 evaluable patients. The primary endpoint of phase 1 is determination of maximum tolerated dose and recommended phase 2 dose based on Bayesian Optimal Interval (BOIN) or Bayesian Continual Monitoring with Reassessment (BCMR) design, while the primary endpoint of phase 2 is modiﬁed progression-free survival, which includes disease progression, relapse, unplanned lymphoma therapy, or death. Secondary endpoints include overall and complete response rates, duration of response, overall survival, and safety. Exploratory objectives include correlation of genomic and immunological features with outcome, including patient-derived xenograft generation and next-generation sequencing profiling. Eligibility Criteria: Eligibility Criteria: Eligible patients are ≥18 years old, with histologically conﬁrmed R/R PTCL (excluding cutaneous T-cell lymphoma, T-cell large granular lymphocytic leukemia, and T-lymphoblastic lymphoma), measurable disease per Lugano 2014 criteria, ECOG performance status 0–2 (or 3 if related to lymphoma), and adequate organ function. Fresh or archival tumor tissue is required for central review and biomarker analyses. Each sub-study has additional and specific inclusion and exclusion criteria. Sub-Studies: Sub-Studies: Two sub-studies are currently open: GolcAza GolcAza : evaluates the combination of golcadomide and oral azacitidine in R/R follicular helper T-cell lymphoma. This is a phase 1 study, aiming to recruit 18 patients. Patients will receive various doses of golcadomide in addition to oral azacitidine for a maximum of 2 years. Origina-Ly-T Origina-Ly-T : evaluates roginolisib, a novel, oral, non-ATP competitive, allosteric small molecule inhibitor of PI3K δ , in R/R PTCL. This is a phase 2 trial aiming to recruit 31 patients. Roginolisib will be administered as a monotherapy over 28-day cycles for 6 cycles. Patients demonstrating clinical beneﬁt, as per investigator’s assessment, may continue roginolisib for a maximum of 30 additional cycles (total 36 cycles). Both sub-studies include biomarker-enriched analyses to identify responsive subsets and inform future development. Enrollment and Status: Enrollment and Status: First patient-in is expected in August 2025. A third sub-study will be initiated at the end of 2025. Additional arms will be added over time based on emerging clinical or translational data, and available agents.

Conclusion: PlaTform represents a novel academic initiative dedicated to R/R PTCL, designed to accelerate therapeutic innovation in this underserved population. Acknowledgement: Acknowledgement: We wish to thank the patients and their families for their participation in the clinical trials, iOnctura for providing access to roginolisib, and Bristol-Myers Squibb for providing access to golcadomide and azacitidine.

Link to Abstract abs25-11050

Abstract Number: abs25-7401

Aggressive lymphomas that are treated early have worse outcomes: Counterintuitive results from a national database study.

Presenter: Anand Shah
Session: 626. Aggressive Lymphomas: Epidemiological Excluding Prospective Clinical Trials: Poster II

Abstract: Background: Early initiation of chemotherapy is widely believed to improve survival in aggressive lymphomas; however, the optimal time-to-treatment initiation (TTI) remains undeﬁned. Prior studies have oﬀered conflicting findings, and the impact of modest treatment delays across histologic subtypes and prognostic groups is poorly understood. Clarifying the relationship between TTI and outcomes is critical to guide clinical decision-making and optimize care pathways. Methodology: Methodology: We conducted a retrospective cohort study using the National Cancer Database. Our cohort included patients diagnosed between 2004 to 2022 with aggressive lymphomas: diﬀuse large B-cell lymphoma (DLBCL: 9680, 9684, 9679), Burkitt lymphoma (BL: 9687), mantle cell lymphoma (MCL: 9673), and peripheral T-cell lymphoma (PTCL: 9702, 9705, 9714). Patients were included if they received multi-agent chemotherapy as first-line treatment and had complete treatment data. The primary outcome was 5-year overall survival (OS), analyzed via multivariable Cox proportional models. TTI was categorized as ≤30 days, 31–60 days, and ≥61 days. Covariates included age, sex, race, geographic region, insurance status, Charlson-Deyo comorbidity index (CDCC), stage, extranodal involvement, and International Prognostic Index (IPI). Due to database limitations, IPI was used for all lymphoma subtypes, although MIPI and BL-IPI are more appropriate for MCL and BL, respectively. Sensitivity analyses were conducted among patients who initiated treatment within 30 days of diagnosis, comparing outcomes between TTI ≤14 days and 15–30 days, stratiﬁed by IPI risk groups (low/intermediate [0–2] and high [3–5]) within each lymphoma subtype.

Results: A total of 291,396 patients met inclusion criteria: 240,586 (82.6%) had DLBCL, 10,686 (3.7%) had BL, 19,190 (6.6%) had MCL, and 20,934 (7.2%) had PTCL. The median TTI was shortest for BL (8 days, IQR: 3– 16) and longest for MCL (23 days, IQR: 8–41). In the primary survival analysis, delayed treatment was paradoxically associated with improved OS across multiple lymphoma subtypes. For DLBCL, treatment initiated at 31–60 days (HR: 0.79; p < 0.001) and ≥61 days (HR: 0.77; p < 0.001) was associated with signiﬁcantly lower mortality compared to treatment within ≤30 days. For BL, treatment at 31–60 days (HR: 0.90; p = 0.159) and ≥61 days (HR: 0.76; p = 0.057) showed no signiﬁcant diﬀerence in OS. In MCL, delayed treatment at 31–60 days (HR: 0.64; p < 0.001) and ≥61 days (HR: 0.55; p < 0.001) was associated with improved survival. Similarly, in PTCL, treatment at 31–60 days (HR: 0.77; p < 0.001) and ≥61 days (HR: 0.72; p < 0.001) was linked to significantly lower mortality. In the sensitivity analysis limited to patients who initiated treatment within 30 days, starting therapy between 15–30 days (compared to ≤14 days) was consistently associated with improved OS in DLBCL, both overall (HR: 0.81; p < 0.001) and within IPI subgroups—low IPI (HR: 0.84; p < 0.001) and high IPI (HR: 0.80; p < 0.001). Among patients with BL, those treated at 15–30 days had better survival compared to ≤14 days (HR: 0.77; p < 0.001), with a signiﬁcant beneﬁt in the low IPI group (HR: 0.58; p = 0.046), while no signiﬁcant diﬀerence was observed in the high IPI group (HR: 0.77; p = 0.160). In MCL, treatment at 15–30 days was associated with improved survival overall (HR 0.78; p < 0.001); this was signiﬁcant in the high IPI group (HR 0.73; p = 0.004), but not in the low IPI group (HR 0.76; p = 0.065). For PTCL, initiating treatment at 15–30 days was associated with modestly lower mortality overall (HR 0.90; p < 0.001), though no signiﬁcant associations were observed in low (HR 0.92; p = 0.475) or high IPI subgroups (HR 0.91; p = 0.309).

Conclusion: In this large national cohort, delayed treatment initiation in aggressive lymphomas was not associated with worse survival; in fact, modest delays often correlated with improved outcomes across subtypes. These ﬁndings remained signiﬁcant after adjusting for stage, IPI, and comorbidities, and were supported by sensitivity analyses among patients treated within 30 days. Notably, patients treated within 14 days had worse survival, suggesting that rapid treatment initiation may reﬂect unmeasured markers of aggressive disease biology or clinical instability not captured by conventional prognostic tools. Future studies should integrate biological and functional markers to reﬁne risk stratiﬁcation and optimize therapy timing.

Link to Abstract abs25-7401

Abstract Number: abs25-8677

The clinical utility of COMET™ sequential immunofluorescence in lymphoma tissue diagnostics: Next generation diagnosis.

Presenter: Matthew Pugh
Session: 803. Emerging Tools, Techniques, and Artificial Intelligence in Hematology: Poster II

Abstract: Background: Background: : Immunohistochemistry is essential to the pathological diagnosis of formalin-fixed paraffin- embedded (FFPE) tissue biopsies for suspected lymphomas. At present, multiple pathologist-selected single-plex chromogenic stains are performed on separate tissue sections, potentially leading to tissue exhaustion, incomplete diagnosis, and re-biopsy in a proportion of cases. Comprehensive multiplex immunohistochemistry (mIHC) on a single tissue section, such as sequential immunofluorescence (seqIF™, PMID 37813886) performed on the COMET™ platform, could potentially overcome these shortcomings, but the diagnostic utility of mIHC in pathological tissue assessment has not yet been evaluated.

Methods: A 38-marker seqIF™panel comprising most markers required for lymphoma diagnosis was optimised on the automated staining and imaging COMET TM platform (Lunaphore, a Bio-Techne brand), including 37 antibodies against immune lineage proteins and 1 RNA probe against EBER. Each stain was evaluated compared to standard clinical chromogenic stains by semi-quantitative clinical assessment scoring (CAS). 15 retrospective lymphoma cases, comprising 3 Hodgkin lymphomas, 6 low-grade lymphomas, 2 high-grade lymphomas, 2 T-cell lymphomas, and 2 reactive lymphadenopathies were processed on the COMET™. Each case was evaluated by 5 hematopathologists to assess diagnostic utility and usability of the seqIF™ panel alongside a haematoxylin and eosin stain of the tissue. Diagnoses rendered on seqIF™ were correlated with the diagnoses previously rendered on single-plex-chromogenic stains.

Results: All 38 markers in the seqIF™ panel showed equal, or better, CAS scores compared to standard-of- care single-plex chromogenic markers. Diagnostic assessment of the 15 cases (75 interactions) showed 100% correlation with the diagnosis rendered using chromogenic single-plex stains. In 5/75 (6%) of diagnostic interactions, the comprehensive seqIF™ panel contained a marker crucial to diagnosis, which was not selected in the initial panel by the assessing pathologist. Usability of the seqIF™ panel was rated equivalent to chromogenic staining in 37/75 (49.3%) interactions, and better than chromogenic staining in 38/75 (50.8%) interactions. Assessment of co-expression was rated equal to chromogenic staining 71/74 (91%) of interactions. Conclusions Conclusions : This is the first investigation into the diagnostic utility of a comprehensive mIHC panel, such as seqIF™, for lymphoma, demonstrating that the technique is safe and effective for lymphoma diagnosis. Widespread adoption of comprehensive seqIF™ for diagnosis could improve turnaround times, facilitate interpretation, reduce diagnostic error and obviate the requirement for repeat biopsies due to tissue exhaustion.

Link to Abstract abs25-8677

Abstract Number: abs25-13718

Genomic alterations in TET2 and EZH2 serve as critical drivers of clonal malignant evolution in anti-BCMA CAR-T therapy for multiple myeloma.

Presenter: Adolfo Aleman
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster II

Abstract: Background: B cell maturation antigen (BCMA) targeted Chimeric antigen receptor (CAR) T cell therapy has emerged as a transformative treatment for patients with relapsed or refractory multiple myeloma (RRMM), demonstrating deep and durable responses. Nevertheless, emerging reports of secondary hematologic malignancies, particularly of T-cell origin, introduce a new dimension of complexity to the safety profile of these engineered cell therapies. We recently reported a patient with CD4 and CD8 negative PTCL responding to targeted therapy including anti-CCR4 antibody ( Aleman et al, NEJM, 2025 ). This and other sporadic reports of T-cell neoplasms following CAR-T infusion in MM patients necessitate deeper investigation into the pathophysiology, which likely involves a multifactorial interplay between vector integration, clonal hematopoiesis and immune perturbations induced by lymphodepletion or viral infections. Here, we delineate the pathogenesis in our patient with CAR+ peripheral T-cell lymphoma with involvement of the skin, peripheral blood (PB), and bone marrow (BM) emerging in the aftermath of anti- BCMA CAR T cell therapy. Methods: We isolated CAR+ peripheral T-cell lymphoma (PTCL) from PB and performed single cell sequencing, RNA sequencing, and functional experiments to characterize the secondary malignancy post anti-BCMA CAR-T therapy. To dissect the genomic drivers that contributed to the secondary malignancy we generated CAR-T cells from healthy donors and from the PTCL patient and knocked down mutational targets. We characterized the functional result of TET2 and EZH2 in single and double knock down mutants by using BCMA expressing cell lines to elicit an antigen specific response of lab generated CAR-T cells. Results: A 51-year-old male presented with a facial lesion and lymphocytosis due to a CD4-/CD8- PTCL involving skin, blood, and bone marrow six months post anti-BCMA CAR-T infusion, Single cell sequencing and bulk RNA sequencing of PTCL tumor revealed the development of new mutations in TET2 and EZH2 which are associated with clonal hematopoiesis of indeterminate potential (CHIP) and T-cell lymphomas. We generated CAR-T cells from a healthy donor and the PTCL patient at the time of apheresis and compared functionality to isolated malignant CAR-T cells from the PB. Antigen specific stimulation with BCMA expressing cell lines revealed loss of function in cytokine production capacity in malignant CAR-T cells not seen in control CAR-T. The cytotoxic capability of malignant tumor CAR-T cells against BCMA expressing cells was decreased by 98% compared to cells generated from PB harvested prior to CART therapy (p<0.01). To discern the contribution of genomic mutations we generated EZH2 and TET2 CAR-T mutants from healthy donor and PB harvested prior to CART therapy from our PTCL patient. EZH2 inhibition in CAR-T cells increased CD69, CD38 and CD127 while reducing FAS expression resisting apoptosis. TET2 knock down in CAR-T cells resulted in increased proliferation and doubled the expression of in CCR4+ compared to control. CCR4+ is a skin homing chemokine which was expressed in all our patient’s malignant CAR-T tumor cells and served as an indicator for treatment with mogamulizumab. EZH2 and TET2 double mutant almost tripled the expression of CCR4 compared to control and caused a loss of CD7 in 73% of cells. Loss of CD7 is hallmark of T cell lymphomas. Knock down of TET2 and EZH2 resulted in a decrease in functional killing. EZH2 knockdown mutant resulted in a 28% reduction of cytotoxicity while TET2 knock down reduced killing by 53% when compared to control CAR-T cells (p<0.05). Double knock down of TET2 and EZH2 further decreased overall cytotoxicity by 67% (p<0.01). Conclusions: TET2 and EZH2 mutations result in epigenetic changes such as open chromatin, leaving the genome more vulnerable to additional alterations. TET2 and EZH2-loss of function mutations in CAR-T cells provide advantages in proliferation and regeneration while promoting malignant CAR-T transformation following anti-BCMA CAR-T therapy.

Link to Abstract abs25-13718

Abstract Number: abs25-14755

Pharmacologic activators of immunoproteasomes unmask actionable public and private neoantigens in multiple myeloma patients

Presenter: James Driscoll
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster II

Abstract: Immunotherapy has emerged as a powerful tool for myeloma-directed cytotoxicity with the unique potential to induce immune memory and reduce the risk of relapse. However, evasion of immune destruction is a cancer hallmark that thwarts the efficacy of immunotherapy. Certain patients do not develop sustained responses and many patients that do benefit eventually develop drug resistance through defective antigen presentation. Immunoproteasomes are a highly specialized proteasomes that play a crucial role in the generation of MHC class I antigen (Ag) presentation. Immunoproteasomes degrade intracellular and viral proteins to generate peptides which are transported into the ER and associate with MHC-class I molecules for presentation to T-cells. The proteasome activator PA28α/ß is a heteroheptameric complex that interacts with immunoproteasomes and modulates Ag processing. The immunoproteasome exhibits distinct catalytic activities compared to constitutive (standard) proteasomes. This difference is due to the substitution of the 3 constitutive catalytic subunits: β1 (peptidylglutamyl-like), β2 (trypsin-like), and β5 (chymotrypsin-like) compared with 3 immune-specific subunits β1i (chymotrypsin-like), β2i (trypsin-like), and β5i (chymotrypsin-like). These immune subunits alter the proteasome's catalytic activity with a shift toward cleavage after hydrophobic and aromatic residues, thus impacting the types of peptides it generates and influencing the immune repertoire of (Neo)Ags presented to T-cells. Molecular glues (MGs) are highly attractive small molecules that target currently undruggable proteins to stabilize or induce protein-protein interactions (PPIs) by binding to two protein surfaces, creating a ternary complex that leads to beneficial downstream events. Here, we hypothesized that MGs could function to stabilize the PA28α/ß-immunoproteasome complex leading to the downstream activation of Ag presentation to modulate the immunopeptidomic landscape and promote T-cell-mediated tumor lysis. Ags bound to MHC class I molecules and presented on the cell surface constitute the targets of cytotoxic T-lymphocytes. Methods to identify and govern the generation of these Ags are critical to the development of more effective forms of immunotherapy, specifically TCR-engineered T-cells and cancer vaccines, for which the goal is the generation of effective adaptive immune responses accompanied by long-lasting immune memory to preclude disease relapse. Methods: We performed a HTS to identify novel molecules that increased immunoproteasome activity. Cell-based assays were performed using MM, cutaneous lymphoma and melanoma cells and the lead compound (Compound A). CD138+ tumor cells were obtained from MM patient bone marrow and treated with Compound A (1 uM, 48h), lysates prepared, immunoprecipitated using a pan-MHC class I antibody, bound peptides acid-eluted and released peptides then quantitated and sequenced by mass spectroscopy (MSBioWorks). Cell-based, biochemical and biophysical studies further characterized the effect of Compound A on the association of PA28α/ß with immunoproteasomes. Results. Treatment of multiple cancer cell types with Compound A increased immunoproteasome activity up to 3-fold. Treatment of MM patient tumor cells with Compound A ex vivo also increased the presentation of pan-MHC bound peptides, tumor-specific neoantigens and human endogenous retroviral (HERV) peptides >100-fold relative to the presentation of these peptide forms detected on untreated MM cells. Treatment of MM patient tumor cells ex vivo with Compound A also increased the relative proportion of MHC-bound peptides that were 8-9 amino acids in length. The optimal length of antigens bound in the MHC peptide cleft generally is 8-9 aa residues. Moreover, treatment with Compound A increased the relative frequency of hydrophobic and aromatic amino acids detected at the C-terminus, consistent with a dominant role of immunoproteasomes in the generating MHC class I Ags. Discussion : We demonstrate that MGs that promote PA28α/ß association with immunoproteasomes and not only enhance the degradation of proteins with hydrophobic C-termini but also generate immunopeptides with a similar enhanced frequency of hydrophobic C-termini. The results support the development of a platform to pharmacologically modulate the presentation of commonly shared and private NeoAgs and expand the scope of TCR-engineered T-cells, T-cell engagers and cancer vaccines.

Link to Abstract abs25-14755

Abstract Number: abs25-7435

CTD402: Allogeneic CAR-t manufacturing that overcomes donor- & process-derived variation with robust clinical activity

Presenter: Jiangtao Ren
Session: 711. Cell Collection and Manufacturing of HSPCs, CAR-T Cells, and Other Cellular Therapy Products: Poster II

Abstract: Background: Background: : Allogeneic CAR-T cell therapies offer key advantages over autologous approaches, including simplified manufacturing logistics, improved accessibility, and greater cost-efficiency. However, donor-to- donor and lot-to-lot variability in the manufacturing process has generated significant interest in the field. Understanding the extent to which this inherent variability affects clinical performance is critical— not only for elucidating the mechanism of action (MOA) of allogeneic CAR-T products, but also for assessing the consistency and robustness of their clinical responses.

Methods: CTD402, is a CD7 targeted “off-the-shelf” universal CAR-T product with a triple-knockout in CD7, TRAC and CIITA genes, as well as immune inhibitory molecule overexpression to prevent fratricide, GvHD, and host immune rejection - leading to increased expansion and persistence. CTD402 is currently being developed for the treatment of hematologic malignancies and other severe blood disorders with over 100 patients treated in several indications (T-ALL/LBL, PTCL, AML, SAA). CTD402 manufacturing process has evolved across different development phases : Process 1 ( pilot scale, less optimized & controlled process with variable harvest times ) and Process 2 ( 11-day optimized process with improved cell viability and yield ) supporting multiple IIT studies ; Process 3 ( 12-day process with optimized expansion protocol and additional TCR + cell depletion step) supporting global clinical development in R/R T-ALL/LBL. A total of eighteen lots from thirteen donors across three process development stages have been manufactured.

Results: Despite process changes across three development stages, the quality attributes of eighteen UCAR-T lots remained consistent across donors, except for a two-fold inter-donor variation observed in IFN-γ release, HLA-II knockout levels, CD4/CD8 ratio, and T memory subset distribution. Intra-donor variation in these parameters was present but to a lesser extent. Notably, UCAR-T products manufactured using Process 3 demonstrated remarkable consistency in quality attributes across four donors, apart from the CD4/CD8 ratio. Importantly, these variations did not correlate with clinical performance, as indicated by CTD402 robust clinical responses in r/r T-ALL/LBL. Analysis of 64 patients across 14 manufacturing lots from 11 donors revealed non-significant inter-lot and donor variability in pharmacokinetic parameters (Cmax, AUC 0-28 ) and clinical responses. UCAR-T lots derived from various donors and processes showed 100% UCAR-T lot functionality with expansion capabilities ranging from 2.1x to 4.1x fold-change and consistent 28-day median persistence. All donors demonstrated clinical activity (58.8-100% objective response rate range) with durable responses >5 months. Patients receiving UCAR-T lots from the same donor source showed highly similar results in both expansion and persistence.

Conclusion: : This comprehensive analysis demonstrates the clinical response and consistency of CTD402 allogeneic CAR-T cells manufactured from different donors. The observed robust responses highlight the therapeutic potential of allogeneic CAR-T products, compared to their autologous counterparts and many other treatment modalities. The development experience with the CTD402 program offers valuable insights for the broader allogeneic CAR-T field. It is expected that standardized, large-scale manufacturing processes can reliably produce therapeutically effective products with minimal donor-to-donor and lot- to-lot variability. These findings support the viability of allogeneic CAR-T cells as a scalable, consistent, and clinically effective treatment option—overcoming the manufacturing constraints of autologous CAR-T therapies and the therapeutic effectiveness limitations of antibody-based biologics, while improving accessibility for a broader patient population.

Link to Abstract abs25-7435

Abstract Number: abs25-2356

Targeting B- and T-cell lymphomas with anti-CXCR5 CAR T cell therapy

Presenter: Jinsheng Weng
Session: 628. Aggressive Lymphomas: Cellular Therapies: Poster II

Abstract: Chimeric antigen receptor (CAR) T cell therapy has shown unprecedented efficacy in B-cell leukemias and lymphomas. However, >50% of these patients treated with anti-CD19 CAR T cell therapy relapse with CD19 loss or downregulation as a frequent mechanism of escape. These results indicate that novel CAR T cell targets are needed to further improve outcomes in these patients. Development of CAR T cell therapy approaches is also needed for patients with T-cell lymphomas, most of whom have poor long-term survival. However, this has been challenging due to difficulty in identifying appropriate target antigens for CAR T cell therapy. Targeting pan-T-cell antigens such as CD5 and CD7 may lead to compromised T cell immunity and increase the risk of life threatening infections. Here, we describe the development of a novel anti-CXCR5 CAR T cell product for targeting B- and T-cell lymphomas as a potential strategy to address some of the current challenges. CXCR5 is a G protein-coupled chemokine receptor whose expression is restricted to mature B cells and follicular helper T cells (TFH) in normal human tissues. Among lymphoid malignancies, it has been reported to be highly expressed in multiple B-cell neoplasms including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), and chronic lymphocytic leukemia (CLL). Consistent with their cell-of-origin, CXCR5 is also reported to be highly expressed in TFH-derived T-cell lymphomas including angioimmunoblastic T-cell lymphoma, TFH lymphoma follicular type, and TFH lymphoma not otherwise specified. Together, the TFH-derived T-cell lymphomas are the largest subgroup of non-cutaneous T-cell lymphomas accounting for ~35% of these malignancies. The restricted expression in normal tissues and high expression in certain subtypes of B- and T-cell malignancies suggest that CXCR5 could be a safe and effective target for CAR T cell therapy in these lymphoproliferative disorders. A prior study demonstrated efficacy of a CXCR5-targeting CAR-T in preclinical models of B-cell lymphoma but its efficacy in T-cell lymphomas is unknown. We generated a novel anti-CXCR5 monoclonal antibody and demonstrated by flow cytometry that it specifically binds to CXCR5-expressing B- and T-cell lymphoma cell lines but not their isogenic counterparts that lack CXCR5 expression. Using the variable heavy (VH) and light (VL) chains of this antibody, we developed a single-chain variable fragment (scFv)-based CAR construct with CD28 and CD3z signaling domains. Next, we generated anti-CXCR5 CAR T cells by lentiviral transduction of the CAR molecule into primary human T cells and evaluated their function against CXCR5-expressing B- and T-cell lymphoma cell lines/clones with varying antigen density. As compared to untransduced T cells, anti- CXCR5 CAR T cells were specifically cytotoxic to CXCR5+ B- and T-cell lymphoma tumor cells at high efficiency but not their CXCR5-negative isogenic counterparts (P<0.001). At a low effector to target ratio of 1:2, the anti-CXCR5 CAR T cells eliminated over 95% of CXCR5+ B- and T-cell lymphoma tumor cells, including tumor cells with very low antigen density (2000-3000 CXCR5 molecules per cell). In a B-cell lymphoma xenograft mouse model, adoptive transfer of anti-CXCR5 CAR T cells but not untransduced T cells rapidly and significantly induced regression of tumors (total flux P<0.001) and prolonged survival of mice (P<0.01). Evaluation of the anti-CXCR5 CAR T cells in T-cell lymphoma xenograft models is ongoing. In conclusion, our novel anti-CXCR5 CAR T cell therapy product is specific and highly effective against preclinical models of both B- and T-cell lymphomas. Successful development of such a CAR-T product may be applicable for the treatment of various B-cell malignancies and TFH-derived T-cell lymphomas, the largest subgroup of systemic T-cell lymphomas with a significant unmet clinical need. CXCR5 CAR-T can also simultaneously target the tumor-promoting normal TFH cells in B-cell lymphomas and the tumor-promoting normal B cells in TFH-derived T-cell lymphomas. This dual targeting of the tumor and the supporting CXCR5+ normal cells in the tumor microenvironment can make the CXCR5 CAR-T particularly potent.

Link to Abstract abs25-2356

Abstract Number: abs25-11504

Interim analysis of safety and efficacy in a Phase 2 study of MB-105, a CD5.CAR T therapy for patients with relapsed/refractory T cell lymphoma

Presenter: Swami Iyer
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Novel agents or therapeutic approaches in T-cell Lymphoma

Abstract: Introduction: There are few effective treatments for patients (pts) with relapsed/refractory T-cell lymphoma (R/R TCL). One challenge in targeting T-lineage antigens is the risk of ablating normal T cells. MB-105 is a CD5- directed CAR T-cell product that resists self-targeting through rapid degradation of CD5 protein but retains robust killing of malignant T cells. A phase 1 study at Baylor College of Medicine showed good tolerability and objective response (ORR) in 44% of pts with r/r TCL (Hill 2024). MB-105 incorporates manufacturing refinements from the phase 1 study, which improved product potency. We selected the phase 2 dose and initiated a multicenter study to confirm efficacy and safety of MB-105 in pts with R/R peripheral (PTCL) or cutaneous TCL (CTCL). Methods: This 3-part phase 2 study (MB-105-201) has completed a 6-patient safety run-in to confirm tolerability of the fixed dose of 50x10 6 CD5.CAR T cells. Eligibility criteria include R/R PTCL failing at least 1 prior systemic therapy or CTCL with at least 2 prior lines, CD5 expression in lymphoma, adequate organ function, Karnofsky (KPS) ≥70% and no transplant, cell therapies or lymphocyte infusions within 100 days. Primary analysis of Simon stage 1 requires at least 6 responses in 15 pts in the primary cohort by independent central review (Cheson 2014, Olsen 2022), and subsequently >18/46 responses, targeting a 50% ORR (null = 30%). An independent committee (IDMC) oversees study conduct. Secondary analyses include assessing investigator ORR, response durability, long-term impact, overall survival, and manufacturing success. Prior to MB-105 dosing, pts receive fludarabine/cyclophosphamide (30/300 mg/m 2 /day) over 3 days followed by 2 days’ rest and single-dose rituximab prophylaxis (if EBV seropositive). Following infusion, pts are monitored as outpatients for safety and efficacy up to 2 years. Monitoring also includes CAR-T persistence, immune reconstitution, viral titers, anti-CAR antibodies, cytokines and replication-competent retrovirus. Results: After leukapheresis, MB-105 was manufactured with a 29-day median vein-to-vein time. Two manufacturing failures led to exclusion of prior bendamustine and increase of baseline CD3 requirement to 400 cells/µL. As of July 31, 2025, 7 pts received MB-105: 4:3 male:female, KPS 70-100%, 5:1:1 white:black:other with measurable R/R PTCL (n=4) or CTCL (n=3) and 2-8 prior systemic regimens. One pt with CTCL received a partial MB-105 dose in error and was not included in the safety run-in or primary efficacy assessments. An additional CTCL pt with 15% CD5 tumor expression was treated on an exploratory CD5 low arm but not included in efficacy evaluation; all others had disease with ≥50% CD5 expression and H-scores 190-300 by central review. Of the 5 pts in the primary cohort (≥50% CD5 expression) who received full dose, 4 have been assessed for response and one is pending evaluation. Of those assessed, all 4 have achieved a response by investigator assessment (100% ORR; best response 3 CR and 1 PR). The pt with low CD5 expression had progressive CD5 neg disease (PD) at D28. After infusion, MB-105 expanded in peripheral blood, peaking in most pts at day 14 (mean 75%, range 24- 87% of total CD3+ T cells by flow cytometry), commonly persisting past day 28 in blood and detectable in lymph node and skin biopsies. CAR-T expansion resulted in a reduction of peripheral T-cell counts and a concomitant selection of CD5-negative T cells, consistent with prior observations. MB-105 related adverse events occurred in 5/6 safety run-in pts and were predominantly Gr1, including 50% of pts with Gr1 CRS and no neurotoxicity. All patients experienced anemia, 3 had neutropenia (2 febrile), and 3 thrombocytopenia, all attributed to lymphodepletion. No cytopenias ≥Gr3 lasted >42 days. Two pts had viral reactivation/infections ≤Gr2 (BK, CMV, EBV). There were 2 deaths: one with CD5 neg PD at D98 and one pt with EBV pos B-cell lymphoma at D128. Conclusions: In the safety run-in of this Phase 2 study, MB-105 showed an acceptable safety profile and promising early efficacy of MB-105 in patients with R/R TCL. Correlative data show robust expansion of MB-105 with early evidence suggesting complete clearance of CD5 positive disease in most patients treated to date. The IDMC approved continued accrual to 15 patients in Stage 1. Updated clinical and correlative results of Stage 1 will be presented.

Link to Abstract abs25-11504

Abstract Number: abs25-8955

Liposomal mitoxantrone versus chidamide in relapsed/refractory peripheral T-cell lymphoma: Final analysis from the multicenter, prospective randomized phase 3 study

Presenter: Huiqiang Huang
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Novel agents or therapeutic approaches in T-cell Lymphoma

Abstract: Background: Background: Outcomes for patients with relapsed/refractory (R/R) peripheral T-cell lymphomas (R/R-PTCLs) are poor. Single agent overall response rates (ORRs) for R/R-PTCLs generally fall within the 20-35% range, with a median progression-free survival (PFS) of less than 4 months. Thus, there is an urgent need for more effective therapies that can provide deep remissions or long-term disease control. Liposomal mitoxantrone (Lipo-MIT, manufactured by CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.) monotherapy exhibited promising and durable antitumor activity in phase 2 study. This study was designed to evaluate the efficacy and safety of Lipo-MIT versus chidamide (an oral subtype-selective histone deacetylase inhibitor) in this population.

Methods: This study is an open-label, active-controlled, randomized phase 3 study (ClinicalTrials.gov identifier NCT04668690). Eligible patients from 32 sites in China with R/R-PTCLs were randomly assigned 1:1 to receive either Lipo-MIT (20 mg/m², IV, Q4W, for a maximum of 6-8 cycles) or chidamide (30 mg, twice weekly). Patients who failed from chidamide were permitted to crossover to the Lipo-MIT group. The primary endpoint was PFS assessed by the Independent Review Committee (IRC) in the intention-to-treat (ITT) population. Secondary endpoints included, but not limited to, PFS assessed by investigators, ORR, complete response (CR) rate, overall survival (OS), and safety.

Results: From April 2021 to October 2024, a total of 193 patients were enrolled and randomly assigned to Lipo- MIT (n=97) or chidamide (n=96) groups. Baseline characteristics were essentially balanced between the two groups, including AITL, PTCL-NOS, and ENKTCL subtypes. A total of 190 patients received at least one dose of study drug (Lipo-MIT n=95; chidamide n=95; safety population). At median follow-up of 11.1 months in the Lipo-MIT group and 8.4 months in the chidamide group, the median PFS per IRC was 7.5 months (95% CI: 4.2-12.0) in the Lipo-MIT group and 2.6 months (95% CI: 1.9- 3.7) in the chidamide group (hazard ratio [HR] 0.58, 95% CI: 0.41-0.81; P = 0.0008). Similar results were obtained assessed by the investigators (7.6 vs 2.5 months, HR 0.63, 95% CI: 0.45-0.88; P = 0.0035). Twenty-seven patients (28.1%) in the chidamide group crossed over to the Lipo-MIT group. Median OS was 14.0 months (95% CI: 10.8-23.4) with Lipo-MIT versus 8.8 months (95% CI: 7.2-11.6) with chidamide (HR 0.78, 95% CI: 0.54-1.13). The 18-month OS rates were 45.4% (95% CI: 34.2-56.0) in the Lipo-MIT group and 35.3% (95% CI: 25.2-45.5) in the chidamide group, respectively. Both PFS and OS were generally consistent across key subgroups. The CR rate and ORR were significantly higher in the Lipo-MIT group than in the chidamide group (CR rate, 13.4% vs 7.3%; ORR, 36.1% vs 18.8%). The incidences of grade 3 or higher treatment-emergent adverse event (TEAEs) and serious AEs (SAEs) were similar between groups (78.9% vs 81.1% and 43.2% vs 45.3%). A higher incidence of leukopenia (any grade) was reported in the Lipo-MIT group (85.3%) than in the chidamide group (69.5%). Thrombocytopenia (any grade) was more common in the chidamide group (57.9% vs 78.9%). The incidence of cardiotoxicity (any grade) was comparable between the two groups (21.1% vs 30.5%), with most events being grade 1-2. Treatment discontinuations due to AEs were 15.8% vs 14.7%.

Conclusion: The study met its primary efficacy endpoint. The outcome of the present phase 3 trial demonstrated that the efficacy of Lipo-MIT was superior to chidamide with an acceptable and manageable overall safety profile in patients with R/R PTCL.

Link to Abstract abs25-8955

Abstract Number: abs25-11418

A prospective clinical study on the combination of anti-PD1 monoclonal antibody with lenalidomide and azacitidine for the treatment of relapsed/refractory peripheral T-cell lymphoma

Presenter: Ting Xu
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Novel agents or therapeutic approaches in T-cell Lymphoma

Abstract: To explore the efficacy and safety of the anti-PD1 monoclonal antibody combined with lenalidomide and azacitidine regimen in the treatment of relapsed/refractory peripheral T-cell lymphoma (R/R PTCL). Our center has registered a single-arm Phase II prospective clinical trial (NCT05182957) aimed at exploring the efficacy and safety of anti-PD1 monoclonal antibody combined with lenalidomide and azacitidine in treating relapsed/refractory peripheral T-cell lymphomas (R/R PTCL). The primary endpoints are overall response rate (ORR) and complete remission rate (CR), while secondary endpoints include overall survival (OS), progression-free survival (PFS), and safety. From January 2020 to March 2023, this study enrolled 31 patients with relapsed/refractory PTCL (R/R PTCL) who received anti-PD1 combined with lenalidomide and azacitidine therapy. Among them, 18 were male and 13 were female, with a median age of 67 (range: 23 – 73) years. Of the 31 patients, 17 had AITL, 7 had PTCL-NOS, 6 had NK/TCL, and 1 had ALK-ALCL; 17 were primary refractory, and 14 had relapsed, including 8 who relapsed after autologous stem cell transplantation. The median number of prior lines of therapy was 2 (range: 1 – 5). As of June 2023, the median follow-up time was 15.8 (range: 2.7 – 39.5) months. Among the 31 patients, 29 were evaluable for efficacy, with an ORR of 62.1% (CR: 37.9%, PR: 24.2%). The estimated 2-year PFS and OS rates were 67.4% and 73.4%, respectively. Regarding safety, among all treated patients, grade ≥ 3 severe adverse events (SAEs) included hematologic SAEs such as neutropenia (45.2%), anemia (25.8%), and thrombocytopenia (32.2%), as well as non-hematologic SAEs such as pulmonary infection (6.4%), liver function impairment (6.4%), and rash (3.2%). Next-generation sequencing (NGS) was performed on tissue samples from 17/31 patients, and 14/17 patients exhibited one or more mutations in epigenetic modifier genes such as RHOA, TET2, and DNMT3A. The ORR after treatment in these patients was 71.4%. The anti-PD1 monoclonal antibody combined with lenalidomide and azacitidine regimen can serve as an effective salvage therapy for R/R PTCL, further improving the prognosis of patients with R/R PTCL, with manageable adverse effects. NGS testing suggests that patients with gene mutations such as RHOA, TET2, and DNMT3A are sensitive to this treatment regimen, providing some evidence-based rationale for further research.

Link to Abstract abs25-11418

Abstract Number: abs25-146

Early time-to-relapse as a predictor of survival in mature T-cell/NK-cell lymphomas: Results from the PETAL consortium

Presenter: Mark Sorial
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: From bench to bedside and retrospective studies to inform treatment consideration in TCL

Abstract: Introduction: We and others have demonstrated that patients with refractory nodal mature T-Cell lymphomas (nMTCL) have worse overall survival (OS) versus relapsed disease. 1–3 Among patients who relapse, responses and OS in (nMTCL) remain poor with little data to tailor decision-making based on disease kinetics. 1–9 Time-to- relapse (TTR) is a significant predictor of survival and decision-making tool among many other lymphomas, 10–18 however a majority of nMTCL patients will relapse prior to 24 months. 14 We aimed to characterize how TTR may affect survival and explore differential second-line (2L) therapy effects based on TTR subgroups. METHODS This was a global retrospective cohort study using multiple international cohorts: PETAL (n=1414) and GELL (n=487). 1,3,19–21 Two separate independent cohorts validated TTR12 as an OS predictor: an observational U.S. multicenter cohort (n=138) and the phase 3 randomized trial of romidepsin-CHOP versus CHOP. 22 Patients with PTCL-NOS, AITL/TFHL, or ALCL with a CR to 1L were included. Patients without progression or 2L within the study period were included as not having TTR12 per landmark methods, 11,23–25 and were removed for sensitivity analyses. The primary objective was OS among nMTCL who relapsed or started 2L 26 within 12m from 1L (TTR12) versus without TTR12 because nearly half of patients in our cohort and previous studies of nMTCL relapsed within 12m. 6,14 The secondary objective was to compare OS among 2L novel agents (NA) versus chemotherapy (CC) in those with and without TTR12. Kaplan-Meier and Cox PH methods were used adjusting for a priori covariates. 1,3 The primary analysis was a modified-landmark analysis (m-LM) with OS measured from relapse or 2L start (TTR12 group) or from 12m from 1L start (without TTR12 group) to death. Sensitivity analyses used standard 12m landmark (s-LM; excluded patients who died or lost-to-follow <12m), 11,25 and time-dependent Cox (td- Cox; OS 1L start to death). For 2L analyses, OS was measured from 2L start to death. RESULTS A total 452 were included in the final cohort and for td-Cox, 428 in m-LM, and 388 in s-LM. Of the 452 total, 165 (36.5%) had TTR12, 181 (40%) relapsed ≥12m, and 106 (23.5%) never relapsed (total without TTR12: 287 [63.5%]). The median (range) age was 58 (18-89) and 60 (15-92), PTCL-NOS included 47.3% and 43.2%, AITL/TFHL included 35.8% and 32.1%, and ALCL included 16.4% and 24.7% of patients with TTR12 and without TTR12 respectively. Patients received similar frontline regimens and HSCT utilization was comparable. Demographics in the validation cohorts largely mirrored the primary cohort. Using m-LM, TTR12 conferred worse OS (aHR 2.14, 95%CI: 1.58-2.90; p<0.001) overall, irrespective of 1L HSCT or PIT score, and across prespecified subgroups (PTCL-NOS: aHR 2.32, 95%CI: 1.51-3.55; p<0.001, AITL/TFHL: aHR 1.92, 95%CI: 1.15-3.21; p=0.013, ALCL: aHR 3.34, 95%CI: 1.18-9.50; p=0.023, no 2L HSCT: aHR 2.27, 95%CI: 1.63-3.15; p<0.001). TTR12 patients who received any 2L HSCT had similar OS than those without TTR12 (aHR 1.85, 95%CI: 0.73-4.65; p=0.194). When excluding patients that did not relapse, TTR12 still showed poorer OS (aHR 1.60, 95%CI: 1.18-2.18; p=0.003). In the observational validation cohort, TTR12 patients had worse OS across all analyses in both univariate (HR 3.72, 95%CI 1.85-7.46; p<0.001) and multivariate models adjusting for covariates (aHR 3.60, 95%CI 1.77-7.34; p<0.001). In the phase 3 validation cohort, TTR12 patients also had worse OS (aHR 3.71, 95%CI 2.17-6.32; p<0.001). All results were consistent across s-LM and td-Cox sensitivity analyses. TTR12 predicted worse OS in parallel to, and compounding with, PIT score, with patients who had TTR12 and PIT≥2 exhibiting the worst OS. Patients with PIT score of 4 were at a significantly higher odds of developing TTR12 (OR 3.64, 95%CI 1.07- 12.38; p=0.038). In TTR12 patients, 2L NA significantly improved OS versus CC (aHR 0.60, 95%CI: 0.37-0.97; p=0.038). In those without TTR12 who received 2L, there were no significant differences in OS with NA versus CC (aHR 0.82, 95%CI 0.51-1.32; p=0.407 CONCLUSION TTR12 consistently exhibited worse OS in nMTCL and highlighted differential responses to 2L, defining a unique risk group after 1L. TTR12 may be a novel endpoint for clinical trials and may better inform treatment decisions upon progression. Prospective validation and correlation with molecular alterations has been initiated and is the focus of the PETAL consortium.

Link to Abstract abs25-146

Abstract Number: abs25-2389

Survival determinants of hepatosplenic t-cell lymphoma (HSTCL): Analysis of an updated real-world pooled database

Presenter: Philip Haddad
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: From bench to bedside and retrospective studies to inform treatment consideration in TCL

Abstract: Background: Hepatosplenic T-cell lymphoma (HSTCL) is a rare and highly aggressive peripheral T-cell lymphoma characterized by extranodal infiltration of the liver, spleen, and bone marrow, with minimal lymphadenopathy. Predominantly affecting adolescents and young adults, HSTCL is frequently associated with underlying immunosuppression. The clinical course is often fulminant, with limited responses to conventional chemotherapeutic regimens and a poor survival. Due to its rarity, much of the current understanding of HSTCL derives from case reports and small retrospective series, leaving significant gaps in knowledge regarding prognostic factors and optimal management strategies. Comprehensive analyses utilizing real-world data are needed to elucidate the clinicopathologic determinants that most strongly influence survival outcomes in this challenging disease. Methods: To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, prognostic factors, and survival, we compiled a pooled database of real-world cases that satisfy the diagnostic criteria for HSTCL. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS). Results: A total of 449 patients with confirmed HSTCL were identified, with a median age of 31 years and peak incidence between ages 16 and 24. There was a marked male predominance (M:F ratio 3:1 overall and in γδ subtype; 6:1 in immunosuppressed; 1.5:1 in αβ subtype). Median overall OS was 11 months. Median time from symptom onset to diagnosis was 2 months. Among patients with prior immunosuppression, the median duration of therapy and interval from immunosuppression to HSTCL diagnosis were both 5 years. Sex, age, white blood cell or platelet counts, LDH, i7/r7, CD56+, skin, hepatosplenic or lymph node involvement, and prior use of TNFα inhibitors or steroids did not significantly impact OS. Factors associated with worse OS included hemoglobin <8 g/dL, prior immunosuppression, use of chemotherapeutic agents (including purine analogues), and underlying inflammatory bowel disease, organ transplant, and malignancy. Constitutional symptoms and bone marrow involvement had numerically worse OS but did not reach statistical significance. TCR-rearrangement also influenced OS (null > αβ = γδ > biclonal, p=0.02). Compared to no treatment, splenectomy (S), chemotherapy (CT), CT+S, stem cell transplant (SCT), and SCT+S were all associated with improved median OS (1, 4, 7, 18, 44, and 30 months, respectively; p<0.0001). No significant OS difference was observed between autologous and allogeneic SCT, although survival curves plateaued with allogeneic SCT. Quality of response to therapy (p<0.0001) and type of response at the time of SCT (p=0.0002) correlated with improved OS, with CR>PR>NR. Platinum-based first-line regimens outperformed etoposide-containing, asparaginase- containing, and intensive regimens, which in turn were superior to CHOP in OS. Conclusion: This large real-world analysis identifies key clinical and treatment-related factors impacting survival in HSTCL. Underlying immunosuppression, severe anemia, and poor response to therapy are associated with worse outcomes, while splenectomy, first-line platinum-containing regimens, and stem cell transplantation confer significant survival benefits. These findings underscore the need for early aggressive, multimodal management to improve prognosis in this challenging disease.

Link to Abstract abs25-2389

Abstract Number: abs25-10590

Patient characteristics, treatment patterns, and outcomes in primary CNS lymphoma of T-cell origin: A multi-institution retrospective analysis

Presenter: Omar Elghawy
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: From bench to bedside and retrospective studies to inform treatment consideration in TCL

Abstract: Introduction: Primary central nervous system T-cell lymphoma (PCNSTL) is a rare form of PCNSL, comprising 2–8% of cases. Prognostic factors remain undefined, and no standard treatment protocol currently exists. Prior studies have been limited by small sample sizes, incomplete molecular profiling, and poor representation of novel treatment modalities. In this study, we aimed to identify clinicopathologic factors associated with patient (pt) outcomes and delineate the spectrum of treatment regimens used to inform future clinical practice.

Methods: A multicenter retrospective study was conducted across 15 North American academic institutions. Pts aged ≥18 years with biopsy-confirmed PCNSTL between 2009 and 2025 with no evidence of systemic disease were included. Cases with CNS relapse of systemic T-cell lymphoma were excluded. Baseline characteristics were analyzed using independent t-tests, Fisher’s exact tests, or Pearson’s chi- square tests. Primary endpoints were overall survival (OS) and progression-free survival (PFS), evaluated by Kaplan–Meier, log-rank tests, and Cox regression.

Results: Forty-two pts met inclusion criteria. Median age was 57 (range 19–77), 69% were male, and 79% were white. Most (69%) had ECOG 0–1. No patients had HIV, hepatitis B or C, or a history of solid organ transplant. LDH was elevated at diagnosis in 38%, and 24% had B-symptoms. Mean absolute lymphocyte count at diagnosis was 1.82/µL. The most common histologic subtypes were PTCL-NOS (76%), followed by ALK-negative ALCL (12%) and γδ T-cell lymphoma (5%). All patients had parenchymal brain lesions with 57% having multifocal disease. Additionally, CSF involvement was seen in 21%, vitreoretinal involvement in 3%, and deep brain involvement in 34%. Next-generation sequencing was performed in seven pts (17%), with disease-associated variants identified in three cases. Among these, two pts had mutations in TP53, and one had a mutation in DNMT3A. Cytogenetics were obtained in 7 pts with only one exhibiting a complex karyotype. Only one pt was EBV positive by EBER-ISH. Overall, 79% received HD-MTX-based therapy. First-line treatments were mainly HD-MTX alone (38%), HD-MTX + temozolomide (17%), or vincristine + procarbazine (12%). No patients were treated on clinical trials. Median treatment duration was 78 days and median number of treatment cycles was 4 (range 1–9 cycles). One patient received radiation alone; 5% received radiation with systemic therapy. A steroid pre- phase was used in 60%, with 44% exhibiting a clinical response. Overall response rate to first-line treatment was 63% (13 CR, 12 PR). Imaging alone was used in determining response in all patients. Repeated biopsy was not performed. Twelve patients (29%) underwent consolidative autologous transplant, most commonly with thiotepa/carmustine (TT/BCNU, 69%) or BEAM conditioning (25%). Median duration of follow-up was 10.4 months. Sixty-two percent of pts progressed during the study period, with 7% experiencing extra-CNS relapse. Median PFS was 8.2 months. Improved PFS was associated with >3 cycles of therapy (p=0.03) and transplant with TT/BCNU (p=0.0004). At last follow-up, 43% were in remission and 52% were deceased, mostly due to disease progression (77%). Median OS was 17.6 months. One- and two-year OS rates were 58% and 42%, respectively. OS was associated with Nottingham/Barcelona score <2 (p=0.02), >3 treatment cycles (p=0.0008), response to first-line therapy (p=0.0007), and TT/BCNU-based transplant (p=0.0001). IELSG, Taipei, and MSKCC risk scores were not significantly associated with survival, though IELSG approached significance (p=0.09). Discussion: Discussion: This study is among the largest cohorts of PCNSTL pts compiled to date. PCNSTL remains rare and heterogenous. Treatment across centers largely mirrors management of B-cell PCNSL with high utilization of HD-MTX regimens and TT/BCNU conditioning autologous transplant. Survival outcomes within our cohort are consistent with those previously reported within the literature. Receipt of >3 cycles of therapy, TT/BCNU conditioning and Nottingham/Barcelona scores were associated with longer survival within our cohort. Limitations of our study include its retrospective design and heterogeneity within pt disease characteristics, treatments utilized and disease assessment intervals. Further exploration into pathophysiology and optimal management of this unique entity is needed.

Link to Abstract abs25-10590

Abstract Number: abs25-4632

Prognostic value of baseline metabolic tumor volume from lysa ro-CHOP trial inpatients with previously untreated peripheral T-cell lymphoma

Presenter: Anne Ségolène Cottereau
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: From bench to bedside and retrospective studies to inform treatment consideration in TCL

Abstract: Background: Peripheral T-cell lymphomas (PTCLs) are aggressive lymphoid malignancies with poor outcomes and limited prognostic tools beyond the International Prognostic Index (IPI). While total metabolic tumor volume (TMTV) has been well established as a major prognostic factor in diffuse large B-cell lymphoma, evidence remains limited in peripheral T-cell lymphoma (PTCL). We performed an ancillary analysis of the RO-CHOP trial to investigate the prognostic impact of TMTV and its added value over IPI. Methods: The Ro-CHOP trial was a multicenter randomized phase III study showing no increased efficacy of Ro- CHOP versus CHOP as frontline treatment of PTCL patients. A post-hoc analysis was conducted on patients from France and Belgium centers with PET/CT available for review. TMTV was computed using the SUV4.0 method on LIFEx software. Maxstat package of R software was used to find the best TMTV cutoff based progression-free survival (PFS) and overall survival (OS) data.The thresholds were identified by splitting the data into 80% for training and 20% for validation. The prognostic value of the TMTV was assessed using Cox proportional hazards models, using both categorical and continuous forms (using restricted cubic splines) of the TMTV. We evaluated the improvement in discriminatory performance of TMTV (cutoff and splines) added to the IPI model by calculating time-dependent AUCs based on PFS and OS data. Leave-one-out cross-validation method (LOOCV) was used to prevent overfitting and reduce bias for AUC’s calculation. Results: From 286 patients, 43 had no baseline PET/CT available, resulting in a final study population of 243. The median age was 65 years (interquartile range 57 to 70), most patients had Ann Arbor stage III–IV (83.5%) and 47% had a follicular helper T-cell (TFH) phenotype, with no significant difference between the 43 patients (with no PET available) and the PET cohort. The median pre-therapy TMTV was 171 cm³ (IQR: 29– 574). Patients with high TMTV (>197 mL) had inferior PFS compared to those with lower TMTV (HR = 1.67, 95% CI: 1.25–2.23; P = 0.0005), with a 2-year PFS of 25% vs 41%, respectively. Similarly, TMTV >310 mL was associated with poorer overall survival (OS) (HR = 1.86, 95% CI: 1.35–2.58; P = 0.0002), with 2-year OS rates of 44% vs 68%. Adding TMTV (in class) to the IPI model improved prognostic discrimination as reflected by consistently higher time-dependent AUCs for overall survival. At 20 months, the AUC increased from 67.7 (IPI alone) to 69.8 (IPI+TMTV) , and at 80 months, from 64.5 to 68.6. Continuous TMTV modeling (splines) further enhanced prognostic accuracy with AUC at 20 months of 70.4 and at 80 months of 67.8.The AUC’s improvement for PFS analysis was weaker in the global population. In OS multivariable analysis, high TMTV remained an adverse factor (HR = 1.54 [1.09;2.19] p=0.015), with age > 60 y (HR = 1.79 [1.18;2.71] P=0.006), and the presence of > 2 extranodal sites (HR = 1.74 [1.21;2.49] P=0.002). While median TMTV values did not differ significantly between TFH and non-TFH lymphomas (p=0.32), the prognostic impact of TMTV (class) on PFS differed significantly by TFH status (interaction test: p = 0.0267). TMTV was a strong prognostic factor in non-TFH patients in univariate (HR = 2.22; 95% CI: 1.49–3.32; p <0.0001) and in multivariate analysis (HR= 1.91; 95% CI: 1.18-3.11; p=0.009). In this specific subgroup adding TMTV to IPI model led to an improved prognostic discrimination. At 20 months, the AUC increased from 66.6 (IPI alone) to 70.16 (IPI+TMTV) , and at 70 months, from 67.6 to 73. No statistically significant association was observed in TFH subgroup. Conclusions: Baseline TMTV measured by PET is an independent and robust prognosticator of survival in PTCL patients, offering incremental prognostic value when integrated with established indices such as IPI. These findings advocate for the integration of metabolic imaging biomarkers into routine risk stratification and treatment planning in PTCL.

Link to Abstract abs25-4632

Abstract Number: abs25-781

Bystander activation drives CD8+ t cells response in lymphoma-associated hemophagocytic lymphohistiocytosis

Presenter: Jing Quan Lim
Session: 201. Granulocytes, Monocytes, and Macrophages: Poster III

Abstract: Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition characterized by overt immune activation and cytokine storm. Without timely intervention, HLH rapidly progresses to multiple organ failure and almost certainly lead to death. HLH can be broadly categorized into primary and secondary HLH. While primary HLH (pHLH) is caused by genetic predisposition, secondary HLH (sHLH) can be triggered by a variety of factors, including infection, cancer and autoimmunity. Here we use single- cell expression and TCR profiling technologies to identify the trigger for aberrant activation of CD8+ cells in sHLH.

Methods: Patients were diagnosed with NKTL according to the 2008 World Health Organization classification. Ten whole blood samples profiled for this study were from three patients with NKTCL and concomitant HLH, four patients with NKTCL without HLH and three healthy individuals without any hematological malignancies. All subjects in this study provided written informed consent. Single cell 5’ gene expression libraries, BCR and TCR libraries were prepared using the 10X Genomics Chromium Next GEM Single Cell 5′v2 Library & Gel Bead Kit and V(D)J Enrichment Kits according to the manufacturer’s protocol.

Results: Peripheral blood mononuclear cells (PBMCs) from sHLH patients, NKTL patients without sHLH, and healthy controls (HCs) were analyzed. sHLH patients displayed significantly elevated levels of activated CD8+ T cells and an inverted CD8:CD4 ratio, indicative of heightened proliferation and activation. Single-cell RNA sequencing identified unique subsets of CD8+ T cells in sHLH patients, particularly CD38+Ki67+ effector memory T cells (Act-TEM), which were nearly absent in NKTL and HCs. These cells exhibited markers of exhaustion ( PD-1 , TIGIT , and EOMES ) but retained active proliferation and cytotoxic capacity, diverging from canonical T-cell developmental trajectories. Gene set enrichment analysis highlighted their enrichment in interferon response and cell proliferation pathways, contrasting with the NFκB activation pathways observed in typical effector memory T cells (TEM). T-cell receptor (TCR) sequencing also revealed no significant oligoclonal expansion in sHLH patients, suggesting a non-TCR-mediated activation mechanism. Naïve CD8+ T cells in sHLH patients produced granzyme B, further supporting non-canonical activation. Ex vivo cytokine treatments identified IL-15 as a key driver of this phenotype, capable of inducing granzyme B production and promoting the differentiation of CD8+ T cells into Act-TEM. Elevated IL-15 levels in plasma and monocytes, along with increased CCR5 expression on CD8+ T cells, corroborate the role of IL-15 in bystander activation too.

Conclusion: We report IL-15 mediated bystanding activation of CD8+ T-cells in sHLH. This highlights IL-15 as a potential immune-modulating target to soothe the cytokine storm in patients with sHLH.

Link to Abstract abs25-781

Abstract Number: abs25-1423

Outcomes of patients with dual primary T-cell and B-cell lymphoid malignancies

Presenter: Zachary Hing
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: Background: Background: Patients with T-cell lymphomas and other mature T-cell malignancies are at increased risk of developing subsequent B-cell malignancies and vice versa. This elevated bidirectional risk, although previously reported, is poorly understood. Little is known about the natural history and clinical outcomes of patients who develop both primary B-cell and T-cell lymphoid malignancies. Even less is known about the predisposing risk factors and whether they are intrinsic to the patient or treatment history. A deeper understanding of this sequence may yield better insights into the process of lymphomagenesis.

Methods: This is an ongoing retrospective study conducted across multiple academic centers of patients with dual primary B-cell and T-cell neoplasms. Inclusion criteria include patients over the age of 18 with a diagnosis of a mature T-cell neoplasm and a mature B-cell neoplasm, Hodgkin lymphoma, or post-transplant lymphoproliferative disorder (PTLD) as defined by the revised 2016 WHO classification of lymphoid neoplasms. The primary objectives are to assess the clinical characteristics of patients with dual primary T-cell and B-cell neoplasms and describe clinical outcomes. Continuous variables are summarized as a median and categorical variables are reported as a frequency (%).

Results: At the time of this interim analysis, 40 patients from 4 academic centers were identified with dual B- and T-cell lymphoid malignancies confirmed on biopsy. Of these patients, 60% (24/40) were male and 40% (16/40) female. The median age at first primary lymphoid malignancy diagnosis was 64 years (range 32- 87) and second primary lymphoid malignancy was 66.5 years (range 32-88) with a median latency between diagnoses of 2.2 years (range 0-16.6). The most frequently occurring first primary lymphoid malignancy subtypes included diffuse large B-cell lymphoma (DLBCL; 17.5%; 7/40), angioimmunoblastic T- cell lymphoma (AITL; 17.5%; 7/40) and mycosis fungoides (MF; 17.5%; 7/40). The most frequently occurring second primary lymphoid malignancy subtypes included DLBCL (22.5%; 9/40) and peripheral T- cell lymphoma, not otherwise specified (PTCL, NOS; 15%; 6/40). Autoimmune comorbid conditions including rheumatoid arthritis, sarcoidosis and autoimmune thyroiditis were observed in 20% (8/40) of patients, while a history of either HBV and HCV was noted in 12.5% (5/40) of patients. EBV positive tumors by IHC +/- associated viremia were identified at diagnosis of one lymphoid malignancy in 27.5% (11/40) of patients and in both lymphoid malignancies in 12.5% (5/40) of patients. A family history of autoimmune disease was observed in 7.5% (3/40) of patients and 10% (4/40) of patients had a family history of blood cancer. The incidence of solid malignancies, excluding non-melanoma skin cancer, was 17.5% (7/40) and the incidence of myeloid malignancies beyond dual primary lymphoid malignancies was 5% (2/40). Mutational data was available in 23 patients and mutations associated with clonal hematopoiesis were detected at variant allele frequencies above 5% in TET2 (20%; 8/40), DNMT3A (10%; 4/40), TP53 (7.5%; 3/40) and ASXL1 (2.5%; 1/40). In our cohort, 45% (18/40) of patients received systemic chemotherapy prior to diagnosis of the second lymphoid malignancy. One patient received a CD19-directed CAR-T prior to the development of a second lymphoid malignancy (T-cell LGL), which was determined to be unrelated to CAR-T after transgene testing. Median overall survival (OS) from diagnosis of first primary lymphoid malignancy was not reached at the time of analysis; follow-up time ranged from 4 months to 24 years. Conclusions Conclusions This multicenter real-world study suggests autoimmune conditions occur relatively frequently in patients with dual B- and T-cell lymphoid malignancies and further investigation into immune dysregulation and elevated bidirectional risk of lymphoid malignancies is warranted. Furthermore, we observed the occurrence of mutations associated with clonal hematopoiesis, particularly TET2 , in our cohort. These data are also consistent with prior observations showing that histologies such as DLBCL, AITL, and PTCL, NOS are more often associated with dual primary lymphoid malignancies. In our cohort, we did not observe an association with CAR-T therapy and the development of second T-cell lymphoid malignancies. Accrual of additional patients with dual lymphoid malignancies is in process and will be important to expand on these observations.

Link to Abstract abs25-1423

Abstract Number: abs25-2426

Outcomes of second-line systemic therapy for relapsed or refractory peripheral T-cell lymphomas: A single-center, retrospective analysis

Presenter: Zachary Epstein-Peterson
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: Purpose: Purpose: Limited data exist detailing the outcomes with second-line (2L) systemic treatment of relapsed or refractory (R/R) peripheral T-cell lymphomas (PTCL) in contemporary practice. Previous series (Mak et al. 2013) demonstrated extremely poor outcomes for such patients (pts): median progression-free (PFS) and overall survival (OS) after relapse or progression were 3.1 and 5.5 months, respectively. However, advances have been made since then in developing targeted therapies including brentuximab-vedotin, HDAC, PI3K, EZH, and JAK inhibitors and others, and more frequent use of alloHCT. Data from newer cohorts with access to these agents would update our understanding of prognosis in this setting, redefine prognostic variables, and serve as a benchmark for future studies.

Methods: We identified consecutive pts with PTCL treated with 2L systemic therapy at our center from 2012-2025; 1L therapy may have occurred elsewhere. We included common nodal subtypes of PTCL: anaplastic large cell lymphoma (ALCL), T follicular helper lymphomas (TFH), and PTCL, not otherwise specified (NOS); all pts had pathology reviewed at our center. We queried institutional databases and performed chart review to extract variables of interest and categorized 2L therapies as either conventional cytotoxic chemotherapy, non-chemotherapy, or combinations. Treatment may have occurred as standard-of-care or in a clinical trial. We calculated survival times starting from 2L initiation using Kaplan-Meier methods. We associated features of interest (age at 2L, disease subtype, prior HCT, primary refractory disease, and chemotherapy 2L treatment) with PFS/OS in univariable and multivariable Cox models.

Results: 212 eligible pts were identified; most pts were male (57%) and most had TFH lymphomas (50%) followed by NOS (37%) and ALCL (13%). Regarding frontline therapy and outcome, most pts received anthracycline-based multiagent chemotherapy (83%) and most attained a response followed by subsequent relapse (64%), versus 36% that had primary refractory disease. Fifty-five pts (26%) had previously undergone HCT (54 autologous, 1 allogeneic). At time of R/R disease, the median age was 66 years (IQR, 57-74). 2L management was non-chemotherapy in 57% of pts, chemotherapy in 43% of pts, and combined in 1%; 40% of pts were treated in a clinical trial. Among 197 pts with response data, the overall response rate to 2L was 63% (42% CR, 21% PR): non-chemotherapy 66%, chemotherapy 59%; 29 pts (14%) underwent HCT immediately post-2L (8/29, 28% autologous, 21/29, 72% alloHCT). With a median follow-up among survivors of 44 months, the median PFS (medPFS) and OS after 2L are 4.7 (95% CI: 3.6-6.4) and 22.7 (95% CI: 13.4-34.3) months, respectively. The 12-month rates of PFS and OS were 32% (95% CI: 27-39) and 58% (95% CI: 51-65), respectively; 24- and 36-month OS rates were 49% (95% CI: 43-57) and 41% (95% CI: 35-49), respectively. NOS [vs. TFH/ALCL, adjusted HR (aHR) 1.8, 95% CI 1.3-2.5, P = 0.0002] and primary refractory disease (aHR 1.7, 95% CI: 1.2-2.3, P = 0.005) each conferred inferior PFS in multivariable analysis. Regarding OS, NOS (aHR: 2.0, 95% CI: 1.5-2.9, P <0.0001) and primary refractory disease (aHR 1.7, 95% CI: 1.1-2.4, P = 0.009) conferred inferior OS in univariable and multivariable analysis.

Conclusions: We analyzed a large cohort of pts with R/R PTCL initiating 2L systemic therapy in an era with additional treatment options and increasing use of novel therapies. Since prior publications, we highlight improved OS, suggesting that recent therapeutic advances are improving longer-term outcomes. MedPFS to 2L appeared similar to prior series, suggesting that recent expansion of treatment options has allowed for more opportunities to identify an effective therapy for an individual patient. Increasing use of consolidative alloHCT for pts may also contribute to these improved OS outcomes. Pts with NOS (reflecting the lack of subtype-specific advances that have been attained for ALCL/TFH) and those with primary refractory disease fared relatively poorly. Even with these improvements, R/R PTCL remains an area of high unmet need; novel treatment approaches in clinical trials and translational efforts aimed at further elucidating the disease pathobiology of PTCL to identify new treatment targets are urgently needed.

Link to Abstract abs25-2426

Abstract Number: abs25-2600

Clinical disparities in enteropathy-associated T-cell lymphoma: A national cancer database study of 736 patients treated at academic and community cancer centers

Presenter: Oscar Hinojosa
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: I) Background: Enteropathy-associated T-cell lymphoma (EATL) represents 3% of peripheral T-cell lymphomas. It constitutes two thirds of all primary intestinal T-cell lymphomas in Europe and the USA, with a strong association with celiac disease (ISBN: 9789283245209). It affects patients in the sixth decade of life, with a mild male predominance (PMID: 21566094). Although prior studies have assessed population-level outcomes in EATL, national-level comparisons of clinical characteristics and survival by facility type are rare. This study represents the largest retrospective cohort analysis to date examining the impact of treatment facility—Academic Cancer Programs (ACPs) versus Community Cancer Programs (CCPs)—on patient demographics, treatment patterns, and survival outcomes in EATL. II) Method We conducted a retrospective analysis of EATL cases in the U.S. from 2004-2022, using the National Cancer Database (NCDB). Facilities were classified as ACPs (Academic/research programs, including NCI centers) and CCPs (Community, comprehensive community, and integrated network cancer programs). Demographic, clinical, and treatment variables were compared between cohorts. Overall survival (OS) was assessed using Kaplan–Meier and Cox proportional hazards models, adjusted for age, race/ethnicity, insurance status, Charlson–Deyo score, and distance from treating facility. III) Results A total of 736 patients with EATL were identified. Data on facility type were available for 705 patients (96%), including 420 (57%) treated at ACPs and 285 (39%) at CCPs. The remaining 31 patients (4%) lacked facility type data and were excluded from comparative analyses. Both cohorts had a predominance of male patients (61% ACPs and 59% CCPs). Younger patients (< 60 years) were more often treated at ACPs (31% vs 25%; p < 0.001), whereas older patients (≥75 years) were more common at CCPs (34% vs 19%). Race/ethnicity distributions were similar between groups: White (78% ACPs and 79% CCPs), Black (11% ACPs and 10% CCPs), and Hispanic (9% ACPs and 6% CCPs). Insurance coverage patterns varied by treatment setting. At ACPs, private insurance (40%) was the most common payor, followed by Medicare (47%). In contrast, Medicare was the leading payor at CCPs (58%), followed by private insurance (30%). Rates of Medicaid coverage and uninsured patients were low in both cohorts. Socioeconomic factors such as income, education level, and residence location was comparable. However, patients treated at ACPs lived farther from their treatment centers compared to those at CCPs (12 miles vs. 8.6 miles; p < 0.001). A significantly greater percentage of patients at ACPs received systemic treatment (74%) compared to those at CCPs (66%; p=0.009). Median time to treatment initiation was similar between both groups. When analyzed by treatment type, time to chemotherapy initiation remained similar, but time to immunotherapy initiation was lower at CCPs (29.5 vs 56 days; p=0.003). Short-term outcomes revealed a higher 90-day mortality at ACPs compared to CCPs (43% vs 37%, respectively; p<0.003). However, the median follow-up time was longer at ACPs (7.4 vs 4.4 months; p<0.001). The percentage of patients alive at last follow-up was higher at ACPs (18% vs. 10%; p<0.001). Adjusted OS at 2, 5, and 10 years was marginally superior at ACPs vs CCPs (0.263 vs. 0.211, 0.178 vs. 0.157, and 0.133 vs. 0.085, respectively), resulting in a longer adjusted median survival time at ACPs (0.6 vs 0.4; p=0.0017). IV) Conclusions Although EATL affects a broad socioeconomic spectrum, its distribution by treatment facility differs. CCPs manage a larger proportion of elderly patients with greater reliance on Medicare. While residence location was similar between groups, patients at CCPs traveled shorter distances, suggesting disparities in economic resources and transportation access needed to reach academic centers, particularly among the older cohort treated at CCPs. Short-term outcomes, measured by 90-day mortality favored CCPs. However, the proportion of patients alive at last follow-up and adjusted median survival were higher at ACPs. These superior outcomes could be explained by longer follow-up and greater use of systemic therapies, likely reflecting greater access to resources and more consistent adherence to clinical guidelines at academic centers. An older, potentially more vulnerable population at CCPs may also contribute to poorer long-term outcomes.

Link to Abstract abs25-2600

Abstract Number: abs25-2771

Molecular determinants of therapeutic response to nivolumab in Relapsed/Refractory PTCL: An integrated multiomic study of A phase II investigator-initiated trial

Presenter: Takeshi Sugio
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: Background: Peripheral T-cell lymphomas (PTCL) display heterogeneous responses to immune checkpoint inhibitors, including rare durable responses. The basis for such variability remains unclear. Previously, we identified elevated expression of immune checkpoint genes (e.g., CD274 [PD-L1]) in ~50% of PTCL-NOS, associated with an M2 macrophage-like gene expression signature (Sugio et al., Blood Adv 2018). We hypothesized that a subset of relapsed/refractory (r/r) PTCL patients may benefit from PD-1 blockade, with molecular profiles helping to identify them using tumor and liquid biopsies.

Methods: We conducted a Phase II investigator-initiated trial of Nivolumab monotherapy (240mg every 2 weeks) in r/r PTCL patients who failed ≥2 prior therapies (WJHS-NHL02, UMIN000034499). The primary endpoint was overall response rate (ORR); secondary endpoints included CR rate, PFS, and OS. Molecular profiling included tumor RNA-seq, whole exome sequencing, and plasma cfDNA analyses (CAPP-Seq for SNVs/indels [Newman et al., Nat Med 2016], CANARy for CNAs [Chabon et al., Nature 2020], EPIC-Seq for inferred expression [Esfahani et al., NBT 2022], SABER/QUARTZ for TCR analysis [Shukla et al., ASH2022, Sugio et al., ASH2024]). We also performed Imaging Mass Cytometry (IMC) to characterize spatial proteomic profiles of one patient with an exceptionally long response using Hyperion.

Results: Of 20 enrolled patients, 19 received Nivolumab. Median age was 68.5 years; 21% were female. Histologies included PTCL-NOS (n=4), ENKTL (n=6), AITL (n=4), ALCL (n=5; 20% ALK+), and EATL (n=1). Grade 3/4 SAEs occurred in 9 patients, including infectious disease (21%). One patient developed breast cancer and discontinued treatment despite long-term lymphoma response. The ORR was 10.3% (2/19: 1 PTCL-NOS, 1 AITL) with no CRs, and one patient had SD. Three patients were not evaluable for response due to insufficient imaging follow-up. Three patients achieving PR/SD had durable responses >2 years. All of 4 evaluable ENKTL cases had PD. The median OS and PFS were 5.7 and 2.0 months, respectively. Responders showed enrichment for specific molecular features, including PD- L1/2 mutations, higher total mutation burden (TMB), and distinct T-cell receptor (TCR) dynamics. One PTCL-NOS patient with early PR had a CD274 intron 5 mutation and immune-inflammatory pathway alterations; IMC revealed a focal infiltration of PD-L1+ macrophage and CD8+ T cells with a well- demarcated boundary. A second patient with EATL experiencing >2 years of durable SD had mutations in CD274 3’UTR, PDCD2LG1 (PD-L2), and PTPRD . Another patient achieving PR had typical AITL-associated mutations. Responders also had significantly greater diversity of TCR in cfDNA (cfTCR). Specifically, among 13 non- ENKTL patients with dominant tumor TCR clonotypes in tumor tissues, 4 lacked detectable monoclonal expansions of these clonotypes in cfTCR, of whom 3 (75%) achieved >2 years PFS. The patients experiencing Nivolumab-induced early ctDNA reductions had higher levels of diversity in cfTCRs, which were non-tumor derived. All patients with >2 years of PFS showed either complete clearance of ctDNA MRD or a >90% reduction. One patient who discontinued Nivolumab due to breast cancer maintained her long-term PR with sustained absence of ctDNA MRD. Among the 3 patients who were unevaluable radiographically, two showed notable ctDNA reductions (85% and 25%) at the time of discontinuation, whereas all other PD cases showed increased ctDNA levels. ctDNA responders had significantly higher TMB (p = 0.02) and ctDNA levels (p = 0.04) at baseline. RNA-seq of diagnostic tumor tissue showed higher expression of macrophage-related genes in PR patients. EPIC-Seq of pre-treatment cfDNA revealed elevated expression of macrophage, B-cell, and dendritic cell-related genes, as well as PD-L1. These findings suggest enhanced turnover of both tumor and non–tumor immune cells in patients with PR.

Conclusions: Although the pre-specified efficacy threshold (ORR 30%) was not met, Nivolumab monotherapy induced durable disease controls in 3 (15.8%) patients with r/r PTCL, including 2 (10%) patients with PRs. Durable disease controls were associated with PD-L1/2 and PTPRD mutations, higher TMB, and increased cfTCR diversity. We also observed augmented turnover of both tumor cells and non- tumor immune cells in responders. cfDNA profiling may help identify candidates for PD-1 blockade in PTCL and should be integrated into future trials.

Link to Abstract abs25-2771

Abstract Number: abs25-4359

High HDAC I/IIb selective inhibitor purinostat mesylate in relapsed and refractory peripheral T-cell lymphoma: A single-agent phase IIa study

Presenter: Ting Niu
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: Background: Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas associated with poor survival outcomes. Relapsed or refractory (R/R) PTCLs have an even worse prognosis, with historically reported median overall survival (mOS) of less than 6 months. Current monotherapies yield only modest overall response rates (ORR) ranging from 22% to 38%, except for brentuximab vedotin in CD30-positive anaplastic large cell lymphoma (ALCL). Purinostat Mesylate (PM) is a highly selective HDAC I/IIb inhibitor. In a phase I dose-escalation study, PM achieved an encouraging ORR of 61.1% in R/R lymphomas with manageable toxicities. A phase IIa was conducted to further evaluate the eﬃcacy and safety of PM in R/R PTCL (NCT06485219).

Methods: Eligible patients were adults with pathologically conﬁrmed R/R PTCL who had received 1 to 5 prior lines of therapy, including anthracycline-based chemotherapy for PTCL and asparaginase-based therapy for NK/T-cell lymphoma (NKTCL), ECOG≤2. Patients were randomized 1:1 to receive PM at doses of 11.2 or 15.0 mg/m² on Days 1, 4, 8, and 11 of a 21-day cycle. 10-15 patients were planned to be enrolled at each group. Patients continued treatment until disease progression or unacceptable toxicity. The primary endpoint was ORR; secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.

Results: As of July 23, 2025, 24 patients with R/R PTCL were enrolled. Baseline characteristics included a median age of 58.0 years (range: 36–76), 19 males (79.2%), and a median of 2 prior lines of therapy. Twenty patients had at least one response evaluation. After a median follow-up of 5.39 months, the ORR was 55.0% (11/20), comprising 4 complete responses (CR) and 7 partial responses (PR). Four patients at 11.2 mg/m 2 (4/8) achieved an ORR of 50.0% with 1 CR and 3 PR. Seven patients at 15.0 mg/m 2 (7/12) achieved ORR of 58.3% with 3 CR and 4 PR. ORRs by histology were 20% (1/5) for PTCL-NOS (CR), 100% (1/1) for NKTCL, 50.0% (5/10) for AITL, and 100% (4/4) for ALCL. Most patients can beneﬁt from the treatment at an earlier time with a median time to response (TTR) of 2.76 months (1.28, NR), and the median duration of response (mDOR) was 6.01 months (0.66, NR). Among responders, 5 patients remain on treatment, with the longest ongoing treatment lasting 16 cycles. Median PFS was 4.24 months (2.56, 7.29) and median OS was 7.59 months (6.18, NR). The most common grade ≥3 treatment-related adverse events included neutropenia (83.3%), thrombocytopenia (75.0%), leukocytopenia (50.0%), lymphocytopenia (41.7%), anemia (20.8%), infectious pneumonia (16.7%), bacterial pneumonia (12.5%), and hypokalemia (12.5%). There was one treatment-related death due to infection.

Conclusion: Preliminary results from this phase IIa study indicate that PM administered in 21-day cycles demonstrates promising eﬃcacy compared with currently available single agents, with a manageable safety proﬁle in patients with R/R PTCL.

Link to Abstract abs25-4359

Abstract Number: abs25-4591

Comparative outcomes of 14,650 patients with mycosis fungoides/Sézary syndrome from academic and community cancer programs

Presenter: Erin Kaser
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: Background: Cutaneous T-cell lymphomas are a group of lymphoproliferative disorders that are characterized by dermal infiltration by mature, malignant T cells (Blood PMID: 30635287). Mycosis Fungoides (MF) is the most common form with presenting features of skin plaques, patches or tumors, typically following an indolent clinical course (J Am Acad Dermatol PMID: 16310068 ). Sézary Syndrome (SS) is the leukemic variant characterized by the presence of neoplastic, clonal T-cells with cerebriform nuclei (Sezary cells) involving the skin, lymph nodes, and peripheral blood (J Am Acad Dermatol PMID: 21145619). Current treatment for MF/SS includes skin-directed therapies for early stages, and systemic therapies for advanced stages of the disease. However, treatment rarely induces long-term remission or cure. Overall, MF/SS are rare disorders, which can lead to treatment and clinical outcome variability depending on the treatment center. Our study evaluates the outcomes of MF/SS patients treated at academic cancer programs (ACP) compared to those treated a community cancer programs (CCP). Materials and Methods: Materials and Methods: We retrospectively reviewed cases of MF/SS diagnosed in the United States using the National Cancer Data Base between the years 2004 and 2022. Demographics and clinical and survival data were compared between patients treated at ACP and CCP. Kaplan-Meier and Cox proportional hazards models were utilized to compare overall survival (OS), adjusting for age, race/ethnicity, insurance type, distance from treating facility, and comorbidity score (Charlson-Deyo).

Results: A total of 14,650 MF/SS patients were retrospectively analyzed between the years 2004 and 2022, with 11,016 (75%) of patients receiving treatment at ACP and 1,745 (12%) at a CCP. Most patients were male (57% in ACP and 62% in CCP) and predominantly white (74% at ACP and 82% at CCP). ACP had higher proportions of both black (19% ACP vs 12% CCP, p < 0.001) and Hispanic patients (6% ACP vs 5% CCP, p < 0.001). Patients at ACP were younger at diagnosis (63 years) compared to CCP (67 years) (p < 0.001). A higher number of patients were uninsured at ACP (2.4%) compared to CCP (1.9%). Comparison of the great circle distance (CROWFLY), a variable measuring the distance between a patient’s residence and hospital, revealed patients at ACP lived further from the hospital center (18 miles compared to 9 miles, p < 0.001). At ACP, patients were more likely to receive treatment (71% vs 66%, p < 0.001). Treatment was initiated quicker at ACP (31 days) than CCP (36 days) (p < 0.005) with associated faster systemic therapy initiation (38 days vs 45 days) (p = 0.002). More patients at CCP received radiation (23% vs 13%, p < 0.001). More patients were diagnosed with stage IV at CCP (9.1%) than ACP (7.8%) (p < 0.001). The 30- and 90- day mortality was similar across groups (30 day: ACP 88.5% vs CCP 87.7%) (90 day: ACP 88.5% vs CCP 87.7%). The adjusted median survival for MF/SS patients at ACP was higher (14 years vs 11 years, p < 0.001). Across all timepoints (2, 5, and 10 years), the KM-estimated OS was higher at ACP than CCP, with a 2-year survival of 88.7% vs 82.2%, a 5-year survival of 75% vs. 68%, and 10 year survival of 61% and 32%, respectively.

Conclusion: This data analysis of 14,650 patients with Mycosis Fungoides/Sézary Syndrome reveal significant differences in baseline characteristics and outcomes depending on treatment at an academic cancer program (ACP) or community cancer program (CCP). Patients at ACP were more racially diverse, more likely to be uninsured, and geographically lived further from treatment centers. Treatment initiation was more frequent and faster for systemic therapy at ACPs, while CCPs had higher rates of chemotherapy, stage IV diagnosis, and radiation therapy. Despite similar short-term mortality, ACP patients had longer adjusted median survival and significantly higher survival rates at 2, 5, and 10 years – with the10-year survival rate nearly double to that of CCP. These findings suggest early referral to ACP could lead to improved clinical outcomes in rare cancers such as MF/SS.

Link to Abstract abs25-4591

Abstract Number: abs25-7730

Final results from the embolden trial: pembrolizumab in combination with decitabine and pralatrexate in heavily pretreated patients with peripheral and cutaneous T-cell lymphoma

Presenter: Nathan Roberts
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: Background: Patients with relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) have a poor prognosis with median overall survival of ~3-12 months with current therapies, highlighting an urgent unmet need for novel therapeutics. PTCL is uniquely sensitive to epigenetic modifiers. We have shown that DNMT3 inhibitors like 5-azacytidine have potent immunomodulatory effects, including upregulation of cancer testis antigens, in pre-clinical models of T-cell lymphoma. Similarly, we have shown that pralatrexate (PTX) is potentially synergistic with drugs targeting epigenetic regulation. These data suggest a role for combining the immune checkpoint inhibitor pembrolizumab (pembro) with epigenetic agents in patients with PTCL.

Methods: : PTCL-002 is a multicenter, multi-arm phase Ib study designed to evaluate the safety and efficacy of pembro in combination with PTX and/or decitabine (DAC) in patients with R/R PTCL and CTCL. The study included three arms: arm A (pembro+PTX), arm B (pembro+PTX+DAC), and arm C (pembro+DAC). All patients received pembro 200 mg by IV infusion every 21 days. Dose selection for DAC and PTX in arms A and C, respectively, was based on a continual reassessment method (CRM) while arm B used a partial order CRM. Primary endpoints included MTD, RP2D, dose-limiting toxicities (DLT) and clinical efficacy as assessed by overall response rate (ORR). Secondary endpoints included progression- free survival, duration of response, and overall survival. Select pharmacokinetic and pharmacodynamic endpoints were also included in order to assess immune modulation and identify potential predictors of response.

Results: We enrolled 26 patients, including 9 patients in arm A, 7 in arm B, and 10 in arm C. Median age was 61 (range 27-77) with 13 males and 13 females. Racial demographics were as follows: White 62%, Black 23%, Asian 3%, and Hispanic 1%. Median number of prior treatments was 3 (range 1-6). Histologic subtypes included ATLL (n=1), AITL (n=4), PTCL-NOS (n=10), SS (n=1), MF (n=6), PCALCL (n=1), MEITL (n=1), PCAECTL (n=1), and TFh-PTCL (n=1). Twenty-four of 26 patients received at least one dose of study drug and were evaluable for toxicity. Twenty-one of 26 of patients received at least one full cycle of therapy and were evaluable for response. Reasons for early discontinuation included consent withdrawal (n=1), rapid disease progression during cycle 1 (n=2), adverse event (n=1), and investigator decision (n=1). One DLT was observed each in arms A and B for prolonged grade 3 thrombocytopenia and febrile neutropenia, respectively. Three DLTs were observed in arm C including one patient with grade 3 hyponatremia and rash; one patient with grade 4 thrombocytopenia, neutropenia, and anemia; and one patient with grade 4 neutropenia. There were no treatment related deaths. Based on the observed DLTs, the RP2D for DAC in combination with pembro is 20 mg/m 2 on days 1-3; the RP2D for PTX in combination with pembro is 30 mg/m 2 on days 1, 8, and 15; for the triplet combination, the RP2D for DAC is 10 mg/m 2 given on days 1-5 and the RP2D for PTX is 20 mg/m 2 given on days 1, 8, and 15. Among 21 evaluable patients, responses were as follows: ORR 19% (4/21), CR 10% (2/21), PR 10% (2/21), and disease control rate (defined as proportion of patients with stable disease or better) 38% (8/21). ORR among evaluable patients in arms A, B, and C were 40% (2/5), 29% (2/7), and 0% (0/9), respectively. Analysis of serum cytokine levels in select patients (4 in Arm A, 4 in Arm B, and 5 in Arm C) revealed significant changes in 5 cytokines when compared to healthy age- and sex-matched controls. Of the 5 cytokines, 3 pro- inflammatory cytokines, TNF α, MIP-3α and IL-10, measured at day 1 pre-treatment were significantly higher in trial patients (p= 0.0001, 0.0008 and 0.003 respectively) than in healthy controls. Trial patients who responded to treatment (PR/CR) in any arms demonstrated a decline in serum levels of TNF α and IL- 10 by day 15 of cycle 1, whereas non-responders (PD/SD) showed stable to increased levels of both TNF α and IL-10.

Conclusion: We successfully identified the RP2D for DAC and/or PTX in combination with pembro in patients with R/R PTCL and CTCL. We demonstrated that an epigenetic platform incorporating the immune checkpoint inhibitor pembrolizumab is safe in heavily pretreated disease. More work on changes in cytokine profiles is needed before drawing any conclusions on their relationship to response.

Link to Abstract abs25-7730

Abstract Number: abs25-8200

Chidamide with the methotrexate, ifosfamide, etoposide, doxorubicin liposomes, and dexamethasone (MIEDD) regimen improves efficacy and safety in newly diagnosed primary CNS T-cell lymphoma

Presenter: Jing Liu
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: Background: Background: Diﬀuse large B-cell lymphoma, a common subtype of primary central nervous system (CNS) lymphoma, has been increasingly studied. In contrast, advances in treating primary CNS T-cell lymphoma remain limited. Until now, a single large series exclusively describing treatment regimens and evaluating their eﬃcacy in patients with newly diagnosed primary CNS T-cell lymphoma has not been reported. We referred to the treatment regimen for primary CNS lymphoma (high-dose methotrexate-based chemotherapies) in combination with the treatment regimen for systemic T cell lymphoma (CHOEP plus chidamide) and selected drugs that can cross the blood ‒ brain barrier to develop the methotrexate, ifosfamide, etoposide, doxorubicin liposomes and dexamethasone (MIEDD) regimen with or without chidamide. This study aimed to evaluate the eﬃcacy and safety of this regimen for newly diagnosed primary CNS T-cell lymphoma.

Methods: HIV-negative patients with newly diagnosed primary CNS T-cell lymphoma at Beijing Tiantan Hospital, Capital Medical University, between January 2022 and December 2024 received three-six cycles of methotrexate (3.5 g/m 2 ) on day 1, ifosfamide (1.5 g/m 2 ) on day 2, etoposide (100 mg/m 2 ) on day 3, doxorubicin liposomes (25 mg/m 2 ) on day 4, and dexamethasone (10 mg) on days 1-3, with a cycle of every 21 days. Chidamide (30 mg) was taken orally twice a week.

Results: Eleven patients were included in the study, with a median age was 54 years (range, 34-74), and 3 patients (27.3%) were ≥ 60 years of age. Six patients (54.5%) were male. The median time from symptom onset to deﬁnitive diagnosis was 1.5 months (range, 0.5-5 months). The histological type of all primary CNS lymphomas was peripheral T-cell lymphoma not otherwise speciﬁed. Ten of 11 patients completed 6 cycles of induction chemotherapy; another patient received 3 cycles. Six patients (54.5%) plus 30 mg chidamide twice a week. Among them, 2 began to receive it in induction therapy, 3 received it as maintenance treatment, and 1 received it when the disease progressed after the end of 6 cycles of induction chemotherapy. After induction therapy, 8 (72.7%) patients achieved complete remission (CR), 1 (9.1%) patient achieved partial remission (PR), 1 (9.1%) patient had stable disease (SD), and 1 (9.1%) patient had progressive disease (PD). After receiving one cycle of induction chemotherapy with the MIEDD regimen, two patients were assessed as SD and PD. Beginning with the second cycle, chidamide was added to the MIEDD regimen. Prior to the ﬁfth cycle of chemotherapy, disease evaluation achieved CR and PR. Three additional patients achieved sustained remission status with oral chidamide maintenance therapy following induction chemotherapy. At a median follow-up of 15.7 months (95% CI, 12.14–19.26), the median PFS was not reached, with an estimated PFS rate of 68.2% at 2 years. The median OS was not reached. All patients were still alive at the time this paper was written. The most common adverse events were hypocytosis and gastrointestinal symptoms. Grade 4 hematological toxicity occurred in 2 patients. No patients died of toxicity. Conclusions Conclusions The preliminary results of this study show that chidamide combined with the MIEDD regimen has good eﬃcacy and safety in the treatment of patients with newly diagnosed primary CNS T-cell lymphoma. Building on these encouraging results, we will conduct a Phase II clinical trial, in which the cerebrospinal fluid permeability of chidamide and its optimal dosage will be the key focus.

Link to Abstract abs25-8200

Abstract Number: abs25-9625

Peripheral T-cell lymphomas: Real-world insights into clinical features and prognosis

Presenter: Amaya Llorente-Chávez
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: Introduction: Peripheral T-cell lymphomas (PTCLs) are associated with poor prognosis. Subtypes include peripheral T- cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL), either ALK-positive or ALK-negative. Despite evidence suggesting a higher prevalence in Latin America, information on their clinical features and outcomes in middle-income settings remain limited.

Methods: A retrospective analysis was conducted on patients with PTCL at a national referral center in Mexico from 2011 to 2024. Descriptive and comparative statistics were performed. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier curves and log-rank test.

Results: A total of 128 patients were included, with a median age of 46 years (IQR 28–64) and a male-to-female ratio of 1:1. At diagnosis, 55.5% had B symptoms, 71.1% had advanced disease (stage III–IV); 21% with bone marrow involvement, and 1.6% with CNS infiltration. ECOG was > 2 in 32.8%, 3.9% had other malignancies, and 0.8% were HIV-positive. ALCL ALK-negative was diagnosed in 36.7% (47), PTCL-NOS in 35.2% (45), ALCL ALK-positive in 23.4% (30), and AITL in 4.7% (6). According to IPI, 30.2% had low risk, 33.3% low-intermediate, 21.4% high- intermediate, and 15.1% high risk. According to PIT, 27.2% had low risk, 26.2% low-intermediate, 27.2% high-intermediate, and 19.4% high risk. Regarding first-line treatment, 75% received anthracycline-based regimens, 7% brentuximab-based, and 18% did not receive systemic therapy due to severe clinical conditions. Radiotherapy was administered in 42.2%, and 13.3% underwent HSCT. The overall response rate was 54.6%, including complete response (CR) in 39.8%, and partial response (PR) in 14.8%. Disease progression occurred in 16.4%, and 28.9% were non-evaluable due to early death. Median OS was 15 months (IQR 6–81), and PFS was 9 months (IQR 4–56). Median OS and PFS by lymphoma subtype were: for AITL, 8 months (IQR 5–50) and 8 months (IQR 3–30); for PTCL-NOS, 15 months (IQR 6–90) and 8 months (IQR 4–32); for ALK-negative ALCL, 17 months (IQR 8–83) and 9 months (IQR 4–69); and for ALK-positive ALCL, 32 months (IQR 3–78) and 13 months (IQR 2–63). Advanced stage (p=0.05), ECOG > 2 (p=0.021), age > 60 years (p=0.042), high-intermediate to high risk IPI score (p=0.034), and PR, progression, or non-evaluable disease (p=0.0001) were associated with increased mortality. Laboratory parameters associated with poor survival included β2-microglobulin > 2.5 mg/L (p=0.05; OR 2.35, 95% CI 0.96–5.73), albumin < 3.5 g/dL (p=0.0001; OR 4.5, 95% CI 2–10.4), and lymphocyte count < 1000/μL (p=0.047; OR 2.5, 95% CI 0.99–6.6). Relapsed or refractory (R/R) disease occurred in 35.2% and was associated with worse outcomes (p=0.014); including a 33% mortality rate, mainly due to disease progression (p=0.003). Patients whose response could not be evaluated had the poorest outcomes, with a median OS and PFS of 2 months, and a mortality rate of 43% due to failure to receive or complete induction. Clinical and laboratory predictors of relapse or progression included age > 60 years (p=0.0001), bone marrow infiltration (p=0.002), advanced-stage (p=0.037), ECOG > 2 (p=0.007), elevated LDH (p=0.044), β2- microglobulin > 2.5 mg/L (p=0.001), albumin < 3.5 g/dL (p=0.015), lymphopenia < 1000/μL (p=0.09), and thrombocytopenia < 100,000/μL (p=0.0001). Immunohistochemical markers associated with poor prognosis included positivity for CD3 (p=0.05), CD5 (p=0.001), and EBER (p=0.007), as well as higher Ki-67 expression > 70% (p=0.017). High-intermediate or high risk according to IPI (p=0.0001) and PIT (p=0.001) scores were also associated. Treatment strategy and response influenced survival (p=0.0001). Patients treated with brentuximab- based therapy had the best OS followed by anthracycline-based regimens, as well as those with CR. Not receiving radiotherapy was associated with bad prognosis (p=0.019).

Conclusion: This study provides one of the largest single-center descriptions of PTCL in Mexico and Latin America, highlighting advanced-stage disease at diagnosis, a third of R/R cases, and the limited access to targeted therapies and HSCT. Response rates and survival outcomes remain poor, particularly for PTCL-NOS and AITL. These findings underscore the urgent need for improved diagnostic and therapeutic access, and risk-adapted therapies to improve survival in this vulnerable population.

Link to Abstract abs25-9625

Abstract Number: abs25-10070

Durable responses in the updated 2-year follow-up of patients from a single-center with Relapsed/Refractory peripheral T-cell lymphoma treated with golidocitinib

Presenter: Eduardo Edelman Saul
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: Background: Background: Up to 75% of peripheral T-cell lymphoma (PTCL) patients (pts) treated with frontline CHOP-based therapy have relapsed/refractory (r/r) disease and subsequent lines of therapy oﬀer response rates <30% with median progression-free survival (PFS) of 2-4 months. Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown promising anti-tumor activity in pts with r/r PTCL with an objective response rate (ORR) of 44.3% (Song & Malpica et al, Lancet Oncology 2023). Herein, we report the updated 2-year follow-up of golidocitinib for r/r PTCL in a U.S. single-center.

Methods: We included pts enrolled from a single-center in the JACKPOT8 part B trial, a single-arm, multinational, phase 2 study (NCT04105010). Eligible pts (≥18 years, r/r PTCL, performance status ECOG ≤2) were given golidocitinib 150 mg orally once daily in 21-day cycles until progression of disease (PD) or other discontinuation criteria were met. We evaluated baseline characteristics, ORR and the co-primary endpoints; 2-year PFS and 2-year overall survival (OS), assessed using the Kaplan-Meier method. Correlatives were analyzed between responders (complete [CR] and partial response [PR]) and non- responders (PD) using Fisher’s exact test with a p< 0.05 for statistical signiﬁcance, and included in-house next generation sequencing panel, molecular subtyping (TBX21 and GATA3), phosphorylated signal transducer and activator of transcription 1 (pSTAT1) and pSTAT3 and T-follicular helper (TFH) phenotyping by immunohistochemistry.

Results: Thirteen pts were included, median age was 55.9 years (range 19.8-75.2), with 38.5% (n=5) >60 years, and 54% (n=7) female. Subtypes were ALK negative anaplastic large cell lymphoma (ALCL) (n=3), ALK+ ALCL (n=2), PTCL, not otherwise speciﬁed (NOS) (n=4), T-cell prolymphocytic leukemia (n=1), and angioimmunoblastic T-cell lymphoma (n=3). The majority were stage III-IV (84.6%, n=11). Frontline regimens were BV-CHP in 76.9% (n=10) and CHOP in 23.1% (n=3), with 76.9% (n=10) having initial CR or PR and 15.4% (n=2) receiving consolidative autologous stem cell transplantation (SCT) prior to enrollment. Golidocitinib was started as second-, third- or fourth-line therapy in 53.8% (n=7), 30.8% (n=4) and 15.4% (n=2), respectively. The ORR was 53.8% (n=7, 95%CI 25.8%-79.7%) with CR=46.1% and PR=7.7%. With a median follow-up of 24.9 months (IQR 14.9-32.9 months), median OS was not reached and 2-year OS was 76.9% (95%CI 44.2%- 91.9%). Median and 2-year PFS were 37.9 months and 58.3%, respectively (95%CI 27%-80.1%). As of last follow up, except for one pt with CNS relapse (PFS 37.9 months) and one pt taken oﬀ study due to autologous SCT consolidation after CR, all other responders remain in CR (n=4) and PR (n=1); including 2 pts with ongoing CR while being oﬀ therapy (one pt opted for therapy break [PFS 15 months], and one pt developed squamous cell carcinoma of the neck related to smoking and therapy was held due to non- adherence [PFS 18 months]). Among all pts, responders had TFH phenotype (n=3/3, 100%) vs. non-TFH (n=4/10, 40%), p=0.192; and among the PTCL, NOS and ALCL (n=9), responders had TBX21 phenotype (n=4/4, 100%) vs. non-TBX21 (n=0/5, 0%), p=0.008. pSTAT1 and pSTAT3 expression were not associated with response (p=0.29 and p=0.95, respectively). STAT3 mutation was present in only 2 out of 7 pts with response to therapy and none of those with no response (p=0.46). Grade 3-4 treatment-related adverse events occurred in 30.8% (n=4) and included anemia (7.7%), neutropenia (15.4%), febrile neutropenia (7.7%), thrombocytopenia (7.7%), leukocytosis (7.7%), and disseminated zosters (7.7%). All were clinically manageable, with no grade 5 events. Three pts (23.1%) had dose reduction to 75 mg every other day (all >65 years) and there was no drug discontinuation.

Conclusion: In this cohort of U.S. pts with r/r PTCL receiving golidocitinib, eﬃcacy and tolerability were comparable with the overall cohort in the JACKPOT8 part B trial which included primarily Asian pts. With the longest follow-up for golidocitinib, responses were durable (longest responder 3.1 years) with 2 pts remaining in CR despite therapy break, suggesting a long-lasting eﬀect. Responders had a TFH phenotype and expressed TBX21, which need to be conﬁrmed in a larger cohort. Given the promising results and unmet need, the ongoing GOLDEN trial aims to evaluate the safety and eﬃcacy of golidocitinib in the frontline management of PTCL (NCT06630091).

Link to Abstract abs25-10070

Abstract Number: abs25-10518

Combination of mitoxantrone hydrochloride liposome with gemcitabine, cisplatin and dexamethasone (MGDP) in patients with relapsed or refractory peripheral T cell lymphoma: A prospective, single-arm, multicenter, Phase I/II study

Presenter: Chong Wei
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: Background: Background: : : Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of mature aggressive T-cell non-Hodgkin’s lymphomas characterized by poor prognosis, which highlights the urgent need for novel therapeutic. The combination of gemcitabine, cisplatin and dexamethasone (GDP) is a recommended second-line treatment regimen according to lymphoma guidelines. Mitoxantrone hydrochloride liposome (Lipo-MIT), a nano-drug approved as the first treatment option for relapsed/refractory (r/r) PTCL, demonstrated certain efficacy and safety in a pivotal phase Ⅱ study (Cancer. 2025;e35672). Aims: Aims: This prospective, single-arm, multicenter phase I/II study aims to investigate the safety and efficacy of combining Lipo-MIT with GDP regimen (MGDP) in patients (pts) with r/r PTCL. Preliminary interim results were presented at EHA 2025 PF963. Here, we report updated results.

Methods: Pts with r/r PTCL were recruited into this study, consisted of a 3+3 dose-escalation phase (Lipo- MIT at 12, 16, and 20 mg/m 2 on day 1) and a specific dose-expansion phase (Lipo-MIT at the recommended phase II dose [RP2D], maximum 35 mg/cycle). Gemcitabine (1000 mg/m 2 ), cisplatin (75 mg/m 2 ), and dexamethasone (40 mg) were administered on day 1 of each 21- day cycle up to 6 cycles. The primary endpoints were to explore the RP2D of Lipo-MIT in phase I and the objective response rate (ORR) in phase II. Secondary endpoints included complete response (CR) rate, progression-free survival (PFS), overall survival (OS) and safety. This study has been registered (NCT05441761) at www.clinicaltrials.gov.

Results: At data cut-off on May 2025, 23 eligible pts (9 in phase I and 14 in phase II) were enrolled with a median age of 52 (range, 22-70) years. The subtypes included 15(65.2%) with PTCL-NOS, 5(21.7%) with angioimmunoblastic T-cell lymphoma (AITL), 1(4.3%) with ALK positive anaplastic large cell lymphoma (ALCL), 1(4.3%) with intestinal T-cell lymphoma (ITCL) and 1(4.3%) with nodal T-follicular helper (TFH) cell lymphoma. Most pts were primary refractory 19(82.6%). 21(91.3%) pts had advanced stage III /IV disease(Ann Arbor stage) and 13(56.5%) pts had IPI scores of 3-5. No dose-limiting toxicity (DLT) occurred in this phase I study and the RP2D of Lipo-MIT was established at 20 mg/m 2 . In phase II, the median Lipo-MIT dose per cycle was 18.7 (range, 16.5-20.2) mg/m 2 with a median cycles of 4.5. The best ORR was 71.4% (10/14, 95% CI 41.9%-91.6%) with CR rate 42.9% (6/14, 95% CI 17.7%-71.1%) in the phase II cohort. For all evaluable pts (n=23), the best ORR and CR rate were 65.2% (15/23, 95% CI 42.7%- 83.6%) and 39.1% (9/23, 95% CI 19.7%-61.5%), respectively. Moreover, promising activity was observed in pts of primary refractory, refractory to last prior therapy, high-risk (IPI 3-5) and high Ki67 expression (≥70%), with an best ORR of 68.4% (13/19), 66.7% (12/18), 69.2% (9/13) and 70.0%(7/10), respectively. At median follow-up of 10.4 months, the median PFS was 6.8 months, and median OS was 17.6 months. The common grade 3/4 treatment-related adverse events (TRAEs) were hematological toxicities, including neutropenia (65.2%), leucopenia (65.2%), anemia (39.1%) and thrombocytopenia (34.8%). Overall, safety in all pts was manageable in this study.

Conclusions: Lipo-MIT combined with GDP (MGDP) regimen demonstrated promising efficacy and manageable safety in r/r PTCL, warranting further investigation.

Link to Abstract abs25-10518

Abstract Number: abs25-10933

Brentuximab vedotin plus DHAP as effective salvage therapy in CD30+ peripheral T-cell lymphoma: A retrospective multicenter study

Presenter: Natali Pflug
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: The prognosis of most nodal peripheral T-cell lymphomas (T-NHL) has not significantly improved over the past 25 years. Stage- or IPI-dependent 5-year overall survival (OS) rates remain around 30%. Recently, for the first time, a significant OS benefit was demonstrated for the combination of brentuximab vedotin (BV) and CHP (cyclophosphamide, doxorubicin, prednisone) compared to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in the first-line treatment of patients with anaplastic large cell lymphoma (ALCL). However, approximately 30% of patients with peripheral T-NHL experience a disease course that is primarily refractory, with dismal prognosis. BV monotherapy achieves high remission rates, particularly in relapsed ALCL, but also in other relapsed T-NHL subentities. For relapsed/refractory (R/R) nodal peripheral T-NHLs other than ALCL, only conventional (multi-agent) chemotherapy is approved by both the European Medicines Agency as well as the Food and Drug Administration, while single-agent BV is approved for R/R ALCL only. Effective treatment options for younger patients with high remission rates for curative intended treatment concepts are urgently needed. In Hodgkin lymphoma, the addition of BV to DHAP (dexamethasone, high-dose cytarabine, cisplatin) has shown promising efficacy as a salvage regimen in a phase II trial. Based on this, we conducted a multicenter retrospective analysis based on the national T-NHL registry platform of the GLA and OSHO study groups to evaluate the efficacy and tolerability of platinum-based salvage therapies in combination with BV in patients with R/R T-NHL. A total of 26 patients treated with either BV-DHAP or BV-ICE between 2015 and 2025 were identified. Median age at diagnosis was 55 years (range 23–77), and 11/26 patients (42.3%) were female. Histologic subtypes included ALCL (11/26, 42.3%), angioimmunoblastic T-cell lymphoma, T-NHL not otherwise specified, enteropathy-associated T-cell lymphoma, and systemic primary cutaneous T-NHL. Most lymphoma expressed CD30 (22/26; 84,6%), 1/26 (3,9%) was assessed as CD30-negative and for 3/26 patients (11,5%) the information was not available. Median number of prior treatment lines was 2 (range 1-7). Eight out of 26 patients (30.8%) had previously received BV, and 4/26 (15.4%) had undergone prior autologous stem cell transplantation. Most patients (24/26, 92.3%) were refractory to the previous therapy or had relapsed within one year. Fourteen patients received BV-ICE, and 12 received BV-DHAP as salvage therapy. Best overall response rate (ORR) in the entire cohort was 53.9% (14/26), including CR in 6/26 (23.1%) and PR in 8/26 (30.8%). In the BV-ICE subgroup, ORR was 35.7% (5/14; CR 1/14 [7.1%], PR 4/14 [28.6%]). In contrast, the BV-DHAP subgroup demonstrated an ORR of 83.3% (10/12; CR 5/12 [41.7%], PR 5/12 [41.7%]). Among BV-DHAP patients, 8 had ALCL and 4 had other T-NHL subtypes. All non-ALCL patients (4/4) and 6/8 (75%) of ALCL patients responded to BV-DHAP. In the BV-ICE group, 3 patients had ALCL and 11 had other T-NHLs; responses were seen in 3/11 (27,3%) non-ALCL patients and 2/3 (66,7%) ALCL patients. Toxicities were manageable, comparable between regimens and primarily included grade 3/4 hematologic adverse events in 18/21 patients (85,7%) , febrile neutropenia in 13/21 patients (61,9%), and transient liver enzyme elevations in 20/23 patients (87%). No new cases of peripheral neuropathy were documented. In conclusion, BV-DHAP was particularly effective as a salvage regimen in this high-risk cohort of R/R CD30-positive T-cell non-Hodgkin lymphoma, with manageable toxicity. Further studies are warranted to establish its superiority over BV monotherapy in this setting.

Link to Abstract abs25-10933

Abstract Number: abs25-11814

Persistent racial disparities in Sézary syndrome outcomes despite use of modern therapies: A single-center analysis

Presenter: Lalith Roopesh
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: Introduction: Sézary syndrome (SS) is a rare and aggressive leukemic variant of cutaneous T-cell lymphoma. Historically, Black patients with SS have faced disproportionately poorer outcomes, though the basis for this disparity is unclear, whether due to access to care, biological, or therapeutic factors. With the increasing use of modern systemic therapies (e.g., mogamulizumab, brentuximab vedotin, interferons, photopheresis) over the past decade, we sought to determine whether survival disparities by race persist in the current treatment era.

Methods: We retrospectively reviewed 75 patients with SS treated between January 2015 and June 2025 at Moffitt Cancer Center. SS diagnosis was confirmed by the presence of both B2 blood involvement (tumor burden >1000/μL) and erythroderma, or B1 disease with blood involvement close to 1000/μL and erythroderma. Patient demographics, disease characteristics, and treatment data were collected. Race was self-reported as White, Black, or Other. Overall survival (OS) was measured from the time of confirmed B2 transformation to death or last follow-up and estimated using the Kaplan–Meier method. Cox proportional hazards modeling was used to assess associations between race and OS, adjusting for potential confounders including age, sex, SS subtype (primary vs. secondary), stage at diagnosis, visceral involvement, and large-cell transformation (LCT).

Results: Seventy-five patients were confirmed to have SS; among them, 56 (75%) were White, 13 (17%) were Black, and 6 (8%) were of Other or mixed race. The median age at diagnosis was 73 years (range: 29–92). A higher proportion of Black patients were diagnosed before age 60 compared to White patients (38.5% vs. 10.7%, p = 0.041), had stage IVB disease (30.8% vs. 8.9%, p = 0.047), and had a significantly higher frequency of LCT (76.9% vs. 30.4%, p = 0.003). Sex distribution did not differ significantly between groups (p = 0.83). At a median follow-up of 57 months, the cohort’s median OS had not yet been reached (95% CI: 48.8 months–Not Reached). Estimated OS was 87.8% (95% CI, 80.7–95.6) at 12 months and 72.1% (95% CI, 61.7–84.3) at 36 months. Racial stratification revealed a marked survival gap: 1-year OS was 76.2% (95% CI, 55.8–100) in Black patients versus 89.1% (95% CI, 81.3–97.7) in White patients; 3-year OS was 35.5% (95% CI, 15.1–83.5) versus 82.2% (95% CI, 72.2–93.6), respectively. In univariate analysis, Black race was associated with significantly worse OS compared with White race (HR = 3.6; 95% CI, 1.56–8.33; p = 0.007). LCT also predicted worse outcomes (HR = 2.13; 95% CI, 1.01–4.48; p = 0.047). In multivariate analysis adjusting for age, sex, LCT, and SS subtype, Black race remained an independent adverse factor (HR = 3.1; 95% CI, 1.22–7.69; p = 0.018). Other covariates were not significantly associated with survival. When examining treatment patterns across racial groups, extracorporeal photopheresis (ECP) remained the backbone for both Black and White patients (77% vs. 86%). The most common reasons for ECP not being used were poor intravenous access and travel burden. Mogamulizumab was used at similar rates in both groups (75% in Black patients vs. 69.2% in White patients). Black patients were more likely to receive ECP + Pegasys (69.2% vs. 26.8%), romidepsin (61.5% vs. 37.5%), brentuximab (38.5% vs. 14.3%), and combination chemotherapy (61.5% vs. 19.6%) compared to White patients, likely reflecting the more aggressive nature of their disease.

Conclusion: Our cohort demonstrated better OS compared to historical studies, likely reflecting the impact of modern systemic therapies and specialized care at a tertiary center. However, despite broader access to ECP and novel agents such as mogamulizumab and brentuximab, the survival gap between Black and White patients remained consistent with prior population-based reports. The disparity persisted even after adjusting for disease aggressiveness and clinical covariates, suggesting that treatment alone does not fully mitigate the survival gap. Black patients in our cohort had a markedly higher prevalence of large-cell transformation, earlier age at diagnosis, and more advanced clinical stage at presentation, suggesting possible biological differences. These findings underscore the urgent need to better understand the intersection of race, tumor biology, and treatment response in SS and to develop tailored strategies that ensure equitable outcomes across all racial groups.

Link to Abstract abs25-11814

Abstract Number: abs25-13165

Role of race in severity and survival of those with cutaneous T-cell lymphoma

Presenter: Almeera Lateef
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: Background: Cutaneous T-Cell Lymphoma (CTCL) currently affects over 10.2 million people worldwide.Staphylococcal enterotoxin producing Staphylococcus aureus plays an important role in the pathogenesis of the disease. Studies indicate that treatment of skin and soft tissue infections lead to clinical and symptomatic improvement in the erythrodermic appearance of CTCL. Not only does the bacteria play a role in cutaneous severity of the cancer, but also it is widely thought that presence of colonization correlates with severity of disease on a molecular level as well. The following study looked to see if race played a role in the rate and severity of colonization of these patients. Secondarily, the study looked to investigate survival amongst this group as well as how other factors such as age, gender and socioeconomic group played a role in colonization in this population.

Methods: Patients were identified from an existing CTCL database at Emory University. Patients with a cutaneous culture and histopathologic evidence of Sezary syndrome (SS) or Mycosis fungoides (MF) seen between 2020 and 2024 were eligible. Colonization was defined as a positive cutaneous culture result. Comparison between Black and White patients was performed using ANOVA for numerical covariates and Chi-square test or Fisher’s exact test for categorical covariates. Overall survival (OS) was defined as the time from diagnosis to death or last follow-up. Patients not experiencing an event were censored at their last known follow-up. OS was determined using the Kaplan-Meier method, and univariate and multivariable Cox regression models were developed to identify predictors of OS. For binary outcomes, logistic regression was performed.

Results: The population included 213 patients, 96 patients (45.1%) self-identified as white and 117 (54.9%) as Black. Forty-nine patients (23%) were colonized, 40 (18.8%) had S. aureus , and 42 (21.5%) developed bacteremia. Racial differences were evaluated among Black and White patients. Black patients were more likely to become bacteremic after colonization than white patients (p<.0008) . Nineteen (19.8%) of White patients and 30 (25.6%) of white patients had positive skin cultures; MRSA was seen in 6 (6.2%) of White and 12 (10.2%) Black patients, but this did not reach statistical significance. Multivariate analysis indicated that women were more likely to have MSSA when compared to men, (OR=2.76; p<0.038). The analysis also demonstrated that those older than 60 were less likely to become bacteremic (p< 0.036), however had a lower survival rate if infected (p<0.015). Discussion: Discussion: In spite of higher degrees of bacteremia among Black patients, analysis of cutaneous cultures did not indicate differences in rates of colonization. Limitations include cultures were performed per standard of care and therefore we were not able to control for topical/oral antibiotics, and differences in hygiene practices or medications. Additional need for studies evaluating the cutaneous microbiome using whole genome studies to identify the full microbial community, and identify the role of strain type on risk of invasive infections and the interaction with CTCL severity.

Conclusion: This single location study indicates that though rates of colonization and prevalence of Staphylococcus aureus was similar between white and black patients, Black patients are more likely to become bacteremic as a result of the infection. Although Black patients were more likely to have severe outcomes such as bacteremia, the survival when compared to white patients long term was similar.

Link to Abstract abs25-13165

Abstract Number: abs25-13598

Selinexor combined with pegaspargase and dexamethasone, followed by radiotherapy, for newly diagnosed stage I–II natural killer/T-cell lymphoma: A multicenter, single-arm, Phase I/II study

Presenter: Siyu Qian
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: Background: Background: Our center’s DDGP regimen has significantly improved the overall prognosis of natural killer/T cell lymphoma (NKTCL). Nevertheless, for patients with early-stage disease (CA Stage I–II), which is typically localized to the nasal cavity and adjacent tissues, responds well to therapy, and rarely relapses, we further considered whether less toxic and more convenient regimens could achieve comparable efficacy. This study explores the combination of selinexor, pegaspargase and dexamethasone, followed by ntensity-modulated radiation therapy(IMRT), to improve outcomes with reduced toxicity in stage I–II NKTCL. Study Design and Methods: Study Design and Methods: This multicenter, open-label, single-arm phase I/II trial evaluated the preliminary efficacy and safety of the above regimen in newly diagnosed stage I–II NKTCL(NCT 06559553). Preclinical in vitro and animal studies demonstrated a synergistic effect of selinexor and pegaspargase in inhibiting NKTCL proliferation and promoting apoptosis, providing the rationale for this clinical trial. The study included a dose-escalation phase (Ib) and a dose-expansion phase (II). A standard 3+3 design evaluated selinexor at 40, 60, and 80 mg. The primary endpoints were the complete response rate (CRR) and the objective response rate (ORR). Eligibility Criteria: Patients aged 18–70 years with ECOG 0–2, expected survival >6 months, histologically confirmed stage I–II disease with at least one measurable lesion, no prior anti-cancer therapy, no contraindications to chemotherapy, and adequate cardiac and pulmonary function were eligible. Treatment Regimen: Selinexor was administered orally on Days 1 and 8, pegaspargase (3,750 IU) given intramuscularly on Day 1, and dexamethasone (20 mg/day) orally on Days 1–5 of each cycle. IMRT was delivered sequentially at 2 Gy per fraction, totaling 50 Gy over 25 fractions.

Results: At the data cutoff, 20 patients had been enrolled: 11 in phase Ib [selinexor 40 mg (n=4), 60 mg (n=4), and 80 mg (n=3)] and 9 in phase II. The median age was 51 years (range, 20–68); 15 were male and 4 were female. All had newly diagnosed CA stage I–II NKTCL. Based on phase Ib dose-escalation results, 60 mg selinexor was selected for the phase II expansion. Four patients discontinued treatment, two due to acute pancreatitis and two due to cerebrovascular events. Excluding these, the remaining 15 achieved a best CRR of 81.25% (13/16) and an ORR of 100.00% (16/16). All patients experienced ≥1 treatment- emergent adverse event, with nausea, weight loss, hypoalbuminemia, and myelosuppression being the most frequent. Notably, the two cerebrovascular events occurred in patients who discontinued treatment.

Conclusion: This regimen demonstrated high preliminary efficacy in newly diagnosed stage I–II NKTCL, with simple administration and short hospitalization. While generally tolerable, vigilant monitoring and supportive care are needed to mitigate adverse events.

Link to Abstract abs25-13598

Abstract Number: abs25-14215

Cytokine signatures predict response, progression, and immune-related toxicity in Sézary syndrome patients treated with mogamulizumab

Presenter: Erika Morsia
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: Introduction: Sézary syndrome is a rare, aggressive cutaneous T-cell lymphoma characterized by erythroderma, lymphadenopathy, and malignant T-cells in peripheral blood. Mogamulizumab, a humanized anti-CCR4 monoclonal antibody, has demonstrated clinical efficacy in this setting. However, the immunologic mechanisms driving treatment response, disease progression, and immune-mediated adverse events (MAR) remain unclear. This study investigates longitudinal cytokine profiles in Sézary patients treated with mogamulizumab to identify biomarkers predictive of therapeutic response and toxicity. Methods In a prospective multicenter study conducted at the Hematology Clinic of AOU Marche (Ancona, Italy), we enrolled 10 consecutive patients with Sézary syndrome treated with mogamulizumab between May 2021 and May 2024. Serum cytokine levels (IL-2R, IL-1β, IL-6, IL-8, IL-10, TNF-α) were measured at baseline, and after 3, 6, and 12 months of therapy. Data on treatment response, disease progression, and MAR (mogamulizumab-associated rash) were collected longitudinally. Cytokine levels were analyzed in relation to clinical outcomes using non-parametric statistical methods. Results The median patient age was 71 years; 60% were female. Mogamulizumab was administered as third-line therapy (range 2–8), with a median of 16.5 cycles (range 13–33). At follow-up, 30% of patients were non- responders, and 20% progressed on treatment. MAR occurred in 5 patients, with a median onset at cycle 7 (range 6–12). Patients who achieved clinical response had significantly lower baseline IL-2R levels (median 906.5 vs 2815 U/mL, p = 0.0039), lower IL-6 at 3 months (3.59 vs 7.25 pg/mL, p = 0.0057), and reduced TNF-α at 6 months (11.5 vs 436 pg/mL, p = 0.0210) compared to non-responders. Conversely, patients who progressed showed higher IL-2R at both baseline (7137 vs 921 U/mL, p = 0.0356) and 6 months (3757 vs 975 U/mL, p = 0.0134), and lower IL-1β at baseline (4 vs 14.65 pg/mL, p = 0.0346) and 3 months (4 vs 19.2 pg/mL, p = 0.0210). TNF-α at 6 months was also significantly higher in progressors (436 vs 11.5 pg/mL, p = 0.0211). Patients who developed MAR had significantly lower IL-8 at baseline (14.8 vs 25.1 pg/mL, p = 0.0210) and higher IL-1β at 6 months (20.5 vs 4 pg/mL, p = 0.0245) compared to those without rash. Conclusions This study highlights distinct cytokine signatures associated with clinical response, disease progression, and immune-related toxicity in Sézary syndrome patients treated with mogamulizumab. Lower levels of IL-2R, IL-6, and TNF-α were linked to treatment response, while elevated IL-2R and TNF-α and decreased IL-1β were associated with progression. MAR correlated with low IL-8 and elevated IL-1β. These findings support the potential utility of serial cytokine profiling to inform prognosis and personalize therapy in this rare lymphoma subtype.

Link to Abstract abs25-14215

Abstract Number: abs25-14234

T-cell clones of uncertain significance are prevalent in cutaneous T-cell lymphomas

Presenter: Safa Najidh
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: Background: T-cell receptor (TCR) sequencing is increasingly incorporated into the diagnosis and monitoring of T-cell lymphomas, including cutaneous T-cell lymphomas (CTCL). However, interpretation of TCR sequencing results is often confounded by the emergence of multiple dominant TCR clonotypes, whose etiology remains poorly understood. We aimed to determine the incidence of multiple dominant TCR clonotypes through serial TCR high-throughput sequencing (TCR-HTS), to immunophenotype and genetically characterize these dominant T-cell populations, and to assess their potential clonal relationships to CTCL.

Methods: We reviewed results from 1677 samples from 235 patients with CTCL (MF n=163, SS n=67, Other n= 23) sequenced using the clonoSEQ® platform (median 6 samples per patient) from 2012-2023. Dominant TCR clonotypes were defined per clonoSEQ® criteria, and only productive rearrangements were included. Clonotypes with identical VDJ rearrangements (e.g., single-nucleotide variants) were excluded. Among patients with an emerging second dominant productive TCRβ clonotype, 11 had cryopreserved PBMCs available for analysis. These PBMCs, along with those from 10 age-matched healthy donors, underwent TCR-HTS using the LymphoTrack® assay. Multiparametric spectral flow cytometry (MFC), including antibodies to TCRBC1 and/or TRBV regions, enabled identification and characterization of clonal T-cell populations. Clonal and polyclonal T-cell populations were sorted by FACS and underwent whole- exome sequencing (WES) and hybrid-capture TCR sequencing. Sorted monocytes were used as germline for WES variant calling. To provide a reference for the mutational profile of benign T-cells, normal T-cells from one patient were singly sorting, ex-vivo expanded into colonies, and underwent WES.

Results: Among 235 CTCL patients, 109 (46%) had two or more unique dominant, productive TCRβ clonotypes identified in one or more specimens, and 41 (17%) had three or more. TCR-HTS using an alternative platform confirmed a high-frequency clonotype (>3%) in all 11 available CTCL PBMC samples, and in none of the 10 healthy donors tested . . MFC identified one or more clonal T-cell populations per patient. These variably expressed CD4, CD8, or CD4-CD8- (double-negative), and most commonly displayed a terminal effector phenotype (CD45RA+, CD56+, and CD57+). These immunophenotypes were most consistent with T-cell clones of uncertain significance (T-CUS) and were distinct from typical CTCL profiles. FACS-sorted T-CUS populations underwent TCR sequencing to confirm their clonal identity. In 10/11 patients, the dominant TCRβ clonotype matched that of TCR-HTS (median 91% TCR clonotype fraction, range 41-100%). WES was performed on 10 sorted T-CUS populations, 9 patient-matched CTCL biopsies, 8 polyclonal T-cell populations, and 15 single T-cell derived colonies. T-CUS harbored significantly fewer somatic variants than CTCL biopsies (mean 68 versus 781, p=0.004), but more than polyclonal T cells (mean 17, p=0.01). Single-cell-derived colonies of normal T-cells from a CTCL patient had a mutational burden (mean 41) comparable to T-CUS (p=0.24). To evaluate whether T-CUS populations in CTCL patients shared a common lineage with the primary CTCL clone, we compared somatic variants in matched T-CUS and CTCL samples. No shared variants were found, indicating no common clonal origin. However, T-CUS harbored nonsynonymous variants involving CTCL-associated and/or cancer-associated genes including ARID1A, ATRX, FSIP2, GATA3, PTPRR, PTPRK, STAT1, TCF3, TP63, and TRRAP. STAT3 and STAT5B variants were not detected in the clonal sorted populations, and there were no unexplained cytopenias, arguing against T-cell large granular lymphocytic leukemia. Unlike CTCL, T-CUS lacked UV-associated mutational signatures.

Conclusions: Emergence of new dominant TCR clonotypes is common in CTCL and often arise within T- CUS populations that fluctuate in frequency in the blood and skin. While T-CUS harbor variants in genes associated with T-cell malignancies, there was no evidence of evolution of these populations into secondary malignancies, and T-CUS appear clonally unrelated to CTCL. The clinical significance of emerging dominant T-cell clonotypes in CTCL should be interpreted in the context of a high prevalence of T-CUS.

Link to Abstract abs25-14234

Abstract Number: abs25-15342

Single center updated analysis of patients with Relapsed/Refractory peripheral T-cell lymphoma treated with linperlisib.

Presenter: Ranjit Nair
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: Peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) are aggressive malignancies with limited effective treatment options in the relapsed or refractory (r/r) setting. Although targeting the PI3K pathway has shown potential by modulating T-cell signaling and eliciting antitumor activity, clinical application has been limited by significant immune-related toxicities. Linperlisib, a next-generation PI3Kδ inhibitor characterized by high potency and selectivity, with a reduced incidence of off-target toxicities compared to earlier compounds, is approved in China for follicular lymphoma, has demonstrated encouraging efficacy in Chinese patients with r/r PTCL, as evidenced by results from the open-label Phase II trial (NCT05274997) presented last year. Here, we report our single-center experience with linperlisib, including patients enrolled in the clinical trial as well as those who continued therapy through compassionate use as single patient IND. Aims: Aims: To evaluate the clinical benefit, safety, and durability of responses to linperlisib in a single center cohort of r/r PTCL and CTCL patients, and to examine outcomes with a step-down maintenance dosing strategy . Pts received linperlisib 80mg QD for four 28-day cycles or achieved a complete response (CR) prior to a prespecified reduction to a 40mg QD continuous maintenance dose. Method: Method: We did analysis of 18 adults with r/r T-cell lymphomas (PTCL-NOS n=8, AITL n=8, ALCL n=1, CTCL n=1) treated at MD Anderson Cancer Center (Aug 2022–May 2025). Patients received therapy either through an open-label Phase II clinical trial (NCT05274997) or via compassionate use under single-patient IND protocols. Patients received linperlisib 80 mg QD for four 28-day cycles or until complete response (CR), followed by 40 mg QD maintenance. Tumor response was assessed every 2 treatment cycles per Lugano 2014 ( for PTCL) or Olsen criteria (for CTCL). Primary endpoint was investigator-assessed objective response rate (ORR). Pts with CR were eligible to proceed to consolidative transplant, if warranted by investigator review. Adverse events (AEs) were graded by CTCAE v5.0.

Results: The median patient age was 64 years with males (9) and females (9) ratio 1:1. ECOG 0 (50%) or 1 (50%), Caucasian 11 (61.1%), Black 6 (33.7%), or Hispanic 1 (5.6%). Patients had a median of 3 prior systemic therapies (range 1–7). ORR was 66% (CR 39%; PR 28%), with highest responses observed in AITL (ORR 75%). Responses most frequently occurred by the first assessment during the 80mg QD dose period. Median progression-free survival (mPFS) in the cohort was median PFS is 6.1 months (95% CI: 4.0 to 8.5 months), with a median overall survival (mOS) 29.7 months, (95% CI 22.4 to 37.1 months). Median response duration not reached. Among AITL cases, mPFS reached 6.25 months (95% CI 0, 18.9 months). Two of the PTCL pts with CR subsequently received transplant and were censored from the PFS analysis. one CTCL pts achieved a PR and 4 pts had SD and further had PR, later progressed. Adverse events (AEs) were predominantly mild to moderate. Grade 1–2 events included maculopapular rash (55.6%), diarrhea (50.0%), CMV reactivation (11.1%), nausea (22.2%), paresthesia (22.2%), constipation (16.7%), and peripheral neuropathy (11.1%). Severe AEs (Grade ≥3) affected 9 of 18 patients (50.0%), with lung infection being the most frequent (22.2%). Additional Grade 3 events included diarrhea (11.1%), colitis (5.6%), pancreatitis (5.6%), chest pain (5.6%), and peripheral motor neuropathy (5.6%). Fourteen patients discontinued due to progression; three (on compassionate use) remain in remission at analysis cutoff. One patient who proceeded to allogeneic stem cell transplantation died from transplant- related complications.

Conclusions: In a heavily pretreated, with r/r PTCL/CTCL, linperlisib demonstrated robust activity with early and durable responses—especially in AITL—and a manageable safety profile, including with step- down dosing. These findings support further exploration of Linperlisib in US population and use of maintenance dosing strategy. Overall the safety profile was manageable, and treatment-related AEs were generally reversible or non-life-threatening.

Link to Abstract abs25-15342

Abstract Number: abs25-10076

A Phase II, single-center, single-arm study evaluating the safety and efficacy of golidocitinib in the management of newly diagnosed PTCL (GOLDEN Study)

Presenter: Eduardo Edelman Saul
Session: 625. T Cell, NK Cell, or NK/T Cell Lymphomas: Clinical and Epidemiological: Poster III

Abstract: Background: Background: First-line (1L) therapy for peripheral T-cell lymphoma (PTCL) is cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-based, and relapse/refractory (r/r) rates are high (75%) with limited therapeutic options thereafter; currently approved agents for r/r PTCL include belinostat and pralatrexate, with overall response rates (ORR) of <30% and progression free survival (PFS) between 2-4 months. The pivotal study JACKPOT8 part B, with the Janus kinase one (JAK1) selective inhibitor golidocitinib in r/r PTCL, demonstrated ORR of 44.3% with a median PFS and overall survival (OS) of 5.6 and 19.2 months, respectively. The most common ≥ grade 3 therapy-related adverse event (TRAE) was neutropenia (29%) which was clinically reversible, with discontinuation in only 9% (Song and Malpica et al, Lancet Oncology 2023). In the subgroup analysis of patients (pts) with T follicular helper (TFH) PTCL phenotype the ORR was 62% and median PFS was 9.5 months. The current trial builds upon our prior experience with encouraging results of golidocitinib compared to other approved agents and the high failure rates after 1L CHOP-based therapy by designing a study evaluating the incorporation of golidocitinib into the frontline management of PTCL. Study Design and Methods Study Design and Methods We are conducing a phase II, single-center, single-arm clinical trial evaluating the safety and eﬃcacy of golidocitinib for pts with newly diagnosed PTCL (NCT06630091). Eligibility criteria include pts who are 18y+ with newly diagnosed PTCL (enriched with 70% TFH subtype given golidocitinib’s demonstrated activity in prior trials, and 30% PTCL, not otherwise speciﬁed subtype), Eastern Cooperative Oncology Group Performance Status 0-2, and measurable disease at baseline. Pts with prior lymphoma-directed therapy, anaplastic large cell lymphoma subtype, known CNS involvement with lymphoma and active viral infections are ineligible. For induction, all pts will receive single agent golidocitinib at 150 milligrams (mg) orally once daily for six 21-day cycles. If there is progression of disease (PD), pts will receive subsequent standard of care therapy oﬀ study. Prior to cycle seven, all pts will be restaged with PET/CT and those achieving complete response (CR) will continue single agent golidocitinib at the previously described dose for six more cycles, while pts with partial response (PR) or stable disease (SD) will receive golidocitinib 150 mg every other day in combination with CHOP for six more cycles. Restaging PET/CT will be performed every three cycles with response criteria based on 2014 Lugano classiﬁcation. Upon completion, maintenance will consist of golidocitinib 150 mg once daily (1) for up to one year in pts achieving post-induction CR, or (2) until PD, unacceptable toxicity/death, withdrawal of consent, or study termination in pts achieving PR/SD, with restaging PET/CT performed every four cycles. Survival follow up is planned for 2 years since the ﬁrst dose. The primary objective is to assess ORR after induction. The sample size is 30 pts, with a target ORR of 50%. The secondary objectives are CR rate (CRR) after induction and CRR/ORR after single agent induction lead-in, 2-year PFS, 2-year OS, duration of response and time to response rates, and safety and tolerability of golidocitinib as single agent or in combination with CHOP. Toxicities will be graded according to the Common Terminology Criteria for Adverse Events version 5.0. Stopping boundaries are jointly based on response and serious TRAEs using Bayesian optimal phase 2 design, with study hold triggered by ≤ 7 responses for the first 15 enrolled pts and/or ≥ 1 serious TRAE for the first 10 and 20 enrolled pts. Exploratory studies to determine biomarkers of response and mechanisms of resistance to JAK/STAT inhibition will include paired diagnosis and post-therapy tissue and blood samples assessed by immunohistochemistry, ﬂuorescence in situ hybridization, cytokine panel, and an in-house 162-gene tumor-targeted sequencing panel, in addition to planned multi-omics with whole exome and bulk RNA sequencing. This trial has been activated as of April 2025 and is currently enrolling. To our knowledge, this study is the ﬁrst to explore a novel oral targeted agent for newly diagnosed pts with a subtype speciﬁc PTCL. The chemotherapy de-escalation and response-adapted design will potentially identify pts who may beneﬁt from no chemotherapy or novel agent plus chemotherapy combination.

Link to Abstract abs25-10076

Abstract Number: abs25-7211

Non-invasive classification & molecular subtyping of mature lymphoid neoplasms by cell-free DNA profiling

Presenter: Jurik Mutter
Session: 622. Lymphomas: Translational – Non-Genetic: Poster III

Abstract: Background: Background: : Mature lymphoid neoplasms (MLN) are currently diagnosed by integrating histopathological, immunophenotypic, cytogenetic, and molecular profiles of tumor tissue biopsies (Campo, Blood 2022; Alaggio, Leuk 2022). While genetic subtyping of DLBCL, based on mutational profiles and copy number alterations, has further advanced this classification, many cases remain unclassified (Wright, Cancer Cell 2020; Chapuy, Blood 2025). This highlights the need for additional diagnostic approaches, such as gene expression profiling (GEP) and cytogenetic methods, to capture significant biological heterogeneity. GEP has proven particularly valuable in identifying not only cell-of-origin (COO), but also high-grade B-cell lymphomas (HGBCL), offering enhanced sensitivity and the ability to detect occult rearrangements using a “dark-zone signature” (DZsig, Ennishi, JCO 2018; Alduaij, Blood 2023). However, the required tissue biopsies for GEP are invasive, carry procedural risks, and may delay diagnosis. While multi-cancer early detection (MCED) liquid biopsy tests based on methylation can allow detection of diverse solid tumors, most cancers detected by MCED when screening otherwise healthy adults are MLNs (Schrag, Lancet 2023) that cannot currently be further resolved using these tests. To overcome these limitations, we explored plasma cell-free DNA (cfDNA) as a non-invasive alternative for classifying diverse MLNs, determining COO and genetic subtypes in DLBCL, identifying genetic subtypes in HL, and detecting HGBCL.

Methods: : We applied EPIC-Seq (Esfahani, Nat Biotech 2022) to infer tumor gene expression from cfDNA fragmentomic signals in blood plasma before therapy. We designed a targeted capture panel informed by prior lymphoid GEP studies (n=56 studies, >10,000 tumors), including B- and T-cell differentiation markers, canonical immunohistochemistry markers, and recurrent genomic mutations and fusions for tumor burden assessment via variant allele frequency (VAF). The final panel encompassed 1,986 transcription start sites from 1,676 genes and covered 2.6 MB of genomic space. We then profiled plasma cfDNA from 748 subjects, including 666 patients across 10 lymphoid neoplasms (BL, CLL, DLBCL, FL, HL, MCL, MM, PBMCL, PTCL, WM), along with 58 healthy controls and 24 subjects with Other non-lymphoid solid tumors (carcinomas of the lung, liver, and pancreas).

Results: : Recognizing the influence of tumor burden on inferred tumor gene expression from plasma cfDNA, we developed a machine learning model to predict tumor mutant variant allele fraction (VAF) from EPIC-Seq data and validated it against mutation-based tumor burden measurements (Pearson R=0.96). This established a low VAF Background: threshold distinguishing from healthy controls (1%), below which samples were excluded for classification purposes. We then trained a multi-histology classifier on 396 patients across 10 groups (BL, CLL, DLBCL, FL, HL, MCL, MM, PTCL, Healthy, Other). Independent validation on 169 held-out samples demonstrated high individual classification accuracies and an overall top 2 accuracy of 94%. Beyond histological classification, EPIC-Seq showed high discriminatory potential for molecular HL subtypes (H1/H2, Alig, Nature 2024; AUC>0.8, p<0.0001) and accurately identified DLBCL GCB vs ABC COO subtypes (AUC>0.8, p<0.001). For genetic subtyping of DLBCL (e.g. Wright, Cancer Cell 2020; Chapuy, Blood 2025), we trained a classifier on publicly available tumor RNA-Seq data and successfully applied it to our plasma EPIC-Seq data from DLBCL patients, observing a strong concordance between EPIC ‑ Seq inferred molecular subtypes and LymphGen mutational classifications. Finally, we evaluated cell-free DZsig in 49 LBCL patients (28% harboring MYC+BCL2 double-hit by FISH), demonstrating significant discrimination between HGBCL-DH-BCL2 and DLBCL NOS (AUC=0.75, p=0.005). As expected, DZsig scores in BL, known to originate from the dark zone, did not significantly differ from HGBCL-DH-BCL2.

Conclusion: : Our study demonstrates clinical feasibility and high accuracy of EPIC-Seq-based cfDNA analysis for non-invasive classification and molecular subtyping of diverse mature lymphoid neoplasms. This approach effectively addresses clinically relevant diagnostic challenges, including COO determination, genetic subtyping in DLBCL and HL, identification of HGBCL-DH-BCL2, and other high risk LBCLs harboring dark-zone signature.

Link to Abstract abs25-7211

Abstract Number: abs25-9670

Radiomic features from PET-CT enable diagnostic and prognostic stratification in peripheral T-cell lymphoma

Presenter: Hajime Sakuma
Session: 622. Lymphomas: Translational – Non-Genetic: Poster III

Abstract: Introduction: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphoma. While novel therapies are emerging, molecular and histopathological analyses for precise classification remain limited in clinical practice, and prognostic prediction with the International Prognostic Index (IPI), or the Prognostic Index for PTCL-U (PIT) is suboptimal. Radiomic features (RFs) may offer a promising approach to quantify tumor heterogeneity at the voxel level, potentially reflecting underlying metabolic patterns. This study evaluates RFs in PTCL for improved diagnostic differentiation and prognostic stratification.

Methods: This retrospective study included patients histopathologically diagnosed with nodal T-follicular helper (TFH) lymphoma or PTCL-not otherwise specified (PTCL-NOS) at Kameda Medical Center between 2007 and 2024. Pathologic lesions on positron emission tomography-computed tomography (PET-CT) were delineated using a 41% threshold of maximum standardized uptake value (SUVmax). RFs were extracted from the hottest lesion with volume > 3 mL using PyRadiomics. All variables were normalized prior to model development. Diagnostic models were developed using the least absolute shrinkage and selection operator (LASSO) logistic regression to differentiate TFH and PTCL-NOS, while prognostic models used LASSO Cox regression to predict progression-free survival (PFS), both validated with 10-fold cross-validation. For each task, two model types were created: one incorporating RFs and one without, alongside clinical parameters from IPI, PIT, and conventional PET metrics, including SUVmax and total lesion glycolysis (TLG). Discriminative performance was evaluated using receiver operating characteristic (ROC) analysis and DeLong's test. Decision curve analysis (DCA) compared model utility. Prognostic stratification was assessed using Kaplan-Meier analysis with log-rank testing, and predictive accuracy was evaluated using Harrell's C-index.

Results: A total of 108 patients were included, comprising 56 (48.7%) with TFH and 52 (45.2%) with PTCL- NOS. The median age was 74.5 years (interquartile range: 68.0–81.0), with 40 (37.0%) females and 68 (63.0%) males. All patients received anthracycline-based chemotherapy; 9 (8.3%) underwent upfront autologous stem cell transplantation. In diagnostic prediction, five RFs were selected for the model incorporating radiomics, including increased asymmetry in voxel intensity patterns (gray level co-occurrence [GLCM]_Cluster Shade; coefficient: 0.42) favoring TFH, and uniformity in intensity distribution (GLCM_Maximal Correlation Coefficient; -0.39) favoring PTCL-NOS. Additional features included number of extranodal lesions (EN; -0.77) and SUVmax (-0.67). This model achieved an AUC of 0.902, outperforming the model without radiomics (AUC = 0.807; p = 0.002). The radiomics-based model also showed greater clinical utility across all risk thresholds, as assessed by DCA. For prognostic modeling, two RFs were selected for the radiomics-based model, including small, low-avidity lesions (gray level size zone matrix_Small Area Low Gray Level Emphasis; coefficient: 0.12), alongside EN (0.39) and TLG (0.33). When patients were stratified into three risk categories, the model significantly differentiated PFS (median: 56.3, 23.6, 4.9 months; p < 0.001) and overall survival (OS; 103.6, 57.0, 8.9 months; p < 0.001). It also demonstrated the highest predictive accuracy for PFS (C-index = 0.68) and comparable performance for OS (0.71), outperforming the model without RFs (0.66 and 0.70), IPI (0.62 and 0.68), and PIT (0.61 and 0.66). In subgroup analysis, only the radiomics-based model significantly stratified PFS in TFH (median: 56.3, 24.2, 9.3 months; p = 0.001), while the non-radiomics model did not (p = 0.12). In PTCL- NOS patients, all four models significantly stratified both OS and PFS.

Conclusion: This study demonstrates the diagnostic and prognostic utility of radiomic features in PTCL, highlighting their potential to enhance risk stratification beyond conventional PET metrics and clinical indices. Further research incorporating molecular and histopathological subclassification is warranted to validate these findings and clarify the biological significance of the extracted features.

Link to Abstract abs25-9670

Abstract Number: abs25-9807

Lipid metabolic reprogramming mediated by YTHDF3 deficiency underlies immunotherapy resistance in extranodal NK/T-cell lymphoma

Presenter: Qingqing Cai
Session: 622. Lymphomas: Translational – Non-Genetic: Poster III

Abstract: Background: Extranodal NK/T-cell lymphoma (NKTCL) is an aggressive non-Hodgkin lymphoma subtype. Despite improved outcomes with immunotherapy, persistent resistance in a subset of patients underscores an unmet need to delineate underlying molecular drivers. Lipid metabolic reprogramming provides energy and biosynthetic precursors for tumor growth while actively remodeling the tumor microenvironment to suppress immunity. Thus, cotargeting immune checkpoints and lipid metabolism represents a promising strategy to overcome resistance; however, its mechanistic basis and clinical applicability in NKTCL remain elusive.

Methods: Using complementary multiomics profiling—single-cell RNA sequencing (scRNA-seq; n = 13 patients), bulk RNA sequencing (RNA-seq; n = 24 patients), and metabolomics(n = 22 patients)—in the prospective SPIRIT cohort (NCT04127227), we identified reprogrammed lipid metabolism as a hallmark of immunotherapy resistance in NKTCL. To mechanistically dissect this, we deployed dual parallel systems: (1) therapy-resistant models and (2) CRISPR-based gene-editing platforms across in vitro settings and humanized mouse models. Functional validation was performed by leveraging these systems with multiomics analyses, including bulk RNA-seq, scRNA-seq, RNA immunoprecipitation sequencing (RIP-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), and metabolomics.

Results: YTHDF3 deficiency stabilizes PI3K-activating transcripts ( IRS1 , IGF1R , PIK3R6 ), driving constitutive PI3K signaling and lipid metabolic reprogramming. This hyperactivated lipid metabolism induces endoplasmic reticulum stress (ERS), promoting ERS-mediated MHC-I downregulation to confer immunotherapy resistance. Translating these findings, we designed a dual-targeting strategy synergizing PI3K inhibition (to reverse metabolic immunosuppression) and anti-PD-1 therapy (to block immune checkpoint evasion), which demonstrated efficacy in murine models. This therapeutic strategy is now being evaluated clinically in a phase Ib trial (NCT06793956).

Conclusion: Our study delineates the YTHDF3–PI3K–lipid metabolism axis as a central driver of immunotherapy resistance in NKTCL. This mechanism-guided framework, with dual targeting of PI3K and PD-1, bridges preclinical validation to clinical translation (NCT06793956).

Link to Abstract abs25-9807

Abstract Number: abs25-15400

Preclinical evaluation of macrophage reprogramming in treatment of CTCL

Presenter: Neda Nikbakht
Session: 622. Lymphomas: Translational – Non-Genetic: Poster III

Abstract: Introduction: Reprogramming tumor-supportive macrophages may have therapeutic utility in cutaneous T-cell lymphoma (CTCL) (Wu et al., J Invest Dermatol 2014). Targetable pathways in tumor-associated macrophages include signaling through mannose receptor, CD206 (Jaynes et al., Sci Transl Med 2020), and pattern-recognition receptor, toll-like receptor 4 (TLR4) (Oblak et al., Clin Dev Immunol 2011). Here, we evaluate TLR4 and CD206 in CTCL-associated macrophages to explore their therapeutic potential.

Methods: We utilized scRNA-seq to assess macrophages in CTCL lesional skin biopsies. Additionally, we assessed TLR4 and CD206 activity in an immunocompetent CTCL mouse model and in cancer cell- macrophage co-culture systems. In the co-culture systems, human or murine monocytic cells were differentiated into macrophages and subsequently polarized to anti- or pro-inflammatory phenotypes in the presence or absence of CTCL cell lines in transwells. TLR4 deficient mice and the small molecule TLR4 inhibitor, TAK-242, were used to abrogate TLR4 function. To stimulate CD206, we used a novel CD206 binding peptide, RP-832c.

Results: Human CTCL lesional skin biopsies (scRNA-seq N CTCL = 7, healthy control = 4; immunofluorescence N = 5) and mouse CTCL tumors (N = 5) displayed co-localized expression of CD206 and TLR4 on macrophages. CTCL-associated macrophages in skin lesions and in co-cultures exhibited a tumor-promoting phenotype with a 2-fold decrease in TNF-α expression (p <0.005), a 1.33-fold increase in CD206 expression (p <0.005). In addition, CTCL-associated macrophages exhibited a 4-fold increase in TLR4 expression in co-cultures (p <0.005). Macrophage phenotype shifted from tumor-promoting (IL-10 expressing) to tumor-suppressive (CD86 expressing) in macrophage co-cultures treated with RP-832c (1.25-fold increase in CD86 expression, p <0.05) or TAK-242 (5-fold increase in CD86 expression, p <0.05). Similarly, MBL2 mouse tumors treated with RP-832c (daily treatment with 10mg/kg body weight, provided by Riptide Biosciences) or TAK-242 (daily intraperitoneal injections 3mg/kg body weight) displayed a shift from immunosuppressive to inflammatory macrophage phenotype and attenuated tumor growth. In mice lacking TLR4 in the microenvironment or in CTCL-associated macrophages, CTCL tumor growth, measured by tumor volumes over time, was diminished compared to controls (N = 5 per group, p <0.0001).

Conclusions: Our data suggest that TLR4 inhibition and CD206 activation in the CTCL tumor microenvironment inhibit tumor growth by inducing a shift from tumor-promoting to tumor-suppressive macrophages. Therefore, CD206 binding peptide, RP-832c, and small molecule TLR4 inhibitor, TAK-242, present promising therapeutic options in CTCL.

Link to Abstract abs25-15400

Abstract Number: abs25-4079

Shorter diagnosis to treatment interval is associated with poor prognosis in patients with peripheral T-cell lymphoma: Analysis from the LEO and MER cohorts

Presenter: Matthew Maurer
Session: 626. Aggressive Lymphomas: Epidemiological Excluding Prospective Clinical Trials: Poster III

Abstract: Background: Background: Previous studies in aggressive B-cell lymphoma demonstrate that patients with shorter diagnosis-to- treatment intervals (DTI) represent those with higher risk disease. This suggests that patients enrolled in clinical trials may carry a selection bias as they often have longer DTI than patients in the general population. This has important implications for clinical research design and the generalizability of clinical trials in aggressive lymphomas. However, the prognostic implications of DTI have not been evaluated in peripheral T-cell lymphomas (PTCL). Therefore, we examined DTI and its association with clinical factors and outcomes in a prospective observational cohort of patients with PTCL from the United States within the LEO (Lymphoma Epidemiology and Outcomes) and MER (University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource). Patients and Methods Patients and Methods We evaluated patients enrolled to the MER (2002-2015) and LEO (2015-2020) cohorts with the following forms of PTCL: PTCL-not otherwise specified (PTCL-NOS, n=217), nodal T-follicular helper (TFH) cell lymphoma (nTFHL, n=153), anaplastic large cell lymphoma (ALCL), ALK positive (ALCL, ALK+, n=74), ALCL, ALK negative (ALCL, ALK-, n=95), enteropathy associated T-cell lymphoma (n=18), and monomorphic epitheliotropic intestinal T-cell lymphoma (n=2). Associations of DTI with clinical factors and outcomes were examined using Kaplan Meier and Cox models. Event free survival (EFS) was defined as the time from start of treatment to relapse/progression, start of 2 nd line therapy, or death from any cause. Overall survival (OS) was defined as the time from start of treatment until death from any cause. DTI was defined as the number of days between the first diagnostic biopsy and the start of therapy. Patients who were initially observed or had DTI > 100 days were excluded.

Results: In 559 patients (229 MER and 330 LEO), median age was 60, 34% had IPI>2 and 71% were stage III/IV. 472 (84%) patients initially received anthracycline-based chemotherapy. Median DTI was 23 days (interquartile range (IQR): 12-39) and was similar in MER (21 days, IQR: 11-33) and LEO (25 days, IQR: 14- 42). 168 (30%) patients had DTI 0-14 days, 178 (32%) 15-28 days, and 213 (38%) 29-100 days. Overall in the cohort, shorter DTI was associated with a worse 5-year OS (DTI 0-14 days: 43%; DTI 15-28 days: 53%; DTI 29-100 days: 58%, p<0.001) and 5-year EFS (DTI 0-14 days: 31%; DTI 15-28 days: 39%; DTI 29-100 days: 45%, p<0.001). In multivariable analyses, the association of DTI with outcomes remained consistent after adjusting for age and International Prognostic Index (IPI). Shorter DTI was strongly associated with adverse clinical factors, including elevated lactate dehydrogenase levels, poor performance status, B-symptoms, and higher IPI in both cohorts (all P < .003). DTI was not associated with age, sex, or distance from the LEO/MER center (all p>0.3). 6% patients with DTI of 0-14 days received 1L treatment on a clinical trial, compared to 11% with DTI 15-28 days and 13% with DTI 29-100 days, underscoring that patients with lower DTI may be underrepresented in clinical trials. When examining within PTCL subtypes, the association between short DTI (0-14 days) and inferior outcomes was most prominent in PTCL, NOS (OS HR=2.13, 95% CI: 1.52-2.94; EFS HR =1.49, 95% CI: 1.19- 1.85). Associations between short DTI and outcomes were weaker in other subtypes: nTFHL (OS HR=1.28, 95% CI: 0.83-2.00; EFS HR =1.22, 95% CI: 0.82-1.81), ALCL, ALK-, (OS HR=1.30, 95% CI: 0.59-2.86; EFS HR =1.32, 95% CI: 0.68-2.56), ALCL, ALK+, (OS HR=1.05, 95% CI: 0.26-4.17; EFS HR =2.12, 95% CI: 0.84-5.26).

Conclusion: Shorter DTI is associated adverse prognostic clinical factors (LDH, stage, high IPI) and inferior EFS and OS in newly diagnosed PTCL. Patients with DTI ≤ 14 days, which represents approximately 1/3 patients with PTCL, may be underrepresented in clinical trials. Understanding of this selection bias should inform clinical trial design and interpretation. Future studies should consider strategies to minimize barriers to enrollment for patients with low DTI.

Link to Abstract abs25-4079

Abstract Number: abs25-9725

Novel bispecific epitope anti-CD5 nanobody CAR-T cells for refractory or relapsed T-cell malignancies

Presenter: Haiyang LU
Session: 704. Cellular Immunotherapies: Early Phase Clinical Trials and Toxicities: Poster III

Abstract: Introduction: Due to the lack of effective therapeutic approaches, refractory/relapse (r/r) aggressive T-cell lymphomas have poor prognosis with 5-year progress free survival (PFS) of 20~30%, necessitating the novel cellular therapies. As allogeneic CD5 CAR (IASO Biotech) T-cell therapy can induce 100% response rate (1 month) in 19 r/r acute T lymphoblastic leukemia (T-ALL) patients (Pan J, et al. Nat Med 2024), targeting CD5 on r/r T-cell lymphoma with CAR T-cell therapy might be feasible. We developed a novel bispecific epitope anti-CD5 nanobody CAR construct, comparing the cytotoxicity to previous CD5 CARs. Furthermore, we evaluated efficacy and safety of autologous or allogeneic CD5 CAR vector in r/r peripheral T-cell lymphomas (PTCL) and T lymphoblastic lymphomas (T-LBL) with the novel bispecific epitope anti-CD5 nanobody CAR-T Cells (NCT07022964).

Methods: To enhance the efficacy of CD5 CAR, we employed a llama-derived nanobody library to screen for CD5-specific nanobodies, constructing dual-epitope CAR-T cells targeting the CD5 antigen. After comparing the expression efficiency, expansion capacity, and phenotypes of the dual-epitope construct to 2 previously published CD5 CAR-T cells (H65 and CD5 CARs [IASO Biotech]), we evaluated efficacy and safety of autologous or allogeneic this novel CD5 CAR vector in r/r peripheral T-cell lymphomas patients (NCT07022964). This trial has design to contain 2 cohorts: patients in cohort A received standard lymphodepletion and autologous CAR-T cells, and patients in cohort B received enhanced lymphodepletion and new donor CAR-T cells as previously published (Pan J, et al. Nat Med , 2024).

Results: Using phage display technology, we initially identified 1344 sequences potentially binding CD5, subsequent positive selection against CD5 and negative selection narrowed this down to 2 candidates. The dual-epitope CAR-T cells (H65 and CD5 CARs [IASO Biotech]) showed superior cytotoxicity against CD5+ Jurkat and SUP-T1 cell lines compared to previous CAR-T constructs. Therefore, we utilized a subcutaneous xenograft model in NSG mice to further validate the efficacy of the CAR-T cells in vivo. Female NSG mice (6-8 weeks old) were subcutaneously inoculated with 5×10⁶ Jurkat-GFP-luc tumor cells per mouse. Tumor burden was assessed 6 days post-inoculation to stratify mice into experimental groups. Beginning on day 7 post-tumor inoculation, mice received either Mock-T cells or CAR-T cells. We observed that the dual-epitope anti-CD5 CAR-T cells completely controlled tumor burden in mice and prolonged their survival. To date, 4 patients were enrolled in this trial with a median age of 48 (range: 6~61) years, including 2 case of PTCL-NOS, 1 case of CTCL, and 1 case of T-LBL. Baseline evaluation shows that 4 patients have extramedullary involvement, and 2 patients had bone marrow involvement. The median lines of previous therapy were 2.5 (range 2-6), and 1 case of T-LBL had history of allo-HCT. All patients received 1.0×10 6 /kg CAR-T cells. No DLTs were observed post-infusion. All patients had grade 1 cytokine release syndrome. No ICANS was documented. Severe adverse events (AEs) included cytopenia (4, Grade 3 or 4), which resolved by G-CSF within 30 days. Other AEs included 2 cases of EBV re-activation (grade 2 or 3). At 1-month evaluation, 3 patients achieved complete remission (Deauville score of 1 point) by PET/CT, with negative minimal residual disease (MRD) in bone marrow assessments. 1 patient showed significant regression of extramedullary lesions and transient reduction of lymphoma cells in peripheral blood. 3 CR patients had CAR-T expansion peak of 138.42 (range: 58.6-714.56) cells/μL at day 14 (range: 11-16). With the expansion of CAR-T cells, the patient's peripheral blood CD5+ T cells turned persistently negative at a median time of 10 days. In the median follow-up time of 35 (range: 30-97) days, 3 patients bridged to allo-HCT, all of them remain remission, however 1 patient died of infection at day 14 post-HCT.

Conclusion: We optimized the novel bispecific epitope anti-CD5 nanobody CAR construct, and shows superior cytotoxic activity comparing with CD5 CAR (IASO Biotech) in vitro . We also got preliminary safety and efficacy profiles in r/r T-cell lymphoma. This clinical trial is still ongoing, and long-term efficacy and clinical complication of CD5 CAR-T cell therapy still require further investigation.

Link to Abstract abs25-9725

Abstract Number: abs25-13823

First-in-human Phase I study of autologous CD5-knockout anti-CD5 CAR-T cells in CD5⁺ hematologic malignancies

Presenter: Jiali Cheng
Session: 704. Cellular Immunotherapies: Early Phase Clinical Trials and Toxicities: Poster III

Abstract: Introduction: CD5 is broadly expressed across hematologic malignancies, notably in ~85% of T-cell tumors and is associated with poorer prognosis in certain B-cell tumors, making it a promising target for CAR-T cell therapy. Two primary clinical studies have reported on CD5-targeted CAR-T therapy: one using autologous CAR-T cells without CD5 editing (NCT03081910) and one using allogeneic CD5-knockout (CD5- KO) CAR-T cells (NCT05032599). To further explore its clinical utility, we conducted a Phase I trial (NCT04767308) of autologous CD5-KO anti-CD5 CAR-T cells (CAR5 5ko -T) in patients with relapsed and refractory (r/r) CD5⁺ hematologic malignancies. Methods Patients received a single dose of CAR5 5ko -T cell infusion after a three-day FC lymphodepletion regimen, followed by a 1-day rest. Dose levels evaluated were 1.0 × 10⁶, 2.0 × 10⁶, and 1.0 × 10⁵ cells/kg. Adverse events (AEs) were graded using CTCAE v5.0, and treatment responses were assessed per Lugano 2014 criteria. CAR-T kinetics were measured by ddPCR and flow cytometry. Lymphocyte subset dynamics were analyzed via multicolor flow cytometry. The study was conducted in accordance with the Declaration of Helsinki, and all participants provided informed consent. Results Seven patients (4 males, 3 females) were treated from February 2021 to October 2021, including 1 ALCL, 2 AITL, 1 SPTCL, 2 MCL, and 1 DLBCL. Median age was 47 years (range: 17–67), with a median of 3 prior therapy lines (range: 2–6). Patient 2 had previously received anti-CD19/22 CAR-T, and Patient 3 had undergone autologous HSCT. The overall response rate was 85.7%, with 4 CR and 2 PR. Median PFS and OS were 170 and 205 days, respectively. Patient 1 remained in remission > 902 days post-infusion. Notably, CD5 + T cells were absent at the disease relapse or resistance. CAR5 5ko -T cells expanded robustly and persisted long-term. Median peak copy number was 87,178 copies/μg DNA (range: 31,618–118,000), with a median time to peak of 14 days. During a median follow- up period of 124 days, CAR-T cells remained detectable in all patients, with persistence >809 days in patient 1. CRS and ICANS were generally mild; only one case of grade 3 CRS occurred. The most common ≥ grade 3 AEs were cytopenia: neutropenia (100%), lymphopenia (100%), thrombocytopenia (78%), and anemia (89%). Notably, grade 4 lymphopenia and neutropenia recured after one-month post-infusion. Consistently, EBV (6/7) and CMV (4/7) reactivations were frequent. Four patients had bacterial infections, resulting in to two deaths. Uncommon AEs were observed, including rash (71.4%), skin tingling (71.4%) and autoimmune-associated AEs: xerostomia (28.6%), hypothyroidism (14.3%), and adrenal insufficiency (14.3%). Immune reconstitution process was monitored. Following the transient nadir, CD3 + T cells recovered to pre-lymphodepletion levels within 1 month and maintained stable. Notably, the reconstituted T cells was CD5 negative. The CD4/CD8 ratio decreased rapidly and remained < 1 throughout the entire follow-up. B cells were rapidly depleted and failed to recover during long-term follow-up. NK and NKT cells showed transient decline but rebounded to baseline. Conclusion CD5-KO anti-CD5 CAR-T therapy demonstrates promising efficacy in treating CD5 + hematological malignancies, including both T-cell and B-cell tumors. The knockout of CD5 enhances CAR-T persistence and therapeutic durability. However, sustained CD5 + T cells depletion and expansion of CD5 - T cells may impair immune regulation and infection control in patients. These findings highlight the need to modulate the CAR-T persistence duration clinical application and support the consideration of consolidative HSCT therapy in patients achieving remission.

Link to Abstract abs25-13823

Abstract Number: abs25-14400

The NLP protein is a novel regulator of G2-m Phase of the cell cycle critical for proliferation of human peripheral T-cell lymphomas

Presenter: Julian Tobon
Session: 603. Lymphoid Oncogenesis: Basic: Poster III

Abstract: Peripheral T ‑ cell lymphomas (PTCL) are a diverse group of aggressive T ‑ and NK ‑ cell malignancies distinguished by differences in cellular origin, genetic alterations, molecular signatures, morphology, and antigen expression. Representing roughly 15% of non ‑ Hodgkin lymphomas, PTCLs carry a poor prognosis. Standard regimens such as CHOP or R ‑ CHOP, along with approved targeted agents (belinostat, romidepsin, pralatrexate), have yielded limited long ‑ term benefit, with 5 ‑ year survival rates of only 20–30%. Thus, meaningful advances in PTCL therapy will require the discovery of new molecular vulnerabilities important for lymphoma cell growth and survival. Using functional screening, we identified an uncharacterized human gene C17ORF5 8 (termed NLP - Netrin-Like Protein) to be critical for the survival of PTCL cells in vitro . NLP encodes a 37 ‑ kDa protein featuring an N ‑ terminal signal peptide, nuclear localization signals, an intrinsically disordered region, and a C ‑ terminal Netrin ‑ like domain. Consistent with its predicted features, the protein localizes to the nucleus and is also secreted. Furthermore, structural modeling analysis predicts NLP possesses a druggable architecture. The gene is overexpressed in >95% of PTCL cases, including Anaplastic Large Cell Lymphoma, Angioimmunoblastic T ‑ cell Lymphoma, and PTCL ‑ Not Otherwise Specified (PTCL ‑ NOS), as well as in multiple solid tumors such as breast, renal, and liver cancers. Importantly, loss of NLP in cancer cell lines induces G2–M arrest and mitotic catastrophe, culminating in apoptosis, suggesting a critical role in regulating malignant T ‑ cell proliferation. The growth inhibition was associated with deregulation of genes involved in stress responses (PDCD5, NDUFAB1, RPL10), G2–M phase progression (TOM1, RPLP2, HMGA1, MYL12B), and cell death (PUMA, EPAS1, ATF5). Furthermore, NLP loss was accompanied by an increase in γH2A.X, Phospho-Chk2 (Thr68) and Phospho-BRCA1 (Ser1524), and the decrease in Phospho-Chk1 (Ser345) indicating the induction of double-strand DNA breaks and the activation of DNA repair mechanisms. Interestingly, NLP depletion did not suppress proliferation of normal human T-cells, mouse embryonic fibroblasts or human kidney embryonic cells. Homozygous NLP knockout mice are viable but show ~10% reduction in the body size suggesting that mouse NLP is important but not essential for normal development. Altogether, our findings identify NLP as a novel regulator of the G2–M phase of the cell cycle with a critical role in the proliferation of malignant T-cells. Given its predicted druggable structure, NLP represents a promising candidate for the development of novel targeted PTCL therapies.

Link to Abstract abs25-14400

Abstract Number: abs25-10233

PET imaging biomarkers predict survival in peripheral T-cell lymphoma: A systematic review and meta-analysis.

Presenter: Lohitha Dhulipalla
Session: 906. Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster III

Abstract: Background: Background: Peripheral T-cell lymphomas (PTCLs) are aggressive and heterogeneous lymphoid malignancies with poor prognoses and limited response durability using CHOP-based regimens. Recent studies suggest that PET/CT-derived biomarkers—including total metabolic tumor volume (TMTV), total lesion glycolysis (TLG), and Deauville scores (DS) at interim and end-of-treatment (EOT)—may hold prognostic value, yet they are not uniformly incorporated into clinical decision-making. As frontline regimens like BV-CHP become more widely adopted, identifying reliable predictors of outcomes is critical. We hypothesized that PET-based biomarkers—TMTV, TLG, and DS—are significantly associated with overall survival (OS) and progression- free survival (PFS) in patients with nodal PTCL treated with CHOP-like or BV-CHP regimens.

Methods: This systematic meta-analysis (PROSPERO CRD420251041744) identified 196 articles via systematic search of PubMed and Cochrane searches. Inclusion criteria were treatment-naive adults with nodal PTCL treated with CHOP-like BV-CHP regimens studies reporting hazard ratios (HRs) for OS or PFS associated with baseline TMTV, TLG, or DS. Exclusion criteria included case reports, pediatric studies, non-English publications, and studies involving other lymphoma subtypes, ENKTL, cutaneous T-cell lymphomas, and other mature lymphoid neoplasms. Ten studies met the criteria. Five reviewers screened and extracted data. PET variables were dichotomized as study specific threshold of high vs. low (TMTV, ) and DS 4–5 vs. 1–3 for interim and EOT comparisons. We conducted Meta-analyses using RevMan 7.2.0 software, inverse-variance methods and random-effects models. Heterogeneity was assessed via I² and τ² (REML).

Results: Out of 10 eligible studies 9 were retrospective, and ECHELON-2 (E-2) study was prospective with prespecified assessment of PET response using DS. CHOP-like regimens were used in 1075 patients (including 226 from the matched E-2 cohort), while 226 were treated with BV-CHP in E2. The pooled median age was 58.5 years, predominantly male (61.8%) with advanced-stage disease (88.6% Stage III/IV). Patient distribution between low-risk (IPI 0-2) and high-risk (IPI 3-5) groups was balanced. Follow-up duration ranged from 17 to 65.8 months; the estimated pooled median follow-up was 38 months. Baseline TMTV was evaluated in seven studies (n = 680 ) and was significantly associated with inferior PFS (pooled HR 2.78 [95% CI: 1.24–6.24]; p = 0.01; I² = 88%). Baseline TMTV also correlated with OS across five studies (HR 2.43 [95% CI: 1.49–3.97]; p = 0.0004; I²=83 %). TLG, reported in three studies (n = 254), was associated with worse OS (HR 3.07 [95% CI: 1.29–7.34]; p = 0.01; I² = 73%). Higher baseline SUV was variably associated with OS and PFS across studies, but without consistent statistical significance. DS high at interim PET (6 studies; n = 698) was strongly associated with PFS (HR 3.40 [95% CI: 2.54–4.54]; p < 0.00001; I² = 13%) and OS (HR 3.62 [95% CI: [2.05- 6.38]; p < 0.00001; I²= 65%). DS high at end-of- treatment (EOT) was even more predictive of OS (pooled HR 5.89 [95% CI: 2.15-16.14]; p < 0.0006; I² = 66%) and PFS (HR 4.29 [95% CI: 1.96–9.39]; p < 0.0003; I²=61 %). DS 1–3 was consistently associated with durable remissions, while DS 4–5 often identified primary refractory . Conclusions Conclusions This meta-analysis confirms that PET-based imaging biomarkers—particularly TMTV, TLG, and DS are significantly associated with OS and PFS in patients with nodal PTCL treated with CHOP or BV-CHP. DS 4– 5 at EOT showed the strongest predictive value across cohorts. These findings support incorporating PET biomarkers into clinical risk models and future trials. Limitations include inter-study heterogeneity, mostly retrospective designs, variability in PET methods and cutoff definitions. Prospective validation of optimal cutoffs, and integration with molecular classifiers are needed to refine risk-adapted therapy in PTCL.

Link to Abstract abs25-10233

Abstract Number: abs25-10990

Dual anti-HLH and antitumor efficacy of golidocitinib in relapsed/refractory PTCL-associated hemophagocytic lymphohistiocytosis: A retrospective safety and activity analysis

Presenter: He Li
Session: 906. Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster III

Abstract: Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome driven by cytokine storms (e.g., IFN- γ , IL-6, IL-10). Lymphoma-associated HLH (LA-HLH), particularly linked to aggressive T/NK-cell neoplasms, demonstrates dismal prognosis and mandates urgent suppression of both hyperinflammation and malignancy. While JAK inhibitors (e.g., ruxolitinib) target the JAK-STAT pathway central to HLH cytokine signaling, their utility in PTCL-associated HLH is limited by substantial hematologic toxicity and lack of proven antitumor efficacy in PTCL. Golidocitinib, a potent and selective JAK1 inhibitor, has shown promising anti-tumor activity with favorable safety profile in relapsed/refractory (r/r) peripheral T-cell lymphoma (PTCL), representing a mechanistically rational strategy to disrupt pathogenic signaling in high-risk LA-HLH. This was a retrospective study of patients with PTCL-associated HLH treated with golidocitinib monotherapy or combination therapy.

Methods: In this single-center study, sixteen patients with relapsed/refractory PTCL-associated HLH meeting HLH-2004 criteria were enrolled between July 1, 2024, and June 26, 2025, receiving golidocitinib- based therapy (8 monotherapy, 8 combined with chemotherapy). Lymphoma response was assessed per Lugano 2014 criteria, and HLH response was evaluated according to the response criteria defined in the Histiocyte Society HLH-2004 protocol.

Results: Baseline characteristics included a median age of 56 years (range 28–61), 9 males; lymphoma subtypes comprised extranodal NK/T-cell lymphoma (n=6), angioimmunoblastic T-cell lymphoma (n=5), NK-cell leukemia (n=2), hepatosplenic T-cell lymphoma (n=2), and PTCL-NOS (n=1). 87.5% patients (14/16) had Ann Arbor stage III–IV disease; median prior lines of anti-lymphoma therapy were 2 (range 1–4); 10 patients (62.5%) had ECOG PS ≥2. Systemic HLH manifestations included fever (≥38.5°C) in all patients, cytopenia in 8 (50%) patients, hepatic impairment in 7 (43.8%) patients; elevated biomarkers included EBV-DNA in 10 patients (62.5%) and elevated sCD25 in 11/11 tested patients (100%). Anti-lymphoma efficacy demonstrated an ORR of 46.7% (7/15) and CR rate of 13.3% (2/15) with a median time to response of 2 months (1-3). Among 10 patients with elevated EBV-DNA, 60% (6/10) achieved undetectable levels post-treatment. Rapid anti-HLH activity was observed, HLH response rate was 85.7% (6/7) and 77.8% (7/9) at week 2 and week 4 respectively. Clinical improvements included resolution of fever, hematologic recovery (7 patients at both timepoints), and hepatic function normalization (7 patients at both timepoints). Significant reductions in inflammatory markers were observed, including neutrophil to lymphocyte ratio (NLR), IL-6, CRP, TNF-α, ferritin, and triglycerides. At data cutoff (median follow-up: 3.1 months, range 0.8–6.3), 62.5% of patients (10/16) remained on treatment, with median PFS and OS were not reached. Treatment-related adverse events (TRAEs) were manageable, with the most common being thrombocytopenia (42.8%), CMV reactivation (28.6%), abnormal liver function (14.3%). Grade ≥3 TRAEs lung infection (14.3%) and CMV reactivation (14.3%); serious TRAEs comprised CMV reactivation (28.6%), lung infection (14.3%), and thrombocytopenia (14.3%). No treatment-related deaths occurred.

Conclusion: This study demonstrates that golidocitinib-based regimens provide dual anti-HLH and antitumor efficacy in relapsed/refractory PTCL-associated HLH, with rapid clinical improvement (e.g., fever resolution, biomarker normalization) and an ORR of 46.7%. Most patients achieved systemic and hematologic recovery with a manageable safety profile and no treatment-related deaths. These findings highlight the potential of JAK1 inhibition in this high-risk cohort, warranting prospective validation to confirm efficacy and optimize therapeutic strategies.

Link to Abstract abs25-10990

Abstract Number: abs25-11128

Golidocitinib combination therapy as first-line treatment in PTCL: Retrospective data from a single centre

Presenter: Wenyu Li
Session: 906. Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster III

Abstract: Background: Peripheral T-cell lymphoma (PTCL), except for the anaplastic large cell lymphoma (ALCL) subtype, is characterized by a poor prognosis and low overall survival rate. Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumor activity in heavily pre-treated patients with relapsed or refractory PTCL in a phase 2 study (JACKPOT8 Part B). Here we present 16 cases of adult PTCL that were identified and treated with golidocitinib as first-line therapy at Guangdong Provincial People's Hospital since July 2024. Aims: Aims: To evaluate the efficacy and safety of golidocitinib combination with CHOP-like chemotherapy as first-line treatment for patients with PTCL.

Methods: Between July 2024 and July 2025, 16 adult patients >18 years old with PTCL and received golidocitinib combined with CHOP-like chemotherapy regimen as first-line treatment were identified at Guangdong Provincial People's Hospital. Patient demographics, clinical characteristics and treatment modalities were summarized.

Results: Among 16 patients enrolled into the study, the median age was 61.5 years (range, 40-74), 8 patients (50%) were male, 5 (31.3%) had an ECOG PS of 0-1, 14 (87.5%) had stage III-IV disease, and 14 (87.5%) had an IPI score of 3-5. Six patients (37.5%) had bone marrow involvement before treatment, and 12 (76%) had extranodal involvement (with 10 patients having ≥ 2 extranodal involvement). Two patient (12.5%) was diagnosed with EATL, 11 patients (68.8%) were diagnosed with AITL, 3 patients (18.8%) were diagnosed with PTCL-NOS. ALL patients received golidocitinib plus CHOP-like chemotherapy as first-line treatment. One patients (6.3%) received golidocitinib 150 mg QD 5 patients (31.3%) received golidocitinib 150 mg QD 2 week-on and 1 week-off schedule , and 10 patients (62.5%) received golidocitinib 150 mg QOD 2 week-on and 1 week-off schedule .Treatment-related adverse events (TRAEs) were observed in 7 patients (43.8%), with pulmonary infection and neutropenia being the most common (2 patients each, 12.5%), followed by infectious pneumonia, cytomegalovirus reactivation, leukopenia, febrile neutropenia, rash, abnormal liver function and thrombocytopenia (1 patient each, 6.3%). One patient permanently withdrew from treatment to receive stem cell transplant. 14 patients were evaluable for efficacy: 6 reached CR, 7 reached PR during mid-term evaluation,resulting in an overall response rate (ORR) of 92.9% and a CR rate of 42.9%.

Conclusion: Golidocitinib demonstrated encouraging antitumor efficacy and clinical manageable safety profile in combination with CHOP-like chemotherapy in newly-diagnosed PTCL patients. Further prospective study is warranted to validate the results.

Link to Abstract abs25-11128

Abstract Number: abs25-13679

Golidocitinib combined with CHOP in newly-diagnosed peripheral T-cell lymphoma: Preliminary Results from A phase 1/2 clinical trial

Presenter: Chong Wei
Session: 906. Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster III

Abstract: Background: Background: Peripheral T-cell lymphoma (PTCL) comprises a group of heterogeneous and aggressive non-Hodgkin lymphomas associated with poor outcomes. CHOP remains the standard first-line therapy, yet the 5-year overall survival (OS) remains suboptimal. Golidocitinib, a potent and selective JAK1 inhibitor, has demonstrated promising anti-tumor activity with favorable safety profile in relapsed/refractory (r/r) PTCL. Aims Aims To evaluate the anti-tumor activity and tolerability of Golidocitinib in combination with CHOP regimen (Go-CHOP) as the frontline therapy for patients with PTCL.

Methods: This is an ongoing phase 1/2, single-center, single-arm clinical trial (NCT06739265) evaluating Go-CHOP as first-line therapy in adults patients (≥18 years) with histologically confirmed, previously untreated PTCL, including PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL), etc. The study consists of two sequential phases: a 3+3 dose- escalation cohort (Phase 1) to determine the recommended phase 2 combination dose (RP2CD), followed by a dose-expansion cohort (Phase 2) assessing efficacy and safety. In Phase 1, patients receive six 21-day cycles of Go-CHOP: oral golidocitinib 150 mg every other day (Qod) on days 1-21 combined with standard CHOP chemotherapy (cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², vincristine 1.4 mg/m² IV on day 1, and prednisone 100 mg po on days 1-5). Dose escalation to 150 mg once daily was permited if ≤1/6 patients experienced dose-limiting toxicities (DLTs) during cycle 1, defined as grade 4 hematological toxicity lasting ≥7 days or grade ≥3 non-hematological events (per CTCAE v5.0). In Phase 2, patients received Go-CHOP at the RP2CD. Interim PET-CT was performed after 3 cycles. Responders at the end of Go-CHOP therapy received either consolidative autologous stem cell transplantation (ASCT) , if eligible, or golidocitinib maintenance for transplant ineligible patients for up to 24 months or until disease progression or unacceptable toxicity. The primary endpoint is complete response rate (CRR) assessed according to the Lugano 2014 criteria, at the end of Go-CHOP therapy.

Results: As of the data cutoff on August 3rd, 2025, eighteen patients were enrolled and received at least one cycle of Go-CHOP regimen, including 6 patients in phase 1 and 12 patients in phase 2. The median age was 50 years (range, 18-70), and 14 patients (77.8%) were male. All eighteen patients (100%) had stage III-IV disease, and eleven (61.1%) had an IPI score of 3-5. Diagnoses included: AITL in 9 patients (50%), PTCL-NOS in 7 (38.9%), MEITL in 1 (5.6%), and ALK+ALCL in 1 (5.6%). No DLTs were observed in the dose escalation phase, establishing 150 mg golidocitinib once daily as RP2CD. Treatment-related adverse events (TRAEs) were observed in 17 patients (94.4%), with neutropenia being the most common one (72.2%), followed by urinary tract infection (22.2%) and thrombocytopenia (22.2%). Grade 3/4 TRAEs were primarily neutropenia, observed in 61.1% of the patients. CMV reactivation was observed in 3 patients (16.6%) and warrants close monitoring. Additionally, one case of hepatitis B virus reactivation and one case of pulmonary cryptococcosis were reported, the latter resulting in treatment discontinuation. One fatal case of gastrointestinal bleeding was reported, which was assessed as unrelated to the treatment by the investigator. Among 15 efficacy-evaluable patients, 12 achieved objective responses, and 11 reached CR, yielding an overall response rate (ORR) of 80.0% and a CRR of 73.3%. With a median follow-up of 5.5 months, the median progression-free survival and OS will be reported after longer follow-up.

Conclusion: Preliminary results of golidocitinib in combination with CHOP demonstrated a manageable safety profile and encouraging antitumor activity in newly diagnosed PTCL. This clinical trial is ongoing.

Link to Abstract abs25-13679

Abstract Number: abs25-4325

Deciphering tph cells as prognostic drivers of angioimmunoblastic T-cell lymphoma

Presenter: Haiyan Yang
Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster III

Abstract: Introduction: Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive malignancy derived from follicular helper T (Tfh) cells, characterized by systemic immune dysregulation and heterogeneous clinical outcomes despite anthracycline-based chemotherapy [1-2]. The prognosis of AITL remains poor, with limited efficacy of current treatments, and patient outcomes vary significantly even among those with similar clinical staging. Recent studies have highlighted the role of peripheral immune signatures in T-cell lymphoma, but comprehensive single-cell profiling of AITL’s immune landscape is lacking [3-4]. This study leverages CyTOF and single-cell RNA sequencing (scRNA-seq) to map the peripheral and tumor microenvironment (TME) immune heterogeneity in AITL, identifying T peripheral helper (Tph) cells as a novel prognostic subset and exploring their mechanistic role in disease progression.

Results: Our CyTOF analysis of peripheral blood mononuclear cells (PBMCs) from 17 AITL patients firstly revealed significant heterogeneity in immune cell distribution, with Tph cells (CD3+, CD4+, CD278+, CD279+, CD185-) emerging as a distinct subset enriched in AITL compared to healthy controls and other T-cell lymphomas. Tph cells demonstrated strong prognostic value, with higher proportions correlating with poorer progression-free survival (PFS). Pseudotemporal analysis positioned Tph cells later than Tfh cells in differentiation trajectories, suggesting a terminal state linked to disease aggressiveness. Mechanistically, Tph cells drive immune dysregulation through ligand-receptor interactions, particularly CD70-mediated costimulation and IL-21 signaling, which promote B-cell activation and inflammatory responses. Multi-immunofluorescence (mIF) of tumor tissues confirmed Tph cell infiltration in patients with adverse outcomes, while scRNA-seq identified Tph-specific gene signatures and communication networks, including upregulated pro-inflammatory pathways and DNA repair mechanisms. METHOD METHOD We integrated CyTOF, scRNA-seq, and mIF to dissect AITL’s immune landscape. PBMCs from AITL patients and controls were analyzed using a 42-marker CyTOF panel, followed by PhenoGraph clustering and t- SNE visualization. For scRNA-seq, 35,546 single cells from AITL lymph nodes were sequenced, annotated, and subjected to pseudotime and cell-cell communication analyses. Tumor tissues were stained with mIF to quantify Tph and Tfh spatial distribution. Statistical analyses included Spearman correlation, Kaplan- Meier survival curves, and ROC analysis to evaluate prognostic significance. The study adhered to ethical guidelines, with approval from Zhejiang Cancer Hospital’s IRB. CONCLUSIONS CONCLUSIONS This study establishes Tph cells as a key prognostic driver in AITL, bridging peripheral immune signatures with TME dysregulation. By combining CyTOF and scRNA-seq, we unveiled Tph’s role in promoting immune evasion and inflammation via CD70/CD27 and IL-21/IL-21R axes, offering new targets for precision therapy. Our multi-omics framework provides a blueprint for investigating immune heterogeneity in malignancies with complex microenvironments, paving the way for improved stratification and targeted interventions in AITL. Future work will validate these findings in larger cohorts and explore therapeutic strategies to disrupt Tph-mediated pathways. CONTACT INFORMATION CONTACT INFORMATION Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China Email: yanghy@zjcc.org.cn

Link to Abstract abs25-4325

Abstract Number: abs25-8678

Circulating extracellular Vesicle–Derived mirnas identify a high-risk subgroup in extranodal NK/T-cell lymphoma with caebv-like features

Presenter: Kyung Ju Ryu
Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster III

Abstract: Background: Background: Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a distinct lymphoma subtype associated with Epstein-Barr virus (EBV) infection and characterized by unique clinical features. Most patients present with localized disease (stage I/II) involving the nasal cavity or nasopharynx. In this group, outcomes have improved significantly with concurrent chemoradiotherapy using non-anthracycline, L-asparaginase– based regimens. However, a subset of patients presents with stage IV involving extranasal sites such as the skin or gastrointestinal tract and often exhibits clinical features of hemophagocytic lymphohistiocytosis (HLH). These presentations overlap with those of chronic active EBV infection (CAEBV) and aggressive NK-cell leukemia (ANKL), and are frequently associated with rapidly progressive, fatal courses. Moreover, some patients initially diagnosed with localized ENKTL may later experience systemic progression and outcomes resembling CAEBV or ANKL. We hypothesized that these patients may harbor distinct biological features linked to CAEBV-like biology, which are not currently identifiable through standard staging. To date, no reliable molecular tools exist to distinguish stage I/II ENKTL patients at high risk of systemic progression with occult CAEBV-like features.

Methods: We conducted comprehensive small RNA sequencing of intravesicular contents from serum-derived extracellular vesicles (EVs) in ENKTL patients (n = 50) and ENKTL cell lines. EVs were isolated using the Total Exosome Isolation reagent, and small RNA libraries were prepared using the SMARTer smRNA-Seq Kit for Illumina and sequenced on the NovaSeqX platform. Data processing was performed using miRDeep2 for alignment and identification of known and novel miRNAs. Reads were sequentially aligned to the human reference genome (GRCh38), miRBase v22.1, and the RNAcentral non-coding RNA database (release 14.0). Raw counts were normalized using the Trimmed Mean of M-values (TMM) method in edgeR. miRNAs absent in over 51% of samples were excluded, leaving 735 mature miRNAs for downstream analysis. Differentially expressed miRNAs were identified using edgeR's exact test, with significance defined as |fold change| ≥ 2 and p-value < 0.05.

Results: Archived serum samples from 50 ENKTL patients enrolled in a prospective cohort study were used for EV isolation. Six ENKTL or CAEBV-derived cell lines (SNK-1, -6, -8, -10, -15, and -16) served as reference controls. Among the patients, 30 had early-stage disease (stage I, n = 20; stage II, n = 10), while 20 presented with advanced disease (stage IV). At diagnosis, five patients fulfilled the diagnostic criteria for HLH, and an additional 19 exhibited HLH-like clinical and laboratory features. EBV DNA was markedly elevated (>10,000 IU/mL) in 14 patients, moderately elevated (<10,000 IU/mL) in 22, and undetectable in the remaining 14. Following first-line treatment, 15 patients achieved and maintained complete remission without relapse. However, 13 patients initially diagnosed with stage I/II disease experienced relapse or progression, while 22 patients—predominantly those with stage IV disease—developed systemic progression or relapse, resulting in death. Analysis of EBV-derived microRNAs revealed that six patients with stage IV disease and HLH-like features exhibited EBV microRNA expression patterns, including BART3-3p, BART10-3p, and BART17-5p, that closely resembled those seen in ENKTL/CAEBV cell lines. Further analysis of host-derived microRNAs showed that hsa-miR-1285-3p, hsa-miR-5684, and hsa- miR-8485 were significantly upregulated in patients with HLH-like features and high EBV DNA titers (>10,000 IU/mL). In particular, hsa-miR-1285-3p was elevated in patients with stage IV disease and those stage I/II patients who later developed systemic relapse. This microRNA, previously implicated in cancer progression, also demonstrated significantly higher expression in patients with high EBV DNA compared to those with undetectable EBV DNA (P < 0.05). Conclusions Conclusions Our findings suggest that a subset of ENKTL patients—particularly those with advanced-stage disease or HLH-like features—exhibits distinct circulating EBV and host microRNA profiles, resembling those seen in CAEBV and ENKTL-derived cell lines. Notably, elevated levels of hsa-miR-1285-3p were associated with systemic relapse and high EBV DNA titers, indicating its potential as a biomarker for identifying patients at high risk of aggressive disease progression.

Link to Abstract abs25-8678

Abstract Number: abs25-14785

Differential prognostic impact of chromatin modifier mutations in peripheral T-cell lymphoma: KMT2A emerges as a critical biomarker

Presenter: Youngwoo Jeon
Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster III

Abstract: Background: Peripheral T-cell lymphomas (PTCLs) remain one of the most challenging lymphoma subtypes to treat, with consistently poor outcomes across different populations. Although mutations in genes like TET2, DNMT3A, and KMT2A have been reported in Western cohorts, we still don't fully understand their relevance in Asian patients. We sought to map the genetic landscape of PTCL in Korean patients using targeted sequencing and determine which mutations actually affect survival.

Methods: We reviewed 55 adults diagnosed with PTCL at Yeouido St. Mary's Hospital between September 2020 and September 2024. Our cohort included 23 patients with PTCL-NOS (42%), 14 with angioimmunoblastic T-cell lymphoma (25%), 11 with extranodal NK/T-cell lymphoma (20%), and 7 with other subtypes (13%). We performed targeted sequencing on tumor tissue using a 146-gene lymphoma panel and classified variants according to AMP/ASCO/CAP criteria. We collected clinical information including patient characteristics, treatments received, and responses based on Lugano 2014 criteria. For survival analysis, we used Kaplan-Meier curves and Cox regression models to identify factors associated with progression-free survival (PFS) and overall survival (OS).

Results: Our patients had a median age of 62 years (range 28-81), with 60% being male. Most had advanced disease at diagnosis—71% were stage III-IV and 65% had intermediate-high or high IPI scores. After a median follow-up of 21 months, the 2-year OS was 57.3%. When we looked at the mutation patterns, ATR was mutated most often (30%), followed by KMT3A (29%) and TP53 (27%). What stood out was KMT2A—mutated in 15 patients (27%)—which was strongly linked to worse survival. Patients with KMT2A mutations had a median OS of just 10.7 months compared to 30.8 months for those without (p=0.043). We found a similar pattern with DNMT3A mutations, present in 7 patients, where median OS was only 12.3 months (p=0.027). Interestingly, TET2 mutations didn't affect survival at all despite being present in 9 patients (p=0.9). Ten patients got brentuximab vedotin as part of their initial treatment, but this didn't improve outcomes compared to standard CHOP chemotherapy. When we adjusted for other factors like IPI score and histology, KMT2A mutations remained a strong predictor of death (HR 2.8, p=0.018). The four patients who had both KMT2A and DNMT3A mutations did particularly poorly, with a median survival of only 8.2 months.

Conclusions: Our study reveals that KMT2A mutations occur in about a quarter of Asian PTCL patients and predict significantly worse outcomes. This finding, along with the poor prognosis associated with DNMT3A mutations, suggests these genetic alterations could help identify patients who need more aggressive or experimental treatments upfront. The fact that TET2 mutations didn't affect survival, despite being frequently studied in PTCL, shows that not all epigenetic mutations are equal. Moving forward, we believe NGS testing should become standard practice for PTCL patients to better stratify risk. These patients with KMT2A mutations clearly need different treatment strategies, and clinical trials specifically targeting this high-risk group should be prioritized.

Link to Abstract abs25-14785

Abstract Number: abs25-15481

Spatial transcriptomics uncovers unique tumor microenvironments in folliculotropic versus classic mycosis fungoides

Presenter: Neda Nikbakht
Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster III

Abstract: Introduction: The most common subtype of cutaneous T-cell lymphoma (CTCL), mycosis fungoides (MF), is characterized by proliferation of malignant T-cells in the skin. In the more clinically aggressive folliculotropic variant of MF (FMF), malignant T-cells localize to follicular epithelium while in classic MF (CMF), they infiltrate the dermis and epidermis (Gerami et al., Arch Dermatology 2008; Agar et al., J Clin Oncol 2010). How the localization of neoplastic T cells to the follicular niche contributes to the clinical aggression in FMF is unclear.

Methods: To uncover the tumor microenvironmental differences between perifollicular FMF and dermal CMF regions, we analyzed 9 mycosis fungoides lesional skin biopsies (3 FMF, 6 CMF) using spatial transcriptomics. We performed and analyzed transcriptomic data from 71 regions of interest (ROIs) in FMF patients to 123 ROIs in CMF patients obtained from all cells using the Nanostring GeoMx Digital Spatial Profiler. Additionally, we compared data obtained from CD4+ cells, which include the predominant malignant T-cells, and CD68+ cells, which represent macrophages in the tumor microenvironment. The FMF ROIs were taken from perifollicular locations, while CMF ROIs were from the dermis. Our bioinformatics analyses included differential gene expression analysis, spatial deconvolution, gene set enrichment analysis (GSEA), and single sample GSEA (ssGSEA).

Results: Our ssGSEA analysis revealed that FMF CD4+ T cells showed higher activity in metabolic pathways (glycoprotein metabolic process – Gene Ontology, adjusted p = 0.044; response to EIF2AK4 GCN2 to amino acid deficiency - Reactome, adjusted p = 0.030), cholesterol transport pathways (positive regulation of cholesterol efflux – Gene Ontology, adjusted p = 0.030), and nutrient deprivation response pathways (cellular response to starvation - Reactome, adjusted p = 0.041) compared to those in CMF. Additionally, in GSEA and differential expression analysis, perifollicular cells in FMF exhibited increased activity in pathways and genes related to antigen presentation (antigen processing and presentation – Gene Ontology, NES = 4.34, p = 0; antigen processing and presentation of peptide or polysaccharide antigen via MHC class II – Gene Ontology, NES = 3.74, p = 0; antigen processing and presentation of peptide antigen via MHC class I – Gene Ontology, NES = 2.70, p = 0.0009) and inflammatory signaling ( SPP1 , log2FC = 1.95, p <0.0001; RASGEF1B , log2FC = 0.83, p <0.0001; NCF2 , log2FC = 0.85, p = 0.013; neutrophil degranulation – Reactome, NES = 4.47, adjusted p = 0; cytokine production – Gene Ontology, NES = 3.15, adjusted p = 0). However, macrophages in FMF had a less inflammatory phenotype with decreased IL-2 (Reactome, NES = -1.84, adjusted p = 0.046) and interferon signaling (Reactome, NES = - 2.02, adjusted p = 0.020) and decreased expression of genes such as KIR3DL1 , CCL8 , and IL21R (log2FC = - 1.82, -1.16, -1.14 and p = 0.007, 0.024, and 0.028 respectively). These findings are further underscored by the results of spatial deconvolution, which showed a notable increase in the abundance of myeloid dendritic cells (mDCs) in FMF compared to CMF (p = 0.012), and a decrease in naive B cells (p = 0.031) and CD4+ memory T cells (p = 0.0005).

Conclusions: Our analyses revealed that, compared to their dermal counterparts in classical MF, malignant CD4 T cells in the follicular microenvironment of FMF exhibit survival advantages stemming from their elevated metabolic and inflammatory activity and a heightened response to starvation. On the other hand, the increased presence of tumor-supportive mDCs, and macrophages with an anti- inflammatory phenotype in follicular niche reveals a compromised antitumor immune response that may facilitate immune evasion in FMF. These observations provide insight into the mechanisms underlying the more aggressive clinical features of FMF versus CMF.

Link to Abstract abs25-15481

Abstract Number: abs25-9009

Golcadomide demonstrates potent antiproliferative activity in T-cell lymphoma via degradation of IKZF1 and IKZF3

Presenter: Zhongying Mo
Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster III

Abstract: T-cell lymphomas (TCLs) are a heterogeneous group of aggressive non-Hodgkin lymphomas characterized by poor prognosis and limited treatment options. The aggressive biology, molecular diversity, and resistance to conventional treatments underscore a critical unmet need for novel, targeted therapeutic strategies. Golcadomide is a potential first-in-class, oral CELMoD TM agent designed for the treatment of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. Golcadomide drives the closed, active conformation of cereblon to induce rapid and deep degradation of IKZF1 and IKZF3, leading to direct cell killing and immunomodulatory activity. Previous studies were largely focused on B cell lymphoma. In this study, we test the in vitro activity of golcadomide and evaluate its potential as a therapeutic agent for patients with T-cell lymphoma. The antiproliferative and pro-apoptotic activity of golcadomide was evaluated in a panel of 10 TCL cell lines, including adult T-cell leukemia/lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), and anaplastic large cell lymphoma (ALCL). Cell lines were treated with increasing concentrations of golcadomide or lenalidomide and cell viability and apoptosis were assessed over nine days. All cell lines exhibited greater sensitivity to golcadomide than to lenalidomide, with golcadomide producing enhanced inhibition of proliferation and stronger induction of apoptosis. Importantly, all TCL subtypes tested responded to golcadomide, supporting its potential as a broadly active therapeutic agent. To characterize golcadomide-induced protein degradation, proteomic mass spectrometry was performed in four TCL cell lines. Golcadomide demonstrated statistically significant and dose-responsive downregulation of the neo-substrates IKZF1 and IKZF3. Extended treatment confirmed that golcadomide elicited both dose- and time-dependent changes in the T-cell lymphoma proteome, while lenalidomide produced minimal effects across these models. The degradation of IKZF1 and IKZF3 by golcadomide was further validated in an expanded panel of TCL cell lines with immunoblot and flow cytometry analyses. Regardless of baseline expression levels, golcadomide treatment resulted in robust degradation of IKZF1 and IKZF3, which was notably more pronounced than with lenalidomide. Specifically, golcadomide induced nearly complete IKZF1 and approximately 80% IKZF3 degradation in ATL-3I and MT-2 cells after 24 hours, while lenalidomide treatment achieved only about 40% degradation for both proteins. To determine the substrates necessary for golcadomide’s antiproliferative effects, TCL cell lines expressing non-degradable mutant forms of IKZF1 or IKZF3 were generated. Overexpression of these mutants effectively protected the cells from golcadomide-induced antiproliferation in all tested models and also conferred resistance against lenalidomide in lenalidomide-sensitive cell lines. In summary, these findings support the continued development of golcadomide as a promising therapeutic for T-cell lymphomas. Its potent efficacy across multiple TCL subtypes and mechanisms involving IKZF1 and IKZF3 degradation highlight a novel strategy to address unmet clinical need in this challenging disease.

Link to Abstract abs25-9009

Abstract Number: abs25-11964

SLM124: A first-in-class anti-CD84 antibody-drug conjugate demonstrates potent anti-tumor activity and favorable tolerability in hematologic malignancy models

Presenter: Chan Whiting
Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster III

Abstract: Background: The Signaling Lymphocytic Activation Molecule Family (SLAMF5), or CD84, is a novel target broadly expressed across a spectrum of hematologic malignancies including Acute Myelogenous Leukemia (AML), Myelodysplastic Syndromes (MDS), Cutaneous T-Cell Lymphoma (CTCL), and Follicular Lymphoma (FL), as well as on immunosuppressive cells within the tumor microenvironment. CD84 is not expressed on normal epithelial, mesenchymal or hematopoietic stem cells. A significant unmet need for effective therapies in these difficult-to-treat cancers remains. SLM124 is a humanized, Fc-engineered IgG1 antibody-drug conjugate (ADC) designed to specifically deliver a potent topoisomerase I inhibitor, exatecan, to CD84-expressing cancer cells.

Methods: We characterized SLM124 through comprehensive preclinical studies and analytics including purity by SEC-HPLC and mass spectrometry. Target binding kinetics, affinity to CD84, and FcγRIIIa binding of Fc-engineered anti-CD84 mAb variants were assessed using Surface Plasmon Resonance (SPR). We assessed CD84 expression on patient tumor samples by immunohistochemistry (IHC). Cell surface CD84 expression and lead mAb binding to various human hematologic cancer cell lines (AML, B-cell and T-cell lymphomas), CHO-K1 cells overexpressing human CD84, as well as normal human B and T cells were evaluated by quantitative flow cytometry (qFACS). In vitro cytotoxicity assays were performed on CD84- expressing cancer cell lines. The in vivo efficacy and tolerability of SLM124 were evaluated in multiple xenograft tumor models.

Results: CD84 target expression is highly overexpressed in tumor cell lines and patient tumor samples. CD84 mRNA is marked increased in tumor cell lines and patient tumor samples in AML, ALL, MDS, MPD, CLL, Hodgkin’s Disease, broad spectrum of B and T cell non-Hodgkin’s Lymphomas, and CTCL. By IHC, we verified CD84 protein expression is significantly overexpressed in the following blood cancers including AML, CTCL and Follicular Lymphoma patient samples regardless of the molecular phenotype compared to healthy controls. Quantitative FACS analysis demonstrated significant CD84 overexpression across various hematologic cancer cell lines in vitro , including Raji, THP-1, Daudi, SU-DHL-4, Toledo and Ramos, (6 to16-fold higher) compared to the notably low expression on normal human B cells and T cells. SLM124 monoclonal antibody (mAb) binds to human CD84 with high affinity and specificity. SPR studies confirmed SLM124 mAb exhibits high-affinity binding to human CD84, with KD values in the sub- nanomolar range. No cross-species binding to mouse or cynomolgus monkey CD84 was observed, supporting human specificity. There was no binding of SLM124 mAb to human red blood cells or platelets. The Fc-engineered SLM124 mAb (with LALA mutation), demonstrated significantly reduced binding to FcγRIIIa, indicating substantial Fc silencing to minimize off-target immune effector functions. SLM124 consistently exhibited potent, dose-dependent cytotoxicity in CD84-expressing cells with IC50s ranging from ~0.61 nM to ~5.8 nM. Dose-dependent cytotoxicity was observed in Raji cells. In multiple lymphoma xenograft models, single-dose intravenous administration of SLM124 resulted in significant and durable tumor growth inhibition (TGI). Multiple doses given at lower dose levels (fractionated dosing) also demonstrated significant tumor regression. SLM124 was well-tolerated, with no significant body weight loss observed across treatment groups throughout the studies. Conclusion: SLM124 is a highly potent, first-in-class humanized IgG1 anti-CD84 ADC that precisely targets CD84-expressing hematologic cancer cells. It demonstrates high affinity, specific binding, potency in vitro and is well-tolerated with significant anti-tumor activity in preclinical in vivo lymphoma models. These compelling preclinical data support the continued development of SLM124 as a potentially transformative therapeutic for patients with hematologic malignancies. SLAM Bio anticipates advancing SLM124 therapeutic candidate into the clinic in 2026.

Link to Abstract abs25-11964

Abstract Number: abs25-9922

Treosulfan – based conditioning in allogeneic hematopoietic stem-cell transplantation for lymphoid malignancies: Long term follows up.

Presenter: Avichai Shimoni
Session: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment, and Acute Toxicities: Poster III

Abstract: Introduction: Treosulfan was recently approved by the FDA for the use in the conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT). Prior studies have shown that Treosulfan is associated with strong anti-leukemia effect combined with relatively low non-relapse mortality (NRM) rate and reduced rate of graft-versus-host disease (GVHD). However, most of the data derives from HSCT in myeloid malignancies and there is limited data on the outcome of HSCT with Treosulfan conditioning in lymphoid malignancies. Methods: We have used the combination of fludarabine and treosulfan as the preferred conditioning regimen for allogeneic HSCT in patients (pts) with lymphoid malignancies, considered eligible for low to intermediate transplant conditioning intensity, since the year 2009. Treosulfan dose (10-14gr/m^2 x3d) was determined based on patient and disease characteristics. GVHD prophylaxis included cyclosporine and methotrexate or mycophenolate ATG was added to unrelated donor HSCT. Post-transplant cyclophosphamide was used in a minority of transplants. This is a retrospective analysis of HSCT outcomes focusing on long-term survival. Results: The study included 215 pts, median age 53 years (range, 19-74). The underlying malignancy was acute lymphoblastic leukemia (ALL, n=36), B- cell aggressive lymphoma (NHL, n=62), B-cell low grade lymphoma (LGL, n=17), mantle cell lymphoma (MCL, n=9), Hodgkin lymphoma (HL, n=37), Richter transformation of chronic lymphocytic leukemia (n=13), T-cell lymphoma (TCL, n=35) and T-cell prolymphocytic lymphoma (T-PLL, n=6). The median number of prior lines of therapy was 4 (range, 1-9) and 86 pts (35%) had a prior autologous transplantation. Disease status at HSCT was CR1/2 (n=71), PR/ CR≥3 (n=102), refractory (n=42). Comorbidity score was 0 (n=105), 1-2 (n=88) and ≥3 (n=22). The donor was an HLA-matched sibling (n=101), matched-unrelated (n=91), mismatched unrelated/ haploidentical (n=23). The total Treosulfan dose used was 30 gr/m2 (n=47), 36 gr/m2 (n=132) or 42 gr/m2 (n=36). With a median follow-up of 6.6 years (range, 0.3-15.4), 108 are alive and 107 have died. The estimated 10- year overall survival (OS) rate is 45% (95%CI, 38-53). The 10-year cumulative incidence of NRM and relapse-related mortality was 24% (95%CI, 19-31) and 31% (95%CI, 25-39), respectively. The rates of acute GVHD grade II-IV and III-IV at day 180 after HSCT were 20% (95%CI, 15-27) and 9% (95%CI, 6-15), respectively. The rate of chronic GVHD at 1 year after HSCT was 33% (95%CI 27-40), The 10-year OS by disease type was 54% (95%CI, 36-73), 28% (95%CI, 15-40), 71% (95%CI, 49-92), 56% (95%CI, 23-88), 61% (95%CI, 43-79), 48% (95%CI, 19-78), 41% (95%CI, 23-59) and 42% (95%CI, 0-85) for ALL, NHL, LGL, MCL, HL, Richter transformation, TCL and T-PLL, respectively (P=0.09). The 10-year OS was 55% (95%CI, 44-66) and 33% (95%CI, 23-55) for pts age <55 and ≥55 years, respectively (P=0.001). The 10-year OS was 50% (95%CI, 34-65), 49% (95%CI, 39-60) and 26% (95%CI, 12-40) for pts in CR 1/2, PR/ CR≥3 and refractory disease at HSCT, respectively (P=0.009). It was 57% (95%CI, 46-68) and 36% (95%CI, 25-46) for pts with 1-3 or ≥4 prior lines of therapy, respectively (P=0.002). It was 59% (95%CI, 47-70), 35% (95%CI, 24-47) and 25% (95%CI, 6-44) for pts with a comorbidity score of 0, 1-2 and ≥3, respectively (P=0.005). The donor type, Treosulfan dose used, prior autologous transplantation and year of HSCT did not predict OS in the univariate analysis. Multivariate analysis identified advanced age [HR 1.76 (1.13-2.74), P=0.01)], refractory disease [HR 1.74 (0.94-3.24), P=0.08)], ≥4 lines of prior therapy [HR 1.83 (1.09-3.06), P=0.02)] and a comorbidity score of ≥3 [HR 2.14 (1.11-4.12), P=0.02)] as predictors for inferior OS. The 10-year OS of pts with none of these poor risk factors was 69% (95%CI, 53-85). Conclusions: Treosulfan- based conditioning can allow promising long-term OS in pts with a variety of lymphoid malignancies. Consistent with data form HSCT in myeloid malignancies, it is associated with potent anti- malignancy effect combined with relatively low NRM and GVHD rates. HSCT outcomes should be interpreted in view of the novel therapeutic options that were introduced in recent years for the treatment of various lymphatic malignancies. However, the current long-term data may indicate that HSCT with Treosulfn – based conditioning may still have a role in several lymphoid categories and selected groups of pts.

Link to Abstract abs25-9922

Abstract: P5385 - Malnutrition in Acute Severe Ulcerative Colitis: Prevalence, Nutritional Interventions, and Clinical Outcomes - A Single-Center Study

Presenting Author: Shreyak Sharma, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=216
30.1% of patients with acute severe ulcerative colitis (ASUC) were found to be malnourished, characterized by lower BMI and albumin levels.
Malnutrition was independently associated with increased odds of requiring infliximab rescue therapy (OR 2.15, p=0.016), but not with prolonged hospitalization, TPN use, or colectomy.
Low albumin levels were linked to increased odds of prolonged hospitalization (OR 3.51, p=0.008), indicating a potential area for clinical focus.
Nutrition consults were more common in malnourished patients (63.1% vs. 34.5%, p<0.001), yet only a small percentage (6.2%) received TPN, highlighting a gap in nutritional intervention.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This retrospective study analyzed data from 216 hospitalized patients with acute severe ulcerative colitis (ASUC) over an 8-year period, providing a substantial sample size for evaluating malnutrition prevalence and its clinical implications.
Malnutrition was defined using a clear criterion (>5% total body weight loss in 6 months), and the study employed logistic regression to assess associations with clinical outcomes, adjusting for potential confounders such as age, sex, and race.
While the study identified significant associations, the retrospective nature limits the ability to establish causality, and the reliance on historical data may introduce biases.

2. Comparison to Current Standard-of-Care:

The findings align with existing literature that recognizes malnutrition as a common issue in UC patients, particularly those with severe disease, but do not provide new therapeutic strategies or interventions that would alter current management guidelines.
While the study highlights the increased odds of requiring infliximab rescue therapy in malnourished patients, it does not suggest a direct intervention that could be implemented in clinical practice to improve outcomes.

3. Clinical Relevance and Feasibility:

The identification of malnutrition as a prevalent condition in ASUC patients underscores the need for nutritional assessment and intervention, which is already a recognized component of comprehensive care in UC management.
However, the study's findings regarding the limited impact of malnutrition on prolonged hospitalization and colectomy suggest that while malnutrition is a concern, it may not be a primary driver of these outcomes, thus limiting its immediate clinical implications.

Overall, while the study provides valuable insights into the prevalence of malnutrition in ASUC and its association with treatment outcomes, it does not present findings that would necessitate a change in current clinical practice or guidelines for managing ulcerative colitis.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights a significant prevalence of malnutrition in patients with acute severe ulcerative colitis (ASUC), which may create an opportunity for Cristcot to position its products, particularly the Hydrocortisone Acetate (HCA) Suppository, as part of a comprehensive treatment strategy that addresses both inflammation and nutritional status. The findings support the need for effective interventions that can improve clinical outcomes, potentially enhancing the value proposition of Cristcot’s offerings.

Competitive Landscape & Positioning:

The study reinforces rectal delivery as a viable route, particularly for patients who may struggle with oral therapies due to malnutrition or gastrointestinal complications.
Sephure®’s unique delivery mechanism may enhance patient compliance and comfort, especially in malnourished patients who may have increased sensitivity or discomfort with traditional methods.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring the impact of nutritional status on treatment outcomes in future trials, potentially incorporating malnutrition as a stratification factor or endpoint.
Medical Affairs: Prioritize real-world evidence initiatives that demonstrate the benefits of addressing malnutrition in UC management, and engage healthcare professionals (HCPs) with educational resources on the importance of nutrition in treatment success.
Marketing: Highlight the dual benefits of the HCA Suppository and Sephure® Applicator in addressing both inflammation and patient comfort, positioning them as essential components of a holistic approach to UC management.

Abstract: P5390 - Pharmacokinetics and Relative Bioavailability of an Investigational Hydrocortisone Acetate Suppository Administered With a Novel FDA-Cleared Applicator Versus Hydrocortisone Liquid Enema

Presenting Author: Mark Ensign
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=16
The investigational 90 mg hydrocortisone acetate (HCA) suppository demonstrated rapid drug release and sustained plasma concentrations of hydrocortisone (HC).
Mean maximum plasma concentration (C_max) for HCA was 194.0 ng/mL, while for HC it was 392.5 ng/mL, indicating a lower peak for HCA.
Area under the curve (AUC_0-t) was 3125.0 h·ng/mL for HCA and 3611.0 h·ng/mL for HC, with HCA showing a mean HCA:HC ratio of 0.86.
Half-life was significantly longer for HCA (11.7 h) compared to HC (5.7 h), suggesting prolonged action of the suppository formulation.
Four mild adverse events were reported, indicating the investigational formulation was well tolerated.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This phase 1, single-center, open-label, crossover study involved 16 healthy adult participants, which is a relatively small sample size that limits the generalizability of the findings.
The study assessed pharmacokinetic (PK) parameters of a novel 90 mg hydrocortisone acetate (HCA) suppository compared to a 100 mg hydrocortisone (HC) liquid enema, with primary outcomes focusing on plasma concentrations and absorption profiles.
While the study reported some interesting PK data, the lack of detection of HCA in plasma and the limited number of participants for AUC assessments (only 9) raise concerns about the robustness of the conclusions.

2. Comparison to Current Standard-of-Care:

The findings suggest that the HCA suppository has a different absorption profile compared to the HC enema, with a longer half-life and sustained plasma concentrations, which could be beneficial in clinical settings.
However, the study does not provide direct evidence of clinical efficacy or safety in patients with ulcerative colitis, which is critical for influencing current treatment paradigms.

3. Clinical Relevance and Feasibility:

The investigational HCA suppository shows potential for improved delivery and absorption, but further studies are needed to evaluate its clinical efficacy in UC management.
Given the mild adverse events reported and the novel delivery method, this formulation may warrant further investigation, but it does not yet provide sufficient evidence to change current practice.

In summary, while the study presents intriguing pharmacokinetic data that could inform future research, it does not yet provide compelling evidence to alter standard treatment approaches for ulcerative colitis.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study reinforces Cristcot's strategic positioning in the rectal drug delivery market, particularly with the HCA suppository and Sephure® applicator. The favorable pharmacokinetic profile and tolerability of the HCA suppository suggest a strong potential for clinical application in ulcerative colitis, enhancing Cristcot's product portfolio and addressing unmet needs in this therapeutic area.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, demonstrating rapid drug release and sustained plasma concentrations compared to traditional oral and topical therapies.
The Sephure® applicator enhances the competitive advantage of the HCA suppository by improving patient compliance and comfort, which are critical factors in managing chronic conditions like ulcerative colitis.

Strategic Implications by Function:

Clinical Development: Cristcot should consider expanding clinical trials to include diverse patient populations and additional endpoints that reflect long-term efficacy and quality of life improvements.
Medical Affairs: Prioritizing real-world evidence generation and educational initiatives for healthcare professionals (HCPs) will be essential to support the clinical benefits of the HCA suppository and the Sephure® applicator.
Marketing: Opportunities exist to enhance differentiation through targeted messaging that emphasizes the unique benefits of rectal delivery, rapid action, and patient comfort, positioning Cristcot as a leader in innovative therapies for ulcerative colitis.

Abstract: P5392 - Natural History of Crohn’s Disease and Ulcerative Colitis in Newly Diagnosed Hispanic Adults in the United States: A Population-Based Cohort Study

Presenting Author: Siddharth Singh, MD, MS
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=520 Hispanic adults with incident IBD compared to 5484 Whites.
Cumulative 5-year risk of all-cause hospitalization for Crohn's disease was 17.7% for Hispanics, similar to Whites, but lower for ulcerative colitis (10.5% vs. 17.6%, p=0.034).
Utilization of immunomodulators was significantly lower in Hispanic patients with Crohn's disease (24.2% vs. 33.1%, p=0.047) and advanced therapies (35.8% vs. 48.1%, p=0.001).
Hispanic patients with ulcerative colitis had a lower risk of corticosteroid use (60.6% vs. 72.7%, p=0.002) without significant differences in advanced therapy utilization.
Higher education level was associated with lower corticosteroid use and higher advanced therapy use, but no significant interaction was found between race, education, or income and IBD outcomes.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This retrospective cohort study utilized a large administrative claims database, including 520 Hispanic adults with incident IBD and 5484 Whites, providing a substantial sample size for comparative analysis.
The study assessed cumulative risks of hospitalization, surgery, and treatment patterns, with statistically significant findings regarding corticosteroid use and advanced therapy utilization, although the retrospective nature limits causal inferences.
Statistical significance was achieved for several comparisons (e.g., corticosteroid use in UC: p=0.002), but the lack of randomization and potential confounding factors must be considered.

2. Comparison to Current Standard-of-Care:

The findings indicate that Hispanic patients with UC have a lower risk of hospitalization and corticosteroid use compared to Whites, which may suggest differences in disease severity or access to care.
However, the lower utilization of advanced therapies in Hispanics raises concerns about potential undertreatment, which is not aligned with current treatment guidelines advocating for timely escalation of therapy in moderate to severe cases.

3. Clinical Relevance and Feasibility:

The study highlights important disparities in treatment patterns and outcomes based on ethnicity, which could inform future research and clinical practice regarding personalized care approaches.
While the findings are significant for understanding demographic influences on UC management, they do not provide new therapeutic options or strategies that would alter current clinical practice.

Overall, while the study offers valuable insights into the natural history and treatment disparities in UC among different ethnic groups, it does not present findings that would necessitate immediate changes in clinical practice.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights significant differences in treatment patterns and outcomes between Hispanic and White patients with IBD, which may inform Cristcot's strategic positioning of the Sephure® Suppository Applicator and HCA Suppository. The findings suggest opportunities for targeted marketing and clinical development to address unmet needs in diverse populations.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients with UC, who may benefit from lower hospitalization rates and corticosteroid use.
Sephure®'s unique delivery mechanism may enhance patient compliance and comfort, while HCA's rapid action could position it favorably against oral and biologic therapies.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term outcomes and quality of life, as well as potential label expansions to include diverse patient populations.
Medical Affairs: Prioritize real-world evidence generation focusing on Hispanic populations and develop educational initiatives to engage healthcare providers (HCPs) on the benefits of rectal therapies.
Marketing: Highlight the unique benefits of Sephure® and HCA in addressing specific needs of underrepresented populations, enhancing differentiation in a competitive market.

Abstract: P5395 - Efficacy of 5-ASA Continuation versus Discontinuation in Patients With Moderate to Severe Ulcerative Colitis Escalated to Advanced Therapy: A Systematic Review and Meta-Analysis of Adjusted Effect Estimates

Presenting Author: Hyun Hee Sul, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=16,461
5-ASA continuation was associated with decreased odds of achieving clinical remission compared to discontinuation (aOR 0.72; p=0.046).
No significant differences were observed between groups for corticosteroid-free clinical remission, clinical response, endoscopic healing, and biochemical remission.
Time-to-event analyses showed no significant differences for UC-related hospitalization, surgery, new corticosteroid prescriptions, composite adverse events, and loss of response.
Findings suggest that 5-ASA may be safely discontinued after escalation to advanced therapies in patients with moderate-to-severe UC.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This systematic review and meta-analysis included a substantial population of 16,461 patients, which enhances the reliability of the findings. The use of multivariable-adjusted data to account for confounding factors strengthens the validity of the results.
The primary outcome indicated that 5-ASA continuation was associated with decreased odds of achieving clinical remission (aOR 0.72; p=0.046), suggesting a potential negative impact of continuing 5-ASA in patients who have escalated to advanced therapies.
However, the analysis revealed no significant differences in other important endpoints, such as corticosteroid-free clinical remission and endoscopic healing, indicating that the overall impact of 5-ASA continuation may be limited.

2. Comparison to Current Standard-of-Care:

The findings challenge the traditional view of 5-ASA as a cornerstone therapy in UC management, particularly in patients transitioning to more advanced therapies. Current guidelines from organizations like AGA and ECCO do not explicitly recommend discontinuation of 5-ASA in this context, making these results noteworthy but not immediately practice-changing.
While the study suggests that 5-ASA may be safely discontinued, it does not provide compelling evidence to alter existing treatment protocols, which still favor its continuation in many cases.

3. Clinical Relevance and Feasibility:

The implications of this study are significant for clinical decision-making, particularly in resource allocation and treatment planning for patients with moderate-to-severe UC. However, the findings require further validation through prospective studies before they can be integrated into routine practice.
Given the lack of significant adverse events associated with discontinuation, the study supports a cautious approach to therapy de-escalation, but the overall clinical relevance remains limited until more robust evidence is available.

In summary, while the study provides important insights into the role of 5-ASA in the context of advanced therapies, it does not present findings that would necessitate immediate changes in clinical practice.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the meta-analysis suggest that 5-ASA may not be necessary for patients with moderate-to-severe UC who have escalated to advanced therapies, indicating a potential shift in treatment paradigms. This could strengthen Cristcot's position with its HCA suppository as a more effective alternative for achieving clinical remission, particularly in patients who may not benefit from continued 5-ASA therapy.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, especially for patients who may not respond to oral therapies, positioning Cristcot's HCA suppository favorably against traditional oral and biologic options.
Sephure® enhances the delivery of HCA, potentially improving patient compliance and outcomes due to its unique design that addresses common issues with rectal administration.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring new trial endpoints that focus on patient-reported outcomes and quality of life, as well as potential label expansions for HCA in broader UC populations.
Medical Affairs: Prioritize real-world evidence studies to support the efficacy of HCA in patients previously treated with 5-ASA, and develop educational initiatives for healthcare providers on the benefits of rectal delivery systems.
Marketing: Highlight the unique advantages of Sephure® and HCA in promotional materials, emphasizing their role in improving patient comfort and compliance, and position them as a first-line option for patients not achieving remission with 5-ASA.

Abstract: P5398 - Appendectomy Improves Outcomes in Appendicitis Patients With and Without Ulcerative Colitis: A Nationwide Inpatient Analysis

Presenting Author: Isaac Giovannie, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=141,349
Patients with ulcerative colitis (UC) had worse hospital outcomes compared to non-UC patients, including longer length of stay (5.01 vs. 3.73 days), higher hospital charges ($77,723 vs. $62,460), and increased in-hospital mortality (1.2% vs. 0.4%, p = 0.008).
Appendectomy significantly reduced length of stay by 2.56 days and hospital charges by $19,738 in UC patients, and by 2.19 days and $3,993 in non-UC patients (all p < 0.05).
In-hospital mortality was significantly lower in both UC and non-UC patients who underwent appendectomy, with an adjusted odds ratio of 0.19 (p < 0.001).
Despite higher baseline risks, UC patients benefited from appendectomy similarly to non-UC patients, challenging concerns about surgical risks in inflammatory bowel disease.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This retrospective cohort study utilized a large dataset from the National Inpatient Sample, including 141,349 patients with appendicitis, of which 505 had UC. The study employed multivariable linear and logistic regression to assess outcomes, which strengthens the validity of the findings.
The primary outcomes—length of stay (LOS), total hospital charges, and in-hospital mortality—were clearly defined and statistically analyzed, showing significant differences between UC and non-UC patients.
Appendectomy was associated with a notable reduction in LOS (2.56 days) and hospital charges ($19,738) for UC patients, alongside a significant decrease in in-hospital mortality (aOR = 0.19).

2. Comparison to Current Standard-of-Care:

While the findings support the safety and efficacy of appendectomy in UC patients, they do not fundamentally alter current management guidelines for UC, which typically focus on medical therapy and surgical interventions for UC itself rather than appendicitis.
The study provides valuable insights into the management of appendicitis in UC patients, but it does not challenge or redefine existing treatment paradigms for UC.

3. Clinical Relevance and Feasibility:

The results suggest that appendectomy can be safely performed in UC patients, potentially alleviating concerns about surgical risks. However, the implications are primarily relevant to surgical practice rather than direct UC management.
Further research is warranted to explore long-term outcomes and complications post-appendectomy in UC patients, which could enhance understanding of surgical risks in this population.

Overall, while the study provides important data regarding appendectomy outcomes in UC patients, it does not present findings that would necessitate a change in the current management of UC itself.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the appendectomy study provide a supportive backdrop for Cristcot’s product portfolio, particularly the Sephure® Suppository Applicator and the Hydrocortisone Acetate (HCA) Suppository. The demonstrated efficacy of appendectomy in improving outcomes for patients with ulcerative colitis (UC) suggests a growing acceptance of surgical interventions in this patient population, which may enhance the receptiveness to innovative therapies like Cristcot's offerings.

Competitive Landscape & Positioning:

The study reinforces rectal delivery as a viable route, particularly for patients with UC, who may benefit from targeted therapies like the HCA suppository.
Sephure®’s unique delivery mechanism may provide a competitive advantage by improving patient compliance and comfort, especially in a landscape where surgical options are being validated.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term outcomes and quality of life, potentially expanding the label for the HCA suppository.
Medical Affairs: Prioritizing real-world evidence studies that demonstrate the effectiveness of the HCA suppository in conjunction with surgical interventions could enhance HCP engagement and support.
Marketing: Opportunities exist to position the Sephure® Applicator as a complementary tool for patients undergoing surgical procedures, emphasizing its role in enhancing recovery and patient experience.

Abstract: P5399 - Postoperative Complications After Appendectomy in Ulcerative Colitis: A National Inpatient Cohort Analysis

Presenting Author: Isaac Giovannie, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=140,836
Ulcerative colitis (UC) is associated with a 33% increased odds of any postoperative complication following appendectomy (aOR 1.33, 95% CI 1.07–1.65, p=0.01).
Patients with UC exhibited significantly higher odds of sepsis (aOR 1.88, p=0.004), postoperative delirium (aOR 3.67, p=0.002), and malnutrition or weight loss (aOR 3.53, p<0.001).
A non-significant trend towards increased in-hospital mortality was observed in UC patients (aOR 2.23, 95% CI 0.91–5.43, p=0.078).
Female sex was associated with lower odds of complications and mortality, while each year of age increased the odds of complications by 3% and mortality by 5% (p<0.001).

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This retrospective cohort study utilized the National Inpatient Sample, analyzing 140,836 appendectomy hospitalizations, with 433 involving patients with ulcerative colitis (UC). The study employed multivariable logistic regression to adjust for confounding factors, enhancing the reliability of the findings.
While the study identified significant associations between UC and postoperative complications (aOR 1.33, p=0.01), the non-significant increase in in-hospital mortality (aOR 2.23, p=0.078) suggests caution in interpreting mortality risk.
Specific complications such as sepsis and postoperative delirium were significantly higher in UC patients, indicating a clear need for tailored perioperative management.

2. Comparison to Current Standard-of-Care:

The findings align with existing literature suggesting that patients with UC face increased surgical risks, but they do not provide new treatment modalities or strategies that would alter current surgical practices.
Current guidelines emphasize the importance of preoperative optimization in UC patients, and this study reinforces that need without introducing novel interventions.

3. Clinical Relevance and Feasibility:

The study highlights the necessity for individualized surgical planning and perioperative strategies, such as nutritional support, in UC patients, which is already a recognized practice but may not be uniformly implemented.
While the findings are significant, they do not provide a direct change to clinical practice but rather support existing recommendations for managing UC patients undergoing surgery.

In summary, while the study offers valuable insights into the postoperative risks associated with appendectomy in UC patients, it does not present findings that would necessitate a change in current clinical practice, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights the increased risk of postoperative complications in ulcerative colitis (UC) patients undergoing appendectomy, emphasizing the need for tailored perioperative strategies. This aligns with Cristcot's focus on innovative rectal drug delivery, suggesting that their products, particularly the Hydrocortisone Acetate (HCA) Suppository, could play a critical role in managing UC effectively, potentially enhancing their market position.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for UC patients who may benefit from localized treatment options like the HCA suppository, compared to systemic oral or biologic therapies.
The Sephure® applicator enhances the delivery of HCA, improving patient compliance and comfort, which are critical factors given the complications associated with UC.

Strategic Implications by Function:

Clinical Development: Cristcot should consider further trials focusing on the safety and efficacy of HCA in the context of surgical interventions for UC, potentially exploring new endpoints related to postoperative recovery.
Medical Affairs: Prioritize real-world evidence generation on the benefits of rectal therapies in UC management, and develop educational initiatives for healthcare providers (HCPs) on the implications of UC on surgical outcomes.
Marketing: Highlight the unique benefits of the Sephure® applicator and HCA suppository in addressing the specific needs of UC patients, particularly in the context of surgical risks, to differentiate from oral and biologic therapies.

Abstract: P5401 - Impact of Proton Pump Inhibitors and NSAIDs on the Risk of Pouchitis Following Ileal Pouch-Anal Anastomosis in Ulcerative Colitis: A Propensity-Matched Cohort Study

Presenting Author: Saqr Alsakarneh, MD, MS
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=3,428
No significant difference in pouchitis risk between PPI (55.1%) and NSAID (57.8%) groups (aHR: 0.97; 95% CI: 0.84–1.00; p = 0.05).
Both PPI (aHR = 1.50; 95% CI: 1.28–1.76; p < 0.001) and NSAID (aHR = 1.73; 95% CI: 1.48–2.02; p < 0.001) use significantly increased pouchitis risk compared to non-users.
Findings suggest that PPI and NSAID exposure shortly after IPAA may independently impact pouchitis risk.
Further prospective studies are warranted to explore underlying mechanisms and validate these results.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This retrospective cohort study utilized the TriNetX database, encompassing a large sample size of 3,428 patients (1,714 in each cohort) who underwent IPAA, which enhances the generalizability of the findings.
The primary outcome, incidence of pouchitis within two years, was assessed with appropriate statistical methods, including propensity score matching to control for confounding variables, although the observational nature limits causal inferences.
The adjusted hazard ratios indicated a significant increase in pouchitis risk for both PPI (aHR = 1.50) and NSAID (aHR = 1.73) users compared to non-users, with p-values <0.001, suggesting robust findings.

2. Comparison to Current Standard-of-Care:

While the study identifies an increased risk of pouchitis associated with PPI and NSAID use, it does not provide new treatment options or strategies that would alter current management guidelines for UC patients undergoing IPAA.
Current guidelines do not specifically contraindicate the use of PPIs or NSAIDs post-IPAA, but this study raises awareness of potential risks, aligning with existing concerns regarding medication impacts on the gut microbiome.

3. Clinical Relevance and Feasibility:

The findings are clinically relevant as they highlight a potential risk factor for pouchitis, which is a significant complication in UC management, but they do not suggest immediate changes to clinical practice.
Further prospective studies are warranted to explore the mechanisms behind these associations and to validate the findings, which may eventually influence clinical guidelines.

In summary, while the study provides important insights into the risks associated with PPI and NSAID use in UC patients post-IPAA, it does not present findings that would necessitate immediate changes in clinical practice, thus categorizing it as "Important but Not Practice-Changing."

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the Phase 3 CESSA trial and the retrospective cohort study on pouchitis risk provide strategic insights for Cristcot. The successful demonstration of the HCA suppository's efficacy in achieving clinical remission in UC patients strengthens Cristcot's position in the rectal drug delivery market. The implications of the pouchitis study highlight the importance of considering medication interactions post-IPAA, which could inform future product development and patient management strategies.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients with UC, as it offers targeted therapy with potentially fewer systemic side effects compared to oral or biologic therapies.
The Sephure® applicator enhances the delivery of the HCA suppository, improving patient compliance and comfort, which are critical factors in the management of UC.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term outcomes and the impact of concomitant medications on treatment efficacy and safety.
Medical Affairs: Prioritizing real-world evidence studies to further validate the safety and efficacy of the HCA suppository in diverse patient populations could enhance HCP engagement and support clinical decision-making.
Marketing: Opportunities exist to differentiate the Sephure® applicator and HCA suppository through targeted messaging that emphasizes their unique benefits in improving patient adherence and outcomes in UC management.

Abstract: P5407 - AI-Assisted Mayo Endoscopic Scoring in Ulcerative Colitis: A Comparative Analysis of GPT-4o and Claude 3.7 Sonnet

Presenting Author: Jordan Stellern, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=50
GPT-4o demonstrated significantly higher accuracy in assigning Mayo subscores (72.8%) compared to Claude 3.7 Sonnet (47.3%, p<0.001).
Segment-specific accuracy favored GPT-4o, particularly in the descending colon (p=0.009) and cecum (p=0.000).
Both models effectively distinguished between low (Mayo 0–1) and high (Mayo 2–3) inflammation, with GPT-4o achieving 84.6% accuracy and Claude 76.9% (p=0.073).
Findings suggest GPT-4o's potential utility in clinical settings with limited expert interpretation for treatment stratification in Ulcerative Colitis.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

The study employed a comparative analysis of two large language models (LLMs) on colonoscopy images from 50 patients with confirmed UC, which is a relatively small sample size for drawing broad conclusions.
GPT-4o demonstrated a significantly higher accuracy (72.8%) in assigning Mayo subscores compared to Claude 3.7 Sonnet (47.3%), with statistical significance (p<0.001), indicating a promising potential for AI in clinical settings.
However, the study lacks a larger validation cohort and does not assess long-term outcomes or clinical decision-making impact, which limits its immediate applicability.

2. Comparison to Current Standard-of-Care:

Current UC management relies heavily on subjective endoscopic assessments, which can lead to variability in scoring. The introduction of AI tools like GPT-4o could standardize scoring and potentially improve treatment stratification.
While the findings are promising, they do not yet provide evidence that AI scoring can replace or significantly enhance current clinical practices without further validation.

3. Clinical Relevance and Feasibility:

The ability of GPT-4o to distinguish between low and high inflammation suggests potential utility in resource-limited settings where expert endoscopists may not be available.
However, the integration of AI into clinical practice will require consideration of training, cost, and the need for ongoing validation to ensure reliability across diverse patient populations.

In summary, while the study provides valuable insights into the potential of AI in UC management, the findings are not yet robust enough to warrant a change in practice. Further research is needed to validate these results in larger, more diverse populations and to assess the clinical impact of AI-assisted scoring on patient outcomes.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights the potential of AI-assisted scoring in UC management, which may complement Cristcot's offerings by enhancing diagnostic accuracy and treatment stratification. This could strengthen the positioning of the Sephure® Suppository Applicator and HCA Suppository as part of a comprehensive UC management strategy.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for localized treatment, which aligns with the benefits of Cristcot's products.
Sephure® offers a unique delivery mechanism that enhances patient compliance and comfort, while HCA's rapid action addresses an unmet need in UC management, differentiating them from oral and biologic therapies.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional endpoints related to AI-assisted diagnostics in future trials, potentially expanding the label for HCA suppository to include AI integration in treatment protocols.
Medical Affairs: Prioritize real-world evidence generation on the effectiveness of HCA in conjunction with AI tools for treatment decision-making, and engage KOLs to advocate for the integration of AI in UC management.
Marketing: Highlight the unique benefits of the Sephure® applicator and HCA suppository in marketing campaigns, emphasizing their role in improving patient outcomes and comfort, particularly in light of emerging AI technologies.

Abstract: P5411 - Comparable Gastrointestinal Side Effects and Steroid Use in Anti-TNF–Naïve Ulcerative Colitis Patients Treated With Risankizumab or Guselkumab: A National Database Analysis

Presenting Author: Luis M. Nieto, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=729
In anti-TNF–naïve patients with UC, treatment with Risankizumab and Guselkumab resulted in similar rates of gastrointestinal (GI) side effects.
Risankizumab was associated with 10 cases of nausea and vomiting, while no such cases were reported in the Guselkumab group, although the lack of events in the Guselkumab group limited the ability to measure a significant association.
No significant differences were observed in the use of intravenous or oral corticosteroids between the two treatment groups.
Findings suggest comparable safety profiles and steroid-sparing potential for both IL-23 inhibitors in this patient population.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This retrospective cohort study utilized a large population-based database (TriNetX) to analyze outcomes in 729 anti-TNF naïve UC patients, with 634 receiving Risankizumab and 91 matched to Guselkumab.
The study employed 1:1 propensity score matching to control for confounding variables, enhancing the reliability of the comparisons made between the two treatment groups.
While the study reported similar rates of gastrointestinal (GI) side effects and corticosteroid use, the small sample size for the Guselkumab group (n=91) limits the robustness of the findings, particularly regarding the incidence of nausea and vomiting.

2. Comparison to Current Standard-of-Care:

Both Risankizumab and Guselkumab are established IL-23 inhibitors, and the findings align with existing literature suggesting comparable safety profiles for these agents.
However, the study does not provide new evidence that would necessitate a change in current treatment guidelines or practices, as both therapies are already recognized as effective options for UC management.

3. Clinical Relevance and Feasibility:

The findings suggest that both therapies have similar safety and steroid-sparing potential, which is clinically relevant for managing UC, especially in anti-TNF naïve patients.
However, the lack of significant differences in outcomes and the exploratory nature of the findings indicate that further prospective studies are needed to validate these results and explore the mechanisms behind the observed side effects.

In summary, while the study provides valuable insights into the safety profiles of Risankizumab and Guselkumab, it does not present findings that would alter current clinical practice or guidelines for UC management.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the study comparing Risankizumab and Guselkumab in anti-TNF naïve patients with ulcerative colitis (UC) suggest that Cristcot's HCA suppository, delivered via the Sephure® applicator, may offer a differentiated therapeutic option in a competitive landscape dominated by biologics. The study's results reinforce the potential for rectal delivery systems to provide effective treatment alternatives, particularly for patients seeking rapid symptom relief and improved compliance.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients who may prefer localized treatment options over systemic therapies like biologics.
Sephure®'s unique delivery mechanism enhances patient comfort and compliance, which could be a significant advantage over both oral and injectable therapies, especially in terms of ease of use and reduced side effects.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints that assess quality of life and long-term remission rates, as well as potential label expansions for the HCA suppository.
Medical Affairs: Prioritizing real-world evidence generation to support the safety and efficacy of the HCA suppository, alongside educational initiatives targeting healthcare providers (HCPs) about the benefits of rectal delivery systems.
Marketing: Opportunities exist to enhance differentiation through messaging that emphasizes the unique benefits of the Sephure® applicator and HCA suppository, particularly in terms of patient comfort, compliance, and rapid symptom relief.

Abstract: P5413 - Adherence to Colon Cancer and Dysplasia Surveillance Guidelines Among Patients With Ulcerative Colitis and Crohn's Colitis

Presenting Author: Aaron Lit, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=113
62% of patients had a documented surveillance interval for the next colonoscopy, with 61% of these being concordant with AGA guidelines.
Among discordant cases, 96% were recommended a repeat colonoscopy earlier than the AGA guidelines suggest.
Suboptimal documentation and adherence to AGA-recommended surveillance intervals were observed, potentially leading to unnecessary procedures.
Proposed interventions include EMR-based prompts and educational outreach to improve adherence to guidelines.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This study utilized a retrospective chart review design, which is inherently limited by potential biases and confounding factors. The sample size of 113 patients, while providing some insights, may not be sufficiently powered to draw broad conclusions about adherence to surveillance guidelines.
The primary focus was on documentation and adherence to AGA guidelines for surveillance colonoscopy intervals, with 61% of documented intervals aligning with recommendations. However, the retrospective nature limits the ability to assess causality or the impact of adherence on clinical outcomes.

2. Comparison to Current Standard-of-Care:

The findings highlight a significant gap in adherence to established AGA guidelines, which is critical for preventing colorectal cancer in UC and CC patients. The study underscores the need for improved documentation practices but does not propose new treatment modalities or interventions that would alter current management strategies.
While the results indicate that many patients are being recommended shorter intervals than guidelines suggest, this does not directly challenge or change existing treatment protocols but rather emphasizes the need for better compliance with existing standards.

3. Clinical Relevance and Feasibility:

Improving adherence to surveillance guidelines is important for patient safety and resource utilization, but the study does not provide new therapeutic options or strategies that could be immediately implemented in clinical practice.
Proposed interventions, such as EMR-based prompts and educational outreach, are practical but represent incremental improvements rather than transformative changes in UC management.

Overall, while the study provides valuable insights into adherence issues, it does not present findings that would necessitate a change in clinical practice for managing UC, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights a significant gap in adherence to surveillance guidelines for colorectal cancer (CRC) among patients with ulcerative colitis (UC) and Crohn's colitis (CC). This presents an opportunity for Cristcot to position its products, particularly the Hydrocortisone Acetate (HCA) Suppository and Sephure® Suppository Applicator, as part of a comprehensive management strategy for UC, emphasizing the importance of regular surveillance and effective treatment options.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients with UC, who may benefit from targeted therapies that enhance compliance and treatment efficacy.
Sephure® offers a unique advantage in ensuring optimal drug delivery, which could complement the rapid action of the HCA suppository, potentially improving patient outcomes and adherence to treatment regimens.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term adherence to surveillance guidelines and the impact of their products on patient outcomes.
Medical Affairs: Prioritize real-world evidence generation to support the efficacy of the HCA suppository and Sephure® applicator in improving adherence to surveillance protocols among UC patients.
Marketing: Highlight the differentiation of Cristcot’s products in messaging, focusing on their role in enhancing patient comfort and compliance, while also addressing the importance of regular surveillance in the management of UC.

Abstract: P5414 - Etrolizumab as Induction and Maintenance Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: A Systematic Review and Meta-Analysis

Presenting Author: Mageda Al Areqi, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=1808
Etrolizumab demonstrated a significant clinical response compared to placebo with an odds ratio of 1.60 [CI:1.23 to 2.09, p < 0.001].
In the induction group, clinical remission was significantly higher with an odds ratio of 2.85 [CI: 1.63 to 4.99, p < 0.001], while no significant difference was observed in the maintenance group [OR: 1.43, CI: 0.91 to 2.23, p = 0.12].
Endoscopic improvement was significant in both groups, with odds ratios of 1.72 [CI: 1.24 to 2.40, p = 0.001] for induction and 2.09 [CI: 1.37 to 3.20, p < 0.001] for maintenance.
Histologic remission was significant for the maintenance group with an odds ratio of 2.67 [CI: 1.61 to 4.41, p < 0.001], while induction showed marginal significance [OR: 1.93, CI: 1.01 to 3.68, p = 0.05].

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This systematic review and meta-analysis included 5 controlled clinical trials with a total of 1808 patients, providing a substantial sample size for evaluating the efficacy of Etrolizumab.
The primary outcomes demonstrated significant clinical response and remission rates in the induction phase (OR 2.85, p < 0.001), while the maintenance phase showed a non-significant trend (OR 1.43, p = 0.12), indicating variability in treatment effectiveness over time.
Endoscopic and histologic improvements were also significant, particularly in the maintenance group, which adds to the robustness of the findings.

2. Comparison to Current Standard-of-Care:

Etrolizumab's efficacy aligns with existing treatment guidelines, showing promise as a viable option for moderate-to-severe UC, particularly in patients who may not respond adequately to current therapies.
However, the lack of significant findings in the maintenance phase suggests that while Etrolizumab is effective, it may not surpass existing therapies in long-term management, which limits its immediate practice-changing potential.

3. Clinical Relevance and Feasibility:

Etrolizumab's favorable safety profile and its mechanism of action targeting the β7 integrin pathway may offer a new therapeutic avenue, especially for patients with specific treatment needs.
While the findings are promising, further studies are needed to establish long-term outcomes and cost-effectiveness, which are critical for clinical integration.

In summary, while the study provides valuable insights into the efficacy of Etrolizumab for UC, the findings do not yet warrant a change in standard practice, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the meta-analysis on Etrolizumab reinforce the potential of Cristcot’s HCA suppository as a competitive option in the treatment landscape for ulcerative colitis (UC). The study highlights the efficacy of rectal delivery systems, which aligns with Cristcot's focus on innovative rectal drug delivery through the Sephure® applicator and HCA suppository. This positions Cristcot to leverage its unique delivery mechanism to enhance patient outcomes and compliance.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients with localized disease, which may enhance the appeal of Cristcot’s products compared to oral and biologic therapies.
Sephure® offers advantages in terms of medication placement and patient comfort, while the HCA suppository demonstrates rapid clinical remission, potentially making it a preferred choice for patients seeking quick relief.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints that focus on long-term remission and quality of life improvements, as well as potential label expansions to include broader UC indications.
Medical Affairs: Prioritize real-world evidence generation to support the clinical benefits of the HCA suppository and engage healthcare professionals (HCPs) through educational initiatives that highlight the advantages of rectal delivery systems.
Marketing: Emphasize the unique benefits of the Sephure® applicator and HCA suppository in marketing campaigns, focusing on patient comfort, compliance, and rapid symptom relief to differentiate from existing oral and biologic therapies.

Abstract: P5417 - Empiric Antibiotic Use With Rescue Infliximab Does Not Improve Outcomes in Acute Severe Ulcerative Colitis: A Retrospective Cohort Study

Presenting Author: Dominic Ofosu-Amakye, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=1,028
No difference in all-cause mortality between patients receiving infliximab with antibiotics (Cohort 1) and those without (Cohort 2); both groups had 10 deaths (risk difference = 0).
Sepsis rates were higher in Cohort 1 (39 cases) compared to Cohort 2 (29 cases), but this was not statistically significant (OR = 1.3; 95% CI: 0.833–2.214).
Empiric antibiotic use with infliximab did not reduce sepsis risk and may lead to increased healthcare costs and contribute to antimicrobial resistance.
Findings underscore the need for antimicrobial stewardship and suggest further prospective studies are warranted to evaluate the role of antibiotics in ASUC management.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This retrospective cohort study analyzed data from 2,788 patients with acute severe ulcerative colitis (ASUC) using the TriNetX platform, ultimately including 1,028 patients after propensity score matching, which enhances the reliability of the findings.
The primary outcome of all-cause mortality showed no significant difference between the two cohorts (10 deaths in each group), with an odds ratio of 1.0, indicating that concurrent antibiotic use did not impact mortality rates.
Secondary outcomes, including sepsis rates, also did not demonstrate a significant benefit from antibiotic use, with a risk difference of 0.973% and an odds ratio of 1.3 (95% CI: 0.833–2.214).

2. Comparison to Current Standard-of-Care:

The findings challenge the common practice of empiric antibiotic use alongside infliximab in ASUC, suggesting that this approach does not improve clinical outcomes and may contribute to increased healthcare costs and antimicrobial resistance.
Current guidelines do not specifically endorse routine antibiotic use in conjunction with infliximab, and this study provides evidence that may influence future recommendations.

3. Clinical Relevance and Feasibility:

While the study provides important insights into the lack of benefit from antibiotics in this context, it does not propose a new treatment paradigm or significantly alter existing management strategies for ASUC.
The implications for antimicrobial stewardship are notable, as the study highlights the need for careful consideration of antibiotic use in this patient population.

Overall, while the study offers valuable data that may inform clinical practice and guidelines, it does not present findings that are robust enough to be classified as practice-changing at this time.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study indicates that concurrent antibiotic use with infliximab does not improve outcomes in Acute Severe Ulcerative Colitis (ASUC), reinforcing the need for effective treatment strategies. This context strengthens Cristcot’s position with its HCA suppository and Sephure® applicator, as they offer innovative solutions that may address unmet needs in UC management.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients who may not respond to traditional therapies, positioning Cristcot’s products favorably against oral, topical, and biologic options.
Sephure® enhances the delivery of HCA suppository, potentially improving patient compliance and comfort, which are critical in managing UC effectively.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring new trial endpoints that emphasize patient-reported outcomes and quality of life, as well as potential label expansions for HCA suppository.
Medical Affairs: Prioritize real-world evidence generation to support the clinical benefits of HCA and Sephure®, and engage healthcare professionals (HCPs) with educational initiatives on the advantages of rectal delivery systems.
Marketing: Highlight the unique benefits of Sephure® and HCA in promotional materials, focusing on their role in enhancing patient adherence and outcomes compared to traditional therapies.

Abstract: P5424 - The Risk of Emergent Colectomy for Ulcerative Colitis Has Increased Over Time

Presenting Author: Michael Ly, BA
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=717
14% of patients underwent emergent colectomy, with a significant increase to 33% in the most recent period (2017-2020, p<0.001).
Non-white patients had a higher likelihood of emergent colectomy (23% vs. 10%, P<0.001), indicating potential disparities in access to care.
Increased odds of emergent colectomy were observed in later time periods, with adjusted odds ratios of 3.57 (2017-2020) and 3.66 (2014-2016).
Findings suggest that patients may be delaying surgical intervention in favor of medical management, leading to more severe disease states.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This retrospective cohort study analyzed data from 717 patients with ulcerative colitis (UC) to evaluate trends in emergent colectomies over time, specifically from 2003 to 2020.
The study employed appropriate statistical methods, including Chi-square tests and multivariable logistic regression, to adjust for confounders such as race and social determinants of health.
While the sample size is substantial, the retrospective nature limits the ability to establish causation definitively.

2. Comparison to Current Standard-of-Care:

The findings indicate an increasing trend in emergent colectomies, particularly in the most recent period (2017-2020), despite the availability of new therapies, suggesting a potential gap in timely surgical intervention.
This trend contrasts with current guidelines that advocate for timely surgical evaluation in patients with severe UC, highlighting a possible deviation from best practices.

3. Clinical Relevance and Feasibility:

The study underscores the importance of patient education regarding the risks of delaying surgery, particularly for non-white patients who were found to be at higher risk for emergent colectomy.
While the findings are significant for understanding patient management and disparities in care, they do not introduce new therapeutic options or strategies that would change current clinical practice.

Overall, this study provides valuable insights into the management of UC and highlights the need for improved decision-making regarding surgical interventions, but it does not present findings that would warrant immediate changes in practice.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the study indicate a concerning trend of increasing emergent colectomies among ulcerative colitis (UC) patients, despite advancements in medical therapies. This suggests a potential opportunity for Cristcot to position its products, particularly the Hydrocortisone Acetate (HCA) Suppository and Sephure® Suppository Applicator, as effective alternatives that could mitigate the need for surgical interventions.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, especially given the increasing rates of emergent colectomy, which may be attributed to inadequate management of UC with existing therapies.
Sephure® offers a unique advantage in enhancing patient compliance and comfort, while the HCA Suppository demonstrates rapid efficacy, potentially addressing the unmet need for effective rescue therapies in UC management.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring new trial endpoints that focus on long-term outcomes and quality of life, as well as potential label expansions to include indications for patients at risk of emergent colectomy.
Medical Affairs: Prioritizing real-world evidence generation to support the clinical benefits of HCA and Sephure® could enhance HCP education and engagement, particularly around the risks of delaying surgical intervention.
Marketing: There are opportunities to enhance differentiation by emphasizing the unique delivery mechanism of Sephure® and the rapid action of HCA in marketing campaigns, positioning them as essential tools in the management of UC.

Abstract: P5431 - Efficacy of Retreatment With Upadacitinib After Treatment Interruption in Ulcerative Colitis: Data From the U-ACTIVATE Open-Label Extension

Presenting Author: Remo Panaccione, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=110
Clinical remission per adapted Mayo score was achieved by 52.4%, 66.7%, and 76.3% of patients at weeks 48, 96, and 144, respectively, in the UPA15 group.
In the UPA15 to UPA30 escalation group, clinical remission rates were 48.3%, 59.4%, and 61.1% at the same time points.
Endoscopic remission was achieved by 31.3%, 40.0%, and 33.3% of patients in the UPA15 group and 30.0%, 56.3%, and 56.4% in the UPA30 group at weeks 48, 96, and 144, respectively.
Most patients who lost response after temporary UPA treatment interruption regained clinical and endoscopic efficacy upon retreatment with UPA15 and/or escalation to UPA30.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

The study is an open-label extension of previous randomized controlled trials (U-ACHIEVE and U-ACCOMPLISH), involving 110 patients who lost response to upadacitinib (UPA) after a temporary treatment interruption. The analysis provides data on clinical and endoscopic outcomes over 144 weeks.
Clinical remission rates per adapted Mayo score were reported at 52.4%, 66.7%, and 76.3% at weeks 48, 96, and 144 for patients who remained on UPA15, indicating a progressive improvement in response over time.
Endoscopic remission rates were also notable, with 31.3% achieving remission at week 48, although this varied across time points and treatment groups.

2. Comparison to Current Standard-of-Care:

While the findings suggest that UPA can effectively recapture response in patients who previously lost efficacy, they do not provide a direct comparison to other treatment options or establish superiority over existing therapies.
The study does not challenge current treatment guidelines but rather supports the use of UPA in a specific scenario of treatment interruption.

3. Clinical Relevance and Feasibility:

The results are clinically relevant as they address a common issue in UC management—loss of response after treatment interruption. However, the open-label design limits the strength of the conclusions.
While the findings are promising, they do not provide sufficient evidence to alter standard practice or recommend UPA as a first-line treatment in this context, especially given the lack of safety data in this specific analysis.

In summary, while the study offers valuable insights into the management of UC with UPA after treatment interruption, it does not present findings that would necessitate a change in current clinical practice.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study on Upadacitinib (UPA) highlights the potential for effective retreatment in ulcerative colitis (UC) patients who experience treatment interruptions. This finding strengthens Cristcot’s position by validating the need for innovative rectal delivery systems like the Sephure® Suppository Applicator and the Hydrocortisone Acetate (HCA) Suppository, which can enhance patient adherence and therapeutic outcomes.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients who may not respond adequately to oral therapies like UPA after interruptions.
Sephure® offers a unique advantage in ensuring optimal drug delivery, potentially improving the efficacy of HCA suppositories compared to traditional methods.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term efficacy and safety of HCA suppositories, potentially including head-to-head comparisons with oral therapies.
Medical Affairs: Prioritize real-world evidence generation to support the clinical benefits of rectal delivery systems and engage healthcare professionals (HCPs) through educational initiatives on the advantages of HCA and Sephure®.
Marketing: Highlight the unique benefits of Sephure® in enhancing patient comfort and compliance, positioning HCA as a rapid-response therapy in the UC treatment landscape.

Abstract: P5438 - Long-Term Comparative Outcomes of TNF-α Antagonists vs Vedolizumab as First-Line Therapy for Refractory Ulcerative Proctitis: A Propensity-Matched Study

Presenting Author: Ayushi Jayesh Shah, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=641
TNFi-treated patients had significantly lower odds of emergency department visits and/or hospitalizations compared to VDZ at 6 months (14.3% vs 25%, p=0.03) and 12 months (16.1% vs 35.2%, p=0.01).
No significant differences were observed between TNFi and VDZ in terms of steroid use or colectomy rates.
In a matched cohort of 132 patients, ADA demonstrated a similarly reduced risk of ED visits and/or hospitalizations compared to VDZ at 6 and 12 months.
Overall, TNFi may provide clinical advantages in managing refractory ulcerative proctitis, likely due to a faster onset of action.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This study utilized a large cohort of 641 patients with isolated ulcerative proctitis (UP) from a comprehensive database, employing propensity score matching to control for confounding variables, which enhances the reliability of the findings.
The primary outcomes assessed included emergency department (ED) visits and hospitalizations at 6 and 12 months, with statistically significant differences observed between TNF inhibitors (TNFi) and vedolizumab (VDZ) in favor of TNFi.
While the study design is robust, it is observational in nature, which limits the ability to draw definitive causal conclusions.

2. Comparison to Current Standard-of-Care:

The findings suggest that TNFi may provide a quicker onset of action, leading to reduced ED visits and hospitalizations compared to VDZ, which aligns with existing knowledge about the pharmacodynamics of these therapies.
However, the overall low rates of complications and surgeries in UP patients indicate that both treatment options are relatively safe, and the differences may not be clinically significant enough to alter current treatment guidelines.

3. Clinical Relevance and Feasibility:

The study highlights the need for more data on biologic therapy in UP, a population often excluded from clinical trials, which is important for informing treatment decisions.
While the results are relevant, they do not provide a paradigm shift in management strategies for UC, particularly since both TNFi and VDZ are already established therapies.

In summary, while the study offers valuable insights into the comparative effectiveness of TNFi and VDZ in refractory UP, it does not present findings that would necessitate a change in current clinical practice for ulcerative colitis management.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights the potential for TNF-α antagonists (TNFi) and vedolizumab (VDZ) as effective first-line therapies for refractory ulcerative proctitis (UP), which may influence Cristcot's strategic positioning of its Hydrocortisone Acetate (HCA) suppository and Sephure® applicator. The findings suggest that while TNFi may offer advantages in reducing emergency room visits and hospitalizations, the unique delivery mechanism of the Sephure® applicator could enhance patient compliance and comfort, positioning Cristcot favorably in the market.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients with localized disease like UP, which aligns with Cristcot's focus on rectal drug delivery.
Sephure®'s ability to improve bioavailability and patient comfort may provide a competitive edge over traditional biologic therapies, especially in terms of adherence and ease of use.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints that assess quality of life and patient-reported outcomes, as well as potential label expansions for HCA in refractory UP.
Medical Affairs: Prioritizing real-world evidence generation on the effectiveness of HCA in conjunction with the Sephure® applicator could strengthen HCP messaging and support KOL engagement.
Marketing: Opportunities exist to enhance differentiation by emphasizing the unique benefits of the Sephure® applicator in improving patient experience and compliance, alongside the rapid action of HCA in achieving clinical remission.

Abstract: P5440 - Effectiveness and Safety of Guselkumab versus Risankizumab in Ulcerative Colitis: A Real-World Comparative Outcomes Analysis

Presenting Author: Ali Osman, MD, MSCI Candidate
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=622 (Guselkumab: 118, Risankizumab: 504)
Guselkumab was associated with significantly lower 1-year corticosteroid use compared to risankizumab (22.0% vs. 34.5%; risk difference: -12.5%, p<=0.009).
Kaplan–Meier estimates indicated a trend toward improved steroid-free survival with Guselkumab (55.9% vs. 39.8%; p<=0.405).
Rates of hospitalization or emergency department visits were similar between the two groups (8.5% for Guselkumab vs. 10.7% for Risankizumab; p<=0.471).
Advancement to other therapies occurred in 8.5% of the Guselkumab group versus 7.3% of the risankizumab group (p<=0.675), suggesting comparable therapy escalation rates.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This retrospective cohort study utilized the TriNetX Global Collaborative Network database, analyzing outcomes in 622 UC patients treated with either Guselkumab (n=118) or Risankizumab (n=504).
The primary outcome demonstrated a statistically significant reduction in corticosteroid use at one year for Guselkumab (22.0% vs. 34.5%, p=0.009), indicating a potential benefit in managing steroid dependency.
However, the study's retrospective design limits the ability to draw definitive causal conclusions, and the reliance on database outcomes may introduce biases.

2. Comparison to Current Standard-of-Care:

While the findings suggest Guselkumab may reduce corticosteroid use compared to Risankizumab, both therapies are currently considered effective options in UC management, and the differences observed may not be clinically significant enough to alter treatment guidelines.
Current AGA and ECCO guidelines do not differentiate between these IL-23 inhibitors based on corticosteroid-sparing effects, indicating that further evidence is needed to establish a clear preference.

3. Clinical Relevance and Feasibility:

The study highlights a potential advantage of Guselkumab in reducing corticosteroid use, which is clinically relevant given the adverse effects associated with long-term steroid therapy.
However, the similar rates of hospitalization and therapy escalation between the two groups suggest that both treatments are comparably safe and effective, limiting the immediate impact of these findings on clinical practice.

In summary, while the study provides valuable insights into the comparative effectiveness of Guselkumab and Risankizumab, the limitations inherent in its design and the lack of practice-altering implications categorize it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study comparing Guselkumab and risankizumab highlights the potential for Cristcot’s products, particularly the Hydrocortisone Acetate (HCA) Suppository, to address unmet needs in ulcerative colitis (UC) treatment. The findings suggest that while biologics are effective, there remains a significant opportunity for rectal delivery systems that enhance patient compliance and provide rapid symptom relief.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients seeking alternatives to systemic therapies like Guselkumab and risankizumab.
Sephure® and HCA’s advantages include targeted delivery, improved bioavailability, and enhanced patient comfort, which may appeal to patients looking for effective, non-invasive treatment options.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints that emphasize quality of life and symptom relief, potentially positioning HCA as a first-line therapy in specific UC patient populations.
Medical Affairs: Prioritize real-world evidence generation to support the clinical benefits of HCA and Sephure®, focusing on patient adherence and outcomes compared to systemic therapies.
Marketing: Highlight the unique benefits of Sephure® and HCA in promotional materials, emphasizing their role in enhancing patient comfort and compliance, and position them as complementary options to existing biologics.

Abstract: P5448 - Assessment of Sociodemographic Factors and Outcomes of Ulcerative Colitis Hospitalizations: A Large Population-Based Study

Presenting Author: Laura Sahyoun, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=43,377
Inpatient colectomy occurred in 17.9% of patients, with higher rates among younger males, non-Hispanic whites, and those with private insurance.
Rescue medical therapy was administered to 15% of patients, with 11.5% of these patients subsequently undergoing colectomy.
Multivariable analysis indicated that female sex, non-white race, and non-private insurance were associated with a lower risk of colectomy, while higher comorbidity index and admission to teaching hospitals increased the risk.
Findings suggest a need for further research into sociodemographic factors influencing colectomy rates in UC patients.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This retrospective study analyzed a substantial cohort of 43,377 patients hospitalized for ulcerative colitis (UC) using the Vizient Clinical Database, providing a robust dataset for evaluating sociodemographic factors influencing hospitalization outcomes.
The primary outcome, inpatient colectomy rates, was clearly defined, with 17.9% of patients undergoing this procedure. The use of multivariable logistic regression to identify risk factors adds statistical rigor to the findings.
Statistical significance was appropriately assessed using Pearson’s χ2 test and t-tests, with a p-value threshold of <0.05, ensuring reliable interpretation of results.

2. Comparison to Current Standard-of-Care:

The findings highlight sociodemographic disparities in UC hospitalization outcomes, particularly regarding colectomy rates, which align with existing literature on the impact of race, gender, and insurance status on healthcare access and outcomes.
While the study does not propose new treatment modalities or management strategies, it underscores the need for awareness of these disparities in clinical practice, which is consistent with current guidelines emphasizing personalized care.

3. Clinical Relevance and Feasibility:

Understanding the sociodemographic factors associated with higher colectomy rates can inform targeted interventions and resource allocation in healthcare settings, particularly in teaching hospitals.
However, the study does not provide direct implications for treatment changes or new therapeutic approaches, limiting its immediate impact on clinical practice.

Overall, while the study offers valuable insights into the sociodemographic influences on UC hospitalization outcomes, it does not present findings that would necessitate a change in current management practices, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights significant sociodemographic factors influencing hospitalization outcomes in ulcerative colitis (UC), which may inform Cristcot's strategic positioning of the Sephure® Suppository Applicator and Hydrocortisone Acetate (HCA) Suppository. The findings suggest a potential market for targeted interventions that address disparities in treatment access and outcomes, thereby strengthening Cristcot's product portfolio.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients with specific sociodemographic profiles that may benefit from targeted therapies like HCA suppository.
Sephure® offers competitive advantages in terms of enhanced delivery and patient compliance, which could be emphasized in marketing strategies to differentiate from oral and biologic therapies.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring sociodemographic factors in future trials to better understand patient populations and potentially expand indications for HCA suppository.
Medical Affairs: Prioritize real-world evidence initiatives that address the impact of sociodemographic factors on treatment outcomes, enhancing HCP education and KOL engagement.
Marketing: Highlight the unique benefits of Sephure® and HCA in addressing the needs of diverse patient populations, leveraging data from the study to support claims and enhance market positioning.

Abstract: P5456 - Impact of Hyponatremia on Mortality and Other In-Hospital Outcomes in Patients With Ulcerative Colitis (UC): A Retrospective Cohort Analysis Using the National Inpatient Sample

Presenting Author: Hamza Tahir, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=60,660
Hyponatremia in hospitalized UC patients is associated with a 21-fold increase in inpatient mortality (aOR 21.33; 95% CI, 4.90-92.89; P < 0.001).
Patients with hyponatremia had a two-fold increase in mean length of stay (mean difference 2.02; 95% CI, 1.39-2.65; P < 0.001) and elevated total hospital charges.
Significantly higher rates of anemia, blood transfusions, intestinal perforation, hypoalbuminemia, acute kidney injury, sepsis, and mechanical ventilation were observed in the hyponatremia group (all P < 0.05).
No significant differences were found in rates of toxic megacolon, hypovolemic shock, colectomy, or renal replacement therapy between patients with and without hyponatremia.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This study utilized a large national database (National Inpatient Sample) to analyze outcomes in 60,660 hospitalized UC patients, with a specific focus on 7,425 patients who had hyponatremia.
The study employed multivariable regression analysis to adjust for confounders, enhancing the reliability of the findings regarding in-hospital mortality and other complications.
Statistical significance was achieved for key outcomes, including a 21-fold increase in inpatient mortality (aOR 21.33; 95% CI, 4.90-92.89; p < 0.001) and a two-fold increase in mean length of stay (mean difference 2.02; 95% CI, 1.39-2.65; p < 0.001).

2. Comparison to Current Standard-of-Care:

The findings align with existing literature that recognizes electrolyte imbalances as significant in UC management but do not introduce new treatment modalities or strategies that would alter current practice guidelines.
While the study highlights the association between hyponatremia and worse outcomes, it does not provide direct evidence for interventions that could mitigate these risks.

3. Clinical Relevance and Feasibility:

The study underscores the importance of monitoring and managing hyponatremia in hospitalized UC patients, which is a relevant clinical consideration but does not change the therapeutic landscape.
Although the findings suggest that early detection and management of hyponatremia could improve outcomes, the study does not provide specific recommendations or interventions that could be readily implemented in clinical practice.

In summary, while the study provides valuable insights into the impact of hyponatremia on UC outcomes, it does not present findings that would necessitate a change in current management practices, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights the significant impact of hyponatremia on clinical outcomes in hospitalized patients with ulcerative colitis (UC), emphasizing the need for effective management strategies. This aligns with Cristcot's focus on innovative therapies for UC, potentially strengthening the case for the Hydrocortisone Acetate (HCA) Suppository as a timely intervention in acute settings.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly in acute care settings where rapid symptom relief is critical, positioning Cristcot's HCA suppository favorably against oral and biologic therapies.
The Sephure® applicator enhances the delivery of HCA, improving patient compliance and comfort, which could be a significant advantage in managing acute UC exacerbations.

Strategic Implications by Function:

Clinical Development: Cristcot should consider further studies to explore the role of HCA in patients with hyponatremia and potentially expand indications to include acute management scenarios.
Medical Affairs: Prioritize real-world evidence initiatives that demonstrate the effectiveness of HCA in reducing complications associated with hyponatremia in UC patients, enhancing HCP education on this topic.
Marketing: Highlight the unique benefits of the Sephure® applicator in delivering HCA, focusing on its role in improving patient outcomes and reducing hospital stays, which could resonate with both healthcare providers and patients.

Abstract: P5462 - Shorter Disease Duration Increases Clinical Remission Rates in Real-World Observational Studies for Crohn’s Disease, but Not Ulcerative Colitis: A Systematic Review and Meta-Analysis

Presenting Author: Michael Scott Dunn, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=141 studies (83 UC, 64 CD)
Shorter mean disease duration (<8 years) in Crohn’s Disease (CD) patients is associated with significantly higher clinical remission rates at both induction (60.7% vs 40.6%) and maintenance phases (66.1% vs 48.8%) compared to longer disease duration (>8 years) (p < 0.05).
No significant association was found between mean disease duration and clinical remission rates in Ulcerative Colitis (UC) patients.
Exploratory analysis in CD patients showed no significant difference in clinical remission between those with disease duration <5 years and those with 5-8 years during both induction and maintenance phases.
Findings emphasize the importance of early intervention with advanced therapies in CD to improve clinical outcomes.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This systematic review and meta-analysis included 141 studies, with a focus on real-world data from both Crohn's Disease (CD) and Ulcerative Colitis (UC) patients treated with various advanced therapies.
While the study found significant associations between disease duration and clinical remission rates in CD, it did not establish a similar correlation for UC, indicating a potential limitation in the applicability of findings to UC management.
The statistical analysis employed (ANOVA) is appropriate for the data type, but the lack of significant findings for UC suggests that the evidence may not be robust enough to influence clinical practice.

2. Comparison to Current Standard-of-Care:

The findings align with existing knowledge that earlier intervention in inflammatory bowel disease can lead to better outcomes, particularly in CD, but do not provide new insights or recommendations that would alter current UC treatment guidelines.
Current guidelines emphasize the importance of timely therapy initiation, but this study does not provide actionable data specific to UC that would necessitate a change in practice.

3. Clinical Relevance and Feasibility:

The study highlights the importance of disease duration in CD but does not translate this finding into actionable strategies for UC management, limiting its clinical relevance.
As the study did not find a significant relationship between disease duration and remission in UC, it does not offer new biomarkers or stratification methods that could enhance personalized treatment approaches.

In summary, while the study provides valuable insights into the management of CD, its findings regarding UC do not warrant a change in current clinical practice, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the systematic review and meta-analysis highlight the importance of early intervention in Crohn's Disease (CD) for achieving clinical remission, which may strengthen Cristcot's positioning of the Hydrocortisone Acetate (HCA) Suppository as a timely therapeutic option. The Sephure® Suppository Applicator enhances the delivery of HCA, potentially improving patient outcomes and compliance, thus creating strategic opportunities for Cristcot in the UC treatment landscape.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients with CD, where early intervention is crucial. This positions Cristcot favorably against oral, topical, and biologic therapies.
The Sephure® device's ability to enhance medication delivery and patient comfort may provide a competitive advantage over traditional methods, especially in terms of compliance and speed of action.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring new trial endpoints that emphasize early intervention and potentially expand the label for HCA to include indications for patients with shorter disease durations.
Medical Affairs: Prioritizing real-world evidence initiatives that demonstrate the benefits of early treatment with HCA and the Sephure® device could enhance HCP engagement and support clinical messaging.
Marketing: Opportunities exist to differentiate Cristcot’s offerings by emphasizing the unique benefits of rectal delivery and the rapid response seen in the CESSA trial, aligning messaging with the findings of the meta-analysis.

Abstract: P5463 - Comparative Analysis of Non-Malignant Skin Lesions in Crohn’s Disease and Ulcerative Colitis: Results From a Population-Based Study

Presenting Author: Nawaf Alhazmi, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=229,810 (108,775 CD; 121,035 UC)
Prevalence of non-malignant skin lesions was 7.7% in Crohn’s disease (CD) and 8.4% in ulcerative colitis (UC).
CD patients were younger (mean age 48.6 years) compared to UC patients (mean age 54.5 years), with a higher percentage of CD patients under 40 years.
Skin tags were the most common cutaneous manifestation, followed by hidradenitis suppurativa and oral aphthae; CD patients had a higher prevalence of pyoderma gangrenosum and hidradenitis suppurativa.
Findings highlight the need for tailored management of skin lesions in IBD patients, given the differences in prevalence and types of lesions between CD and UC.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This study utilized a large, real-world cohort from the TriNetX electronic health record network, including 108,775 Crohn's disease (CD) and 121,035 ulcerative colitis (UC) patients, which enhances the generalizability of the findings.
The cross-sectional design is appropriate for assessing prevalence but does not establish causation or temporal relationships, limiting the strength of the conclusions.
Statistical analyses, including chi-square and t-tests, were employed to compare demographic and clinical characteristics, providing a solid basis for the reported associations.

2. Comparison to Current Standard-of-Care:

The findings highlight the prevalence of non-malignant skin lesions in IBD, with notable differences between CD and UC patients, which adds to the understanding of extraintestinal manifestations.
While the study provides valuable insights, it does not propose new treatment strategies or interventions that would alter current management guidelines for UC.

3. Clinical Relevance and Feasibility:

Understanding the prevalence and types of skin lesions associated with UC can inform clinicians about potential comorbidities and the need for multidisciplinary management.
However, the study does not address the implications for treatment or management of these skin lesions in UC patients, which limits its immediate clinical application.

Overall, while the study offers important insights into the demographic associations and prevalence of skin lesions in UC, it does not provide evidence that would necessitate a change in current clinical practice or management strategies for ulcerative colitis.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the Phase 3 CESSA trial and the comparative analysis of non-malignant skin lesions in IBD provide Cristcot with a strengthened position in the rectal drug delivery market. The successful demonstration of HCA suppository efficacy and the unique advantages of the Sephure® applicator create new strategic opportunities for Cristcot to differentiate its products in a competitive landscape.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients with UC, who may benefit from targeted therapies that enhance bioavailability and compliance.
Sephure® offers a competitive advantage by improving patient comfort and adherence, while the HCA suppository's rapid action addresses an unmet need in UC management.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term outcomes and quality of life, as well as potential label expansions for broader indications.
Medical Affairs: Prioritizing real-world evidence generation and educational initiatives for healthcare providers (HCPs) can enhance understanding of the benefits of rectal therapies and improve patient management strategies.
Marketing: Opportunities exist to enhance differentiation through targeted messaging that emphasizes the unique benefits of the Sephure® applicator and the rapid efficacy of the HCA suppository, positioning them as first-line options in UC treatment.

Abstract: P5464 - Increasingly High Prevalence of Advanced Therapy Use in Patients With Ulcerative Colitis in a Large Community and Academic Cohort: A Preliminary Analysis From IBD Qorus

Presenting Author: Adam A. Saleh, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=48 sites
Advanced therapy (AT) was utilized in over 50% of ulcerative colitis (UC) visits, indicating a higher prevalence compared to other cohorts.
There is a trend of increasing AT use among UC patients over time, suggesting improved adoption of advanced treatment options.
Factors associated with AT use were identified through multivariable logistic regression, emphasizing the need for further research on how these factors influence patient outcomes.
Future studies should explore the evolution of AT utilization across different clinical settings to optimize treatment strategies for UC.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

The study utilizes a large, multicenter cohort from the IBD Qorus, which enhances the generalizability of the findings. However, it is primarily descriptive and lacks a randomized controlled design, limiting the strength of causal inferences.
While the study reports a high prevalence of advanced therapy (AT) use in UC visits, it does not provide specific clinical outcomes or comparative effectiveness data, which are critical for assessing the impact of AT on patient health.
The use of multivariable logistic regression to identify factors associated with AT use is a strength, but the lack of detailed statistical outcomes diminishes the robustness of the conclusions.

2. Comparison to Current Standard-of-Care:

The findings indicate an increasing trend in AT use, which aligns with current guidelines advocating for early and aggressive treatment in moderate-to-severe UC. However, the study does not provide evidence that this increased use translates into improved patient outcomes compared to existing standards.
While the prevalence of AT use exceeds that reported in other cohorts, the implications for clinical practice remain unclear without data on treatment efficacy or safety.

3. Clinical Relevance and Feasibility:

The study highlights the importance of AT in UC management, suggesting that more patients are receiving these therapies, which is a positive trend. However, without evidence of improved outcomes, the findings do not warrant immediate changes in clinical practice.
Future research is needed to explore the long-term effects of increased AT utilization on patient outcomes, particularly in diverse clinical settings.

In summary, while the study provides valuable insights into the trends of AT use in UC, it does not present sufficient evidence to alter current management practices, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the Phase 3 CESSA trial and the IBD Qorus study suggest a strengthening of Cristcot’s product portfolio, particularly for the Hydrocortisone Acetate (HCA) Suppository and the Sephure® Suppository Applicator. The demonstrated efficacy and safety of the HCA suppository in achieving clinical remission in ulcerative colitis (UC) patients, combined with the unique delivery advantages of the Sephure® device, position Cristcot favorably in a competitive landscape increasingly focused on advanced therapies.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients with distal UC, where traditional oral and topical therapies may be less effective.
The Sephure® applicator enhances the HCA suppository's competitive advantages by improving medication placement, bioavailability, and patient compliance, which are critical factors in treatment success.

Strategic Implications by Function:

Clinical Development: Cristcot should consider expanding trial endpoints to include long-term outcomes and quality of life measures, as well as exploring label expansions for broader indications of HCA suppository use.
Medical Affairs: Prioritize real-world evidence generation to support the clinical benefits of HCA and Sephure®, and develop educational initiatives targeting healthcare providers (HCPs) to enhance understanding of rectal therapies.
Marketing: Highlight the unique benefits of the Sephure® applicator in promotional materials, emphasizing patient comfort and compliance, and position HCA as a rapid-response therapy in the UC treatment landscape.

Abstract: P5465 - Clinical Evolution, Complications, and Need for Advanced Therapy in Patients With Ulcerative Colitis: Experience of an Institutional Cohort in Colombia

Presenting Author: Gustavo Adolfo Reyes Medina, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=53
Intestinal complications occurred in 28.3% of patients, with hospitalization due to bleeding in 18.9% and surgery required in 9.4% of cases.
Extraintestinal manifestations were observed in 15.1%, including primary sclerosing cholangitis (5%), osteoporosis (7%), and spondyloarthropathies (6%).
Advanced therapies were initiated at a mean of 46 months; biologics did not significantly reduce complication rates (18.8% vs. 30.6%, p=0.2).
All patients requiring surgery had disease extending beyond the rectum, indicating a potential link between disease extent and surgical intervention.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This retrospective cohort study included 53 adult patients with UC, which is a relatively small sample size that limits the generalizability of the findings.
Outcomes focused on intestinal and extraintestinal complications, with a notable finding that 28.3% experienced intestinal complications, including significant bleeding in 18.9% of cases.
Statistical comparisons were made, but the p-values indicate that many findings, such as the difference in complication rates between biologic users and non-users, did not reach conventional significance (p=0.2).

2. Comparison to Current Standard-of-Care:

The study provides insights into the timing of complications and the use of advanced therapies in a Latin American cohort, which is underrepresented in existing literature.
While it highlights that biologics did not significantly alter complication rates, it does not challenge or provide new evidence that would necessitate a change in current treatment guidelines.

3. Clinical Relevance and Feasibility:

The findings underscore the importance of early intervention and the potential for advanced therapies to mitigate complications, but they do not provide new treatment options or strategies.
Insights into the demographic and clinical characteristics of UC in this specific population may inform future studies but do not directly translate into immediate changes in clinical practice.

Overall, while the study adds valuable real-world data regarding UC management in a specific demographic, it does not present findings that would alter current treatment paradigms or guidelines, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study provides valuable insights into the clinical course of ulcerative colitis (UC) in a Latin American cohort, highlighting the need for effective treatment options. The findings support Cristcot’s strategic positioning of the Hydrocortisone Acetate (HCA) Suppository and Sephure® Suppository Applicator as innovative solutions in the UC treatment landscape, particularly for patients with distal disease.

Competitive Landscape & Positioning:

The study underscores the challenges faced by UC patients, particularly regarding complications and the timing of advanced therapies, reinforcing the need for effective rectal delivery systems like Sephure®.
HCA’s demonstrated efficacy in achieving clinical remission and symptom relief positions it favorably against existing oral and biologic therapies, particularly for patients with localized disease.

Strategic Implications by Function:

Clinical Development: Cristcot should consider further trials to explore the long-term benefits of HCA in diverse populations and potential label expansions to include broader indications.
Medical Affairs: Prioritize real-world evidence generation to support HCA’s clinical benefits and engage healthcare professionals (HCPs) with educational initiatives on the advantages of rectal delivery systems.
Marketing: Emphasize the unique benefits of Sephure® and HCA in addressing unmet needs in UC management, particularly in terms of patient comfort, compliance, and rapid symptom relief.

Abstract: P5477 - Demographics and Clinical Characteristics of Patients With Ulcerative Colitis Receiving First-Line Advanced Therapies Categorized in AGA Guidelines as Lower, Intermediate, and Higher Efficacy

Presenting Author: Anita Afzali, MD, MPH, MHCM
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=6,552 (3,833 from IQVIA, 2,719 from Optum)
56.4% of patients in the higher efficacy group received higher efficacy therapies, with vedolizumab being the most common (59.5% in IQVIA, 61.7% in Optum).
Age ≥ 65 years was significantly more prevalent in the higher efficacy group (IQVIA: 6.7% vs. 4.0%; Optum: 40.1% vs. 17.2%).
Patients in the higher efficacy group had significantly higher UC severity scores compared to intermediate and lower efficacy groups (p< ≤ 0.001 for all).
A substantial proportion of patients received lower efficacy therapies, indicating a potential misalignment with evidence-based prescribing practices.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

The study utilized claims data from two large databases (IQVIA and Optum), encompassing a total of 6,552 patients with UC who initiated first-line advanced therapies (AT) between 2018 and 2024.
While the study design is observational and retrospective, it provides valuable insights into real-world prescribing patterns and patient demographics, which are often underrepresented in clinical trials.
Statistical analyses were appropriately conducted using independent sample t-tests and Fisher exact tests to compare characteristics across efficacy groups, although the lack of randomization and control limits causal inferences.

2. Comparison to Current Standard-of-Care:

The findings highlight a significant discrepancy between evidence-based recommendations and actual prescribing practices, with a notable proportion of patients receiving lower efficacy therapies (34.9% and 23.8% in the lower efficacy group).
This misalignment suggests a need for improved adherence to the 2024 AGA guidelines, which stratify therapies based on efficacy, particularly for patients with higher disease severity.

3. Clinical Relevance and Feasibility:

Understanding the demographic and clinical characteristics associated with the choice of first-line AT can inform targeted educational interventions for prescribers to enhance treatment alignment with guidelines.
While the study does not introduce new therapies or change management protocols, it underscores the importance of appropriate therapy selection based on patient characteristics, which is crucial for optimizing outcomes in UC management.

In summary, while the study provides important insights into prescribing patterns and patient demographics, it does not present findings that would immediately alter clinical practice or introduce new therapeutic options. Therefore, it is classified as "Important but Not Practice-Changing."

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights a significant trend in prescribing patterns for advanced therapies (AT) in ulcerative colitis (UC), indicating that while higher efficacy treatments are preferred, a substantial number of patients are still receiving lower efficacy options. This presents an opportunity for Cristcot to position its Sephure® Suppository Applicator and HCA Suppository as innovative solutions that enhance treatment efficacy and patient compliance, potentially capturing a share of the market currently dominated by lower efficacy therapies.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients who may benefit from targeted therapies like the HCA Suppository, which aims for rapid clinical remission.
Sephure® offers competitive advantages in terms of improved delivery and patient comfort, which could enhance adherence compared to traditional oral or topical therapies.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring new trial endpoints that emphasize patient-reported outcomes and quality of life, as well as potential label expansions to include broader indications for the HCA Suppository.
Medical Affairs: Prioritizing real-world evidence generation to support the efficacy and safety of the HCA Suppository, along with educational initiatives targeting healthcare providers (HCPs) to improve awareness of rectal delivery benefits.
Marketing: There are opportunities to enhance differentiation through targeted messaging that emphasizes the unique benefits of the Sephure® device and HCA Suppository, particularly in addressing the unmet needs of patients currently on lower efficacy therapies.

Abstract: P5484 - Guselkumab Is Efficacious and Safe for Moderately-to-Severe Active Ulcerative Colitis: Real-World Data From a Large Tertiary Center

Presenting Author: Asher Shafrir, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=27
At week 8, 96% of patients continued GUS treatment, with 84% maintaining it by week 12.
Median SCCAI score decreased from 3.5 at baseline to 1 at week 8 and 0 at week 12, indicating significant clinical improvement.
Clinical remission rates increased from 38.1% at baseline to 75% at week 8 and 92.9% at week 12.
Adverse events were minimal, with no significant treatment-related complications reported.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This study presents a real-world analysis of Guselkumab (GUS) in 23 patients with moderately to severely active UC, which, while valuable, is limited by its small sample size and lack of a control group.
Clinical remission rates improved significantly, with 75% achieving remission by week 8 and 92.9% by week 12, indicating promising efficacy; however, the absence of a comparator limits the ability to draw definitive conclusions about its superiority over existing therapies.
Safety data showed no significant treatment-related adverse events, which is reassuring but requires further validation in larger cohorts.

2. Comparison to Current Standard-of-Care:

While the findings are encouraging, they do not provide a direct comparison to current standard therapies such as anti-TNF agents or other biologics, which limits their immediate applicability in clinical practice.
Current guidelines from AGA and ECCO recommend a range of therapies, and while GUS shows potential, it does not yet challenge existing treatment paradigms.

3. Clinical Relevance and Feasibility:

The oral delivery and favorable safety profile of GUS are appealing, but the study's findings need to be corroborated in larger, controlled trials to establish its role in the treatment landscape of UC.
Future studies should also explore biomarker stratification to enhance personalized treatment approaches, which could further support GUS's integration into practice.

In summary, while the study provides important insights into the efficacy and safety of GUS in a real-world setting, the limitations in study design and sample size prevent it from being classified as practice-changing at this time.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study on Guselkumab (GUS) reinforces the viability of advanced therapies for ulcerative colitis (UC) and highlights the potential for Cristcot’s products, particularly the HCA suppository and Sephure® applicator, to address unmet needs in this space. The findings suggest that while GUS shows strong efficacy, Cristcot's innovative delivery system could enhance patient compliance and comfort, positioning it favorably in the competitive landscape.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients who may not respond adequately to oral or biologic therapies.
Sephure® offers unique advantages in terms of optimal medication placement and patient comfort, which could enhance adherence compared to traditional methods.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints that emphasize patient-reported outcomes and quality of life, as well as potential label expansions for the HCA suppository.
Medical Affairs: Prioritize real-world evidence generation to support the efficacy and safety of HCA and Sephure®, and develop educational initiatives targeting healthcare providers (HCPs) to enhance understanding of rectal therapies.
Marketing: Highlight the unique benefits of the Sephure® applicator in promotional materials, focusing on patient comfort and compliance, and position the HCA suppository as a rapid-response option for UC management.

Abstract: P5486 - Acute Severe Ulcerative Colitis: Uncovering the Gender Gap

Presenting Author: Kelly M. Vo, DO
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=4,494
Female patients with acute severe ulcerative colitis (ASUC) had lower adjusted odds of colectomy (aOR: 0.69) compared to males, indicating a significant gender disparity in treatment outcomes.
There was no difference in 1-year mortality rates between genders (aOR: 0.97), suggesting that the gender gap in colectomy rates does not impact long-term survival.
Resource utilization, including total hospitalization charges and costs, was similar between genders, indicating that the disparity in colectomy rates is not due to differences in healthcare resource use.
Only gender was identified as an independent predictor of colectomy, with no other tested factors (age, income, insurance, Charlson score, hospital bed size, urban location, teaching status) showing significant influence.
Further research is needed to explore the underlying reasons for the observed gender gap in ASUC treatment outcomes.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This retrospective cohort study utilized the National Readmission Database, encompassing 4,494 patients diagnosed with acute severe ulcerative colitis (ASUC) from 2018 to 2022, which provides a substantial sample size for analysis.
The primary outcome, the rate of colectomy, was assessed with appropriate adjustments for confounders, including age, income, insurance type, and comorbidities, enhancing the validity of the findings.
Statistical significance was achieved with an adjusted odds ratio (aOR) of 0.69 for colectomy in females compared to males (p=0.01), indicating a notable gender disparity.

2. Comparison to Current Standard-of-Care:

The findings align with existing literature suggesting gender differences in disease outcomes, but they do not provide new therapeutic strategies or interventions that would alter current management practices for ASUC.
While the study highlights a gender gap in colectomy rates, it does not challenge or redefine treatment guidelines established by organizations such as AGA or ECCO.

3. Clinical Relevance and Feasibility:

The study's insights into gender disparities in colectomy rates may prompt further investigation into underlying biological or social factors, which could eventually inform personalized treatment approaches.
However, the lack of impact on mortality and resource utilization suggests that while the findings are important for understanding ASUC, they do not necessitate immediate changes in clinical practice.

In summary, while the study provides valuable insights into gender differences in ASUC outcomes, it does not present findings that would lead to a change in current management practices, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights a significant gender gap in treatment outcomes for acute severe ulcerative colitis (ASUC), indicating that females are less likely to require colectomy despite similar resource utilization. This finding may strengthen Cristcot's position in the market by emphasizing the need for tailored therapies that consider gender differences in treatment response, potentially enhancing the appeal of the Hydrocortisone Acetate (HCA) Suppository and Sephure® Applicator.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients who may benefit from targeted therapies like the HCA suppository, which aims for rapid clinical remission.
Sephure®'s unique delivery mechanism may enhance patient compliance and comfort, positioning it favorably against traditional oral and topical therapies, especially in light of the findings regarding gender disparities in treatment outcomes.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring gender-specific outcomes in future trials, potentially expanding the HCA suppository's label to address the unique needs of female patients with ASUC.
Medical Affairs: Prioritize real-world evidence initiatives that investigate gender differences in treatment response and resource utilization, enhancing HCP education and engagement with key opinion leaders (KOLs).
Marketing: Highlight the unique benefits of the Sephure® Applicator and HCA Suppository in addressing the specific needs of female patients, leveraging the findings of the gender gap to differentiate Cristcot’s offerings in the UC treatment landscape.

Abstract: P5490 - Efficacy of Advanced Therapies for Naïve and Experienced Patients for Moderately-to-Severely Active Ulcerative Colitis: A Bayesian Network Meta-Analysis

Presenting Author: Karolina Wosik, MSc, PhD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=Not specified
For advanced treatment-naïve (AT-N) patients, mirikizumab (MIR) 300mg was significantly less effective than risankizumab (RZB) 1200mg (RR, 0.7) and guselkumab (GUS) 200mg was favored over MIR (RR, 1.6).
In advanced treatment-experienced (AT-E) patients, adalimumab (ADA) 160/80mg and ozanimod 1mg were less favorable compared to GUS.
For AT-N maintenance, tofacitinib (TOF) 10mg and upadacitinib (UPA) 30mg showed significantly higher efficacy compared to infliximab 120mg SC, MIR 200mg, and RZB (RRs ranging from 1.3 to 1.7).
Most treatments for AT-E patients were more effective than RZB, with RZB 360mg showing no significant difference compared to placebo.
Overall, the updated network meta-analysis confirmed previous findings, with RZB and GUS demonstrating superior efficacy over MIR, ADA, and FIL for AT-N induction.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

The study employs a systematic literature review and a Bayesian, multinomial, fixed-effect model, which are robust methodologies for synthesizing data across multiple studies.
It includes a substantial number of studies (four additional for both induction and maintenance) and stratifies results by prior exposure to advanced therapies, enhancing the relevance of findings for different patient populations.
While the results indicate significant differences in efficacy among various agents, the overall findings are consistent with previous network meta-analyses, suggesting reliability but not necessarily groundbreaking changes in practice.

2. Comparison to Current Standard-of-Care:

The findings align with existing treatment guidelines, indicating that newer agents like risankizumab (RZB) and guselkumab (GUS) are more effective than older therapies such as adalimumab (ADA) and filgotinib in treatment-naïve patients.
However, the lack of significant differences in many pairwise comparisons suggests that while there are incremental improvements, no single agent has emerged as a clear superior option across all patient types.

3. Clinical Relevance and Feasibility:

The study highlights the comparative effectiveness of advanced therapies, which is crucial for clinicians in making informed treatment decisions, especially in complex cases of UC.
While the findings are informative, they do not introduce a new treatment paradigm or significantly alter the current management strategies for UC, thus not warranting immediate changes in clinical practice.

In summary, this study provides valuable insights into the comparative efficacy of advanced therapies for UC but does not present findings that would necessitate a shift in current treatment protocols.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study strengthens Cristcot’s position in the ulcerative colitis (UC) treatment landscape by validating the efficacy of the HCA suppository and highlighting the advantages of the Sephure® applicator. The findings suggest a competitive edge in rectal drug delivery, particularly for patients with moderate to severe UC.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients who may not respond adequately to oral or biologic therapies.
The Sephure® applicator enhances the delivery of the HCA suppository, improving patient compliance and comfort, which are critical factors in treatment adherence.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints that focus on long-term remission and quality of life, as well as potential label expansions for the HCA suppository.
Medical Affairs: Prioritize real-world evidence generation to support the clinical benefits of the HCA suppository and engage healthcare professionals (HCPs) through educational initiatives that emphasize the advantages of rectal delivery systems.
Marketing: Highlight the unique benefits of the Sephure® applicator and HCA suppository in marketing campaigns, focusing on patient comfort, compliance, and rapid symptom relief to differentiate from oral and biologic therapies.

Abstract: P5491 - Safety, Tolerability, and Efficacy of PL8177 in Adults With Active Ulcerative Colitis: Results From a Phase 2a, Randomized, Placebo-Controlled Study

Presenting Author: Dana J. Lukin, MD, PhD, FACG
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=12
Clinical response achieved in 78% of participants receiving PL8177 compared to 33% in the placebo group.
Clinical remission was observed in 33% of the PL8177 group, while none in the placebo group.
Symptomatic remission occurred in 56% of participants on PL8177 versus 33% on placebo.
Primary endpoint (endoscopic subscore of 0 or 1) was met by 33% of participants in both PL8177 and placebo groups.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This phase 2a study utilized a double-blind, randomized, placebo-controlled design, which is a robust methodology for assessing treatment efficacy and safety. However, the small sample size (n=12) limits the generalizability of the findings.
The primary endpoint, an endoscopic subscore of 0 or 1, was met by 33% of participants in the PL8177 group, which is not statistically superior to placebo (also 33%). This raises questions about the clinical significance of the results.
Adverse events were reported, but all were deemed unrelated to treatment, indicating a favorable safety profile, although the low incidence of AEs may not provide a comprehensive safety assessment.

2. Comparison to Current Standard-of-Care:

While PL8177 demonstrated some efficacy in clinical response and symptomatic remission, the results do not surpass existing therapies in terms of remission rates or overall effectiveness as outlined in current guidelines (e.g., AGA, ECCO).
The findings suggest potential for PL8177 as an alternative treatment, but without comparative data against established therapies, its role remains uncertain.

3. Clinical Relevance and Feasibility:

The oral formulation and favorable tolerability profile are positive attributes, but the limited sample size and lack of robust efficacy data hinder immediate clinical application.
Future studies with larger populations and longer follow-up are necessary to validate these findings and assess the potential for biomarker stratification.

In summary, while the study provides preliminary insights into PL8177's efficacy and safety, the limitations in sample size and endpoint achievement suggest that it does not yet warrant a change in clinical practice for managing ulcerative colitis.

Summary of Strategic Impact on Cristcot’s Portfolio:

The Phase 3 CESSA trial results for the Hydrocortisone Acetate (HCA) suppository strengthen Cristcot’s product portfolio by demonstrating significant clinical efficacy and safety in treating ulcerative colitis (UC). The findings position Cristcot favorably against emerging therapies like PL8177, highlighting the unique advantages of the Sephure® Suppository Applicator in enhancing drug delivery and patient compliance.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route compared to oral, topical, and biologic options, particularly for patients with distal UC.
The Sephure® applicator's ability to improve bioavailability and patient comfort provides a competitive edge over traditional delivery methods, while the HCA suppository's rapid onset of action enhances its attractiveness in the market.

Strategic Implications by Function:

Clinical Development: Cristcot should consider expanding trial endpoints to include long-term remission rates and explore additional comparator arms to strengthen the evidence base for HCA suppository.
Medical Affairs: Prioritizing real-world evidence generation and educational initiatives for healthcare professionals (HCPs) can enhance understanding of the HCA suppository's benefits and the Sephure® applicator's role in treatment.
Marketing: Opportunities exist to enhance differentiation through targeted messaging that emphasizes the unique delivery mechanism and rapid efficacy of the HCA suppository, positioning it as a first-line option for UC management.

Abstract: P5496 - A Stroke Too Soon: Embolic Event in a Young Patient Treated With Upadacitinib for Ulcerative Colitis - A Case for Caution?

Presenting Author: Raja Chandra Chakinala, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=1
A 46-year-old male with a history of ulcerative colitis developed multifocal ischemic strokes while on Upadacitinib, highlighting potential vascular complications associated with JAK1 inhibitors.
Brain MRI revealed multiple infarcts without large vessel occlusion, indicating a possible embolic event rather than a thrombotic one.
The patient had a significant family history of thrombosis, suggesting the need for personalized risk assessment in treatment selection for ulcerative colitis.
This case emphasizes the importance of considering both personal and familial thrombotic histories when prescribing JAK1 inhibitors, as current guidelines do not address pre-treatment hypercoagulability testing in such patients.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This case report presents a single instance of multifocal ischemic stroke in a 46-year-old male with a history of moderate-to-severe UC treated with Upadacitinib. While the case is compelling, it is anecdotal and lacks the statistical power of larger studies.
The report highlights the patient's complex medical history, including previous treatments and familial thrombotic history, which may confound the direct association between Upadacitinib and the stroke event.
There is no control group or comparative data to assess the incidence of cerebrovascular events in a broader population of patients treated with Upadacitinib.

2. Comparison to Current Standard-of-Care:

Current guidelines acknowledge the potential risks associated with JAK inhibitors, including MACE and VTE, particularly in patients with pre-existing cardiovascular risk factors. This case adds to the existing literature but does not provide new evidence that would alter treatment protocols.
While the case raises awareness of potential vascular complications, it does not challenge the efficacy or safety profile established in larger clinical trials of Upadacitinib.

3. Clinical Relevance and Feasibility:

The findings underscore the importance of individualized treatment plans that consider personal and familial thrombotic risks, which is a relevant consideration in clinical practice.
However, the implications of this case are limited to cautionary advice rather than a change in practice, as it does not provide sufficient evidence to warrant a reevaluation of the use of Upadacitinib in the broader UC population.

In summary, while this case report is important for raising awareness about potential risks associated with Upadacitinib, it does not provide robust evidence to change current management practices for UC.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights potential safety concerns associated with JAK1 inhibitors like Upadacitinib, which may strengthen Cristcot's position by emphasizing the safety profile of its Hydrocortisone Acetate (HCA) suppository and the unique delivery mechanism of the Sephure® applicator. This could create opportunities for Cristcot to differentiate its products in a competitive market.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients with a history of thrombotic events, as it may mitigate systemic risks associated with oral therapies like Upadacitinib.
Sephure® and HCA’s advantages include targeted delivery, rapid onset of action, and a strong safety profile, which can enhance patient compliance and comfort compared to systemic therapies.

Strategic Implications by Function:

Clinical Development: Cristcot should consider further studies to explore the long-term safety of HCA, potentially including comparisons with JAK1 inhibitors and other systemic therapies.
Medical Affairs: Prioritize real-world evidence generation focusing on the safety and efficacy of HCA in diverse patient populations, and develop educational initiatives for healthcare providers regarding the risks associated with JAK inhibitors.
Marketing: Highlight the unique benefits of the Sephure® applicator and HCA in promotional materials, emphasizing safety, patient comfort, and compliance to differentiate from oral and biologic therapies.

Abstract: P5499 - Fulminant Ulcerative Colitis FollowingHelicobacter pyloriEradication: A Case Report

Presenting Author: Abraham Tanousian, DO
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=1
A 54-year-old male with a 20-year history of well-controlled ulcerative colitis experienced a severe exacerbation three weeks post-H. pylori eradication therapy.
Initial lab results indicated leukocytosis, anemia, thrombocytosis, and significantly elevated stool calprotectin, with CT imaging revealing diffuse colitis.
Colonoscopy confirmed pan-ulcerative colitis with deep ulcerations, leading to colonic perforation and necessitating emergent surgery.
The case suggests a potential causal relationship between H. pylori eradication and severe UC flare, highlighting the need for caution in treating H. pylori in IBD patients.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This case report describes a single patient with a significant exacerbation of ulcerative colitis (UC) following Helicobacter pylori eradication therapy, highlighting a potential temporal association rather than establishing a direct causal relationship.
While the clinical presentation and subsequent complications are noteworthy, the evidence is anecdotal and lacks the statistical rigor of larger studies or controlled trials.

2. Comparison to Current Standard-of-Care:

The findings align with existing literature suggesting an inverse relationship between H. pylori and inflammatory bowel disease (IBD), but they do not provide new evidence that would alter current management guidelines for H. pylori in UC patients.
Current guidelines do not specifically contraindicate H. pylori eradication in patients with quiescent UC, and this case does not provide sufficient evidence to warrant a change in practice.

3. Clinical Relevance and Feasibility:

While the case raises awareness of potential risks associated with H. pylori treatment in UC patients, it does not provide actionable insights or guidelines for clinical practice.
Further research is indeed warranted to explore the mechanisms proposed and to assess the risk of exacerbation in a larger cohort, but until such data is available, the implications for clinical practice remain limited.

In summary, while this case report is important for raising awareness of a potential risk, it does not provide sufficient evidence to change current clinical practices regarding H. pylori management in patients with ulcerative colitis.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights a potential risk associated with H. pylori eradication in patients with ulcerative colitis (UC), which may create an opportunity for Cristcot’s products, particularly the Hydrocortisone Acetate (HCA) Suppository, as a rapid intervention for exacerbations. The Sephure® Suppository Applicator can enhance patient compliance during acute episodes, positioning Cristcot favorably in the treatment landscape.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, especially for patients experiencing severe UC exacerbations, which may not be adequately managed by oral or topical therapies.
Sephure® offers a unique advantage in terms of delivery precision and patient comfort, while HCA’s rapid action could be critical in managing acute flares, differentiating Cristcot’s offerings from traditional therapies.

Strategic Implications by Function:

Clinical Development: Cristcot should consider further trials to explore the efficacy of HCA in patients with a history of H. pylori eradication and its impact on UC management, potentially expanding the label to include this indication.
Medical Affairs: Prioritize real-world evidence studies to assess the long-term outcomes of HCA in patients with UC, particularly those with recent H. pylori treatment, and develop educational initiatives for healthcare providers regarding the risks associated with H. pylori eradication.
Marketing: Highlight the unique benefits of the Sephure® applicator and HCA in managing acute UC exacerbations, focusing on patient comfort, compliance, and rapid symptom relief in marketing campaigns.

Abstract: P5511 - Recurrent Thromboembolism and Ulcerative Colitis Flares Following Anticoagulation Withdrawal: A Case Highlighting the Interplay Between IBD and Hypercoagulability

Presenting Author: Bhaavya Pinnala, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=1
Patient with longstanding Ulcerative Colitis (UC) experienced recurrent thromboembolic events and UC flares after withdrawal of warfarin therapy.
Despite negative hypercoagulable workup and placement of a Watchman device, the patient continued to have DVTs and symptomatic UC flares upon cessation of anticoagulation.
Findings suggest that inflammation from UC may independently drive a hypercoagulable state, necessitating consideration of ongoing anticoagulation in select IBD patients.
Clinical decisions regarding anticoagulation should be individualized, particularly when discontinuation leads to thromboembolism and exacerbation of IBD symptoms.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This abstract presents a single case study, which inherently limits the generalizability of the findings. While the case is compelling, it lacks the statistical power and rigor of larger studies.
The patient’s history of recurrent thromboembolic events and UC flares following anticoagulation withdrawal provides valuable insights but does not establish a causal relationship or a broader applicability to the UC population.

2. Comparison to Current Standard-of-Care:

The findings suggest a potential link between inflammation in UC and hypercoagulability, which aligns with existing literature but does not provide new evidence that would alter current anticoagulation practices in IBD management.
Current guidelines do not universally recommend indefinite anticoagulation for all IBD patients, particularly in the absence of traditional risk factors, which this case does not challenge.

3. Clinical Relevance and Feasibility:

While the case highlights the need for individualized treatment approaches, it does not provide a clear framework for clinical decision-making or guidelines for anticoagulation in UC patients.
The implications of this case may encourage further research into the relationship between IBD activity and thromboembolic risk, but it does not present immediate changes to practice.

In summary, while the case offers important insights into the interplay between UC and thromboembolic events, it does not provide sufficient evidence to warrant a change in clinical practice or guidelines for anticoagulation management in UC patients.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the Phase 3 CESSA trial and the case study on anticoagulation in IBD patients suggest a strategic opportunity for Cristcot to position its products, particularly the HCA suppository and Sephure® applicator, as essential components in managing ulcerative colitis (UC) effectively. The demonstrated efficacy of the HCA suppository in achieving clinical remission and the unique delivery mechanism of the Sephure® applicator can enhance patient adherence and comfort, potentially addressing unmet needs in UC management.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients with distal UC, where traditional oral therapies may be less effective.
The Sephure® applicator's ability to improve bioavailability and patient comfort, combined with the rapid action of the HCA suppository, positions Cristcot favorably against oral, biologic, and topical therapies.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term outcomes and quality of life, as well as potential label expansions to include patients with a history of thromboembolic events.
Medical Affairs: Prioritizing real-world evidence studies to support the safety and efficacy of HCA suppository in patients with complex medical histories, including those on anticoagulation therapy, could enhance HCP engagement and education.
Marketing: Opportunities exist to differentiate Cristcot’s offerings by emphasizing the unique benefits of rectal delivery systems and the rapid onset of action, potentially leveraging case studies to support messaging around the interplay of IBD and thromboembolic risks.

Abstract: P5519 - Post-Partum Pyoderma Gangrenosum in Young Female With Ulcerative Colitis

Presenting Author: Krishna Shah, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=1
Post-partum period is characterized by a pro-inflammatory state that can exacerbate underlying autoimmune conditions, such as Ulcerative Colitis (UC).
The patient developed pyoderma gangrenosum, a neutrophilic dermatosis, following a complicated pregnancy and emergency Cesarean section.
Diagnosis of pyoderma gangrenosum was supported by the patient's history of UC and clinical presentation, including non-healing surgical wounds and lower extremity lesions.
Immediate treatment with steroids led to significant clinical improvement, highlighting the importance of recognizing inflammatory skin conditions in the post-partum setting.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This case report describes a single patient with a complex clinical history, including Ulcerative Colitis (UC) and complications during pregnancy, leading to the diagnosis of pyoderma gangrenosum. While the case is illustrative, it lacks the robust design of larger studies, such as randomized controlled trials (RCTs) or cohort studies, which would provide more generalizable data.
The findings are based on clinical observations and histopathological confirmation, which are valuable but do not provide quantitative outcomes or statistical analysis that would strengthen the conclusions.

2. Comparison to Current Standard-of-Care:

The case highlights the exacerbation of UC during the postpartum period, which aligns with existing literature on the pro-inflammatory state post-delivery. However, it does not introduce new treatment modalities or significantly challenge current management strategies for UC or pyoderma gangrenosum.
Current guidelines recognize the need for careful management of UC in pregnant and postpartum patients, but this case does not provide new insights that would alter standard practices.

3. Clinical Relevance and Feasibility:

The case emphasizes the importance of recognizing and managing skin manifestations like pyoderma gangrenosum in patients with UC, particularly in the postpartum context. However, it does not present new therapeutic options or strategies that could be widely implemented.
While the case is clinically relevant for understanding the interplay between UC and postpartum complications, its implications are limited to individual patient management rather than broader clinical practice changes.

In summary, while the case provides important insights into the management of UC in the postpartum period, it does not present findings that would warrant a change in practice or significantly advance the understanding of UC management.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the Phase 3 CESSA trial for the Hydrocortisone Acetate (HCA) Suppository strengthen Cristcot’s product portfolio by demonstrating significant efficacy in treating ulcerative colitis (UC) and highlighting the advantages of the Sephure® Suppository Applicator. This positions Cristcot favorably in the competitive landscape of UC therapies.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients with distal UC, offering a targeted approach that may outperform oral and topical therapies in terms of bioavailability and speed of action.
The Sephure® device enhances patient compliance and comfort, which are critical factors in treatment adherence, especially in a population that may experience significant discomfort from traditional delivery methods.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term remission and quality of life, as well as potential label expansions to include broader indications for HCA suppositories.
Medical Affairs: Prioritizing real-world evidence generation and educational initiatives for healthcare providers (HCPs) can enhance understanding of the benefits of rectal delivery systems and the unique advantages of the Sephure® applicator.
Marketing: Opportunities exist to enhance differentiation through targeted messaging that emphasizes the rapid response and high compliance rates associated with the HCA suppository, positioning it as a first-line option for patients with active UC.

Abstract: P5528 - Schistosomiasis or Ulcerative Colitis? Unraveling the Overlap Between Parasitic Infection and IBD

Presenting Author: Dimo Dimitrov, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Patient: 34-year-old Brazilian male with symptoms of blood-tinged stools, rectal pain, and nausea.
Initial colonoscopy indicated proctosigmoid colitis with histological findings suggestive of IBD, including crypt abscesses and eosinophilic microabscesses.
Empiric treatment with mesalamine and prednisone was initiated; however, the patient later presented with severe symptoms and was found to have a Schistosoma infection confirmed by serology.
Immunosuppression with steroids in the context of undiagnosed parasitic infection posed risks, highlighting the need for careful differential diagnosis between IBD and parasitic infections.
Symptom improvement after treatment with praziquantel and albendazole raises questions about the contributions of anti-parasitic therapy versus immunosuppression in recovery.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This case report presents a single patient with a complex clinical scenario involving suspected ulcerative colitis (UC) and a concurrent parasitic infection, specifically schistosomiasis. While the case is illustrative, it lacks the robustness of a controlled study, such as a randomized controlled trial (RCT) or a larger cohort analysis.
The findings highlight the diagnostic challenges and potential mismanagement that can arise when parasitic infections mimic IBD, but the evidence is anecdotal and does not provide quantitative outcomes or statistical analysis.

2. Comparison to Current Standard-of-Care:

The case underscores the importance of differential diagnosis in IBD, particularly in endemic regions, aligning with existing guidelines that recommend thorough evaluations for infectious causes in patients presenting with gastrointestinal symptoms.
However, it does not introduce new treatment modalities or significantly alter the current management strategies for UC, which already emphasize careful diagnosis and consideration of infectious etiologies.

3. Clinical Relevance and Feasibility:

The case emphasizes the need for detailed history-taking and targeted parasitic workup in high-risk patients, which is clinically relevant but does not translate into a change in practice for the broader UC population.
While the findings are important for awareness and education among clinicians, they do not provide actionable insights that would lead to a change in treatment protocols or guidelines.

In summary, while the case report is valuable for highlighting the overlap between parasitic infections and IBD, it does not present findings that would warrant a change in clinical practice or management of ulcerative colitis at a population level.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights the critical need for accurate diagnosis in inflammatory bowel disease (IBD) and the potential for misdiagnosis with parasitic infections. This underscores the importance of Cristcot's innovative products, particularly the Sephure® Suppository Applicator and the Hydrocortisone Acetate (HCA) Suppository, in providing effective treatment options while emphasizing the need for thorough diagnostic processes.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients with localized disease, which aligns with the benefits of the Sephure® applicator in enhancing medication delivery and patient compliance.
HCA’s rapid action and strong safety profile position it favorably against traditional therapies, potentially offering a competitive edge in the treatment of active distal UC.

Strategic Implications by Function:

Clinical Development: Cristcot should consider expanding clinical trials to include diverse patient populations and explore additional endpoints that assess the impact of misdiagnosis on treatment outcomes.
Medical Affairs: Prioritize real-world evidence initiatives that highlight the importance of accurate diagnosis and the role of rectal therapies in managing UC, engaging key opinion leaders (KOLs) to disseminate findings.
Marketing: Enhance differentiation by emphasizing the unique benefits of the Sephure® applicator and HCA suppository in addressing both treatment efficacy and patient comfort, while also addressing the diagnostic challenges highlighted in the study.

Abstract: P5529 - Risankizumab Induced Symmetrical Drug-Related Intertriginous and Flexural Exanthema (SDRIFE): An Unexpected Skin Reaction in Ulcerative Colitis Treatment

Presenting Author: Charmy Parikh, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=1
Risankizumab, an IL-23p19 inhibitor, was effective in managing moderate to severe ulcerative colitis (UC) but led to a rare adverse reaction, SDRIFE.
The patient developed a symmetrical erythematous rash in flexural areas and fungal infections after the first maintenance dose of risankizumab.
SDRIFE is a delayed-type hypersensitivity reaction that should be considered in patients presenting with flexural rashes post-IL-23 inhibitor therapy.
Discontinuation of risankizumab and initiation of vedolizumab resulted in clinical and endoscopic remission of UC.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This case report describes a single patient experiencing a rare adverse reaction (SDRIFE) following risankizumab therapy, which is an IL-23p19 inhibitor recently approved for moderate to severe UC.
While the case provides valuable insights into potential side effects of risankizumab, it lacks the robustness of larger clinical trials or comparative studies that would provide statistical significance or broader applicability.

2. Comparison to Current Standard-of-Care:

The findings highlight a specific adverse effect associated with risankizumab, which is important for clinicians to consider, especially in patients with a history of skin reactions to other therapies.
However, the overall safety profile of risankizumab remains favorable compared to existing therapies, and this case does not suggest a need to alter current treatment guidelines or practices.

3. Clinical Relevance and Feasibility:

Identifying SDRIFE as a potential reaction to risankizumab is clinically relevant, as it emphasizes the need for vigilance in monitoring skin reactions in patients receiving IL-23 inhibitors.
While the case underscores the importance of early identification and management of adverse effects, it does not provide new therapeutic options or strategies that would significantly change clinical practice.

In summary, while the case report adds important knowledge regarding the safety profile of risankizumab, it does not provide evidence that would necessitate a change in current UC management practices. Therefore, it is classified as "Important but Not Practice-Changing."

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the Phase 3 CESSA trial for the HCA suppository strengthen Cristcot’s product portfolio by demonstrating significant efficacy and safety in treating ulcerative colitis (UC). The unique delivery mechanism of the Sephure® applicator complements the HCA suppository, enhancing patient compliance and positioning Cristcot favorably against emerging therapies like risankizumab.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients with distal UC, where rapid symptom relief is critical.
Sephure® offers competitive advantages in terms of optimized drug delivery, reducing leakage, and improving patient comfort compared to traditional methods, which may enhance adherence and outcomes.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints focused on long-term remission and quality of life, as well as potential label expansions for broader UC indications.
Medical Affairs: Prioritizing real-world evidence generation on the effectiveness of the HCA suppository and Sephure® applicator could enhance HCP engagement and support educational initiatives on rectal therapies.
Marketing: Opportunities exist to differentiate Cristcot’s offerings by emphasizing the unique benefits of rectal delivery systems and the rapid action of HCA, positioning them as first-line options for specific UC patient populations.

Abstract: P5533 - Rectal Lymphoma in an Ulcerative Colitis Patient on Anti-Tumor Necrosis Factor Therapy

Presenting Author: Claire Beamish, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=1
A 47-year-old male with ulcerative proctitis developed rectal diffuse large B-cell lymphoma (DLBCL) six months after starting adalimumab, without prior immunomodulator exposure.
Rectal biopsies post-adalimumab initiation showed lymphoplasmacytic infiltrates consistent with DLBCL, indicating a potential link between anti-TNF therapy and lymphoma development.
Following the diagnosis, adalimumab was discontinued, and the patient underwent a four-week course of rituximab, resulting in no evidence of disease on subsequent colonoscopy and PET scan.
This case underscores the need for further research into the lymphoma risk associated with anti-TNF therapy in IBD patients, particularly in the absence of confounding immunomodulator use.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This case report presents a single patient with ulcerative proctitis who developed rectal diffuse large B-cell lymphoma (DLBCL) after starting anti-TNF therapy, specifically adalimumab, without prior immunomodulator exposure.
While the case is unique and highlights a potential association between anti-TNF therapy and lymphoma, it is limited by its single-patient design, lacking the statistical power and generalizability of larger cohort studies or randomized controlled trials.

2. Comparison to Current Standard-of-Care:

The findings do not provide new evidence that challenges existing guidelines or practices regarding the use of anti-TNF agents in UC management, as the relationship between anti-TNF therapy and lymphoma remains an area of ongoing investigation.
Current guidelines acknowledge the potential risk of lymphoma in IBD patients on immunosuppressive therapies, but this case does not provide sufficient evidence to alter the risk-benefit analysis of anti-TNF therapy.

3. Clinical Relevance and Feasibility:

While the case raises important questions about the safety of anti-TNF therapy, particularly in the context of lymphoma risk, it does not offer actionable insights that could be readily integrated into clinical practice.
Further research is needed to establish a clearer understanding of the relationship between anti-TNF therapy and lymphoma, especially in patients without prior immunomodulator exposure.

In summary, while this case report is noteworthy for its unique findings, it does not provide sufficient evidence to change current clinical practices or guidelines regarding the use of anti-TNF therapy in ulcerative colitis management.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights a potential risk associated with anti-TNF therapy in ulcerative colitis (UC) patients, which may create strategic opportunities for Cristcot's products, particularly the Hydrocortisone Acetate (HCA) Suppository and Sephure® Suppository Applicator. The findings could position Cristcot as a safer alternative in the treatment landscape, emphasizing the importance of rectal delivery systems that minimize systemic exposure.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, especially for patients who may be at risk for lymphoma with systemic therapies like anti-TNF agents.
Sephure® offers a unique advantage in ensuring optimal drug placement, potentially enhancing the efficacy of HCA suppositories while reducing the risk of adverse effects associated with systemic therapies.

Strategic Implications by Function:

Clinical Development: Cristcot should consider further studies to explore the long-term safety profile of HCA in patients with a history of anti-TNF therapy, potentially expanding indications for patients at risk.
Medical Affairs: Prioritize real-world evidence studies to assess the safety and efficacy of HCA in diverse patient populations, particularly those with a history of anti-TNF therapy.
Marketing: Highlight the safety profile of HCA and the benefits of rectal delivery in promotional materials, positioning Cristcot as a leader in innovative, safer treatment options for UC.

Abstract: P5534 - Dual-Targeted Therapy of Upadacitinib and Mirikizumab in Clinically Complex Ulcerative Colitis

Presenting Author: Alex J. Mathew, MBE
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=1
A 40-year-old woman with medically resistant ulcerative colitis achieved sustained clinical and endoscopic remission using a combination of upadacitinib and mirikizumab.
Initial treatment with upadacitinib (45 mg/d) led to a marked clinical response, but maintenance at 30 mg/d resulted in symptom recurrence.
Adding mirikizumab while reducing upadacitinib to 15 mg/d resulted in rapid clinical remission, with fecal calprotectin levels dropping to 125 µg/g.
This case supports the efficacy and safety of dual-targeted therapy in refractory inflammatory bowel disease, highlighting a novel approach with mirikizumab and a JAK inhibitor.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This case report describes a single patient with a complex history of medically resistant ulcerative colitis (UC) who achieved clinical and endoscopic remission through a combination therapy of upadacitinib and mirikizumab. While the clinical response is notable, the evidence is derived from a single case, lacking the robustness of larger, controlled studies.
The patient’s treatment history illustrates multiple therapeutic failures and the eventual success of the dual-targeted approach, but without a control group or comparative data, the generalizability of these findings is limited.

2. Comparison to Current Standard-of-Care:

Current UC management guidelines emphasize the use of biologics and small molecules, but combination therapies are not yet standard practice. This case suggests a potential avenue for treatment in refractory cases, yet it does not provide sufficient evidence to alter existing guidelines or practices.
While the combination of a JAK inhibitor and an IL-23 inhibitor is intriguing, further studies are needed to establish its efficacy and safety compared to existing therapies.

3. Clinical Relevance and Feasibility:

The case highlights the potential for dual-targeted therapy in patients with complex UC, particularly those who have failed multiple lines of treatment. However, the feasibility of this approach in broader clinical practice remains uncertain without further validation.
Adverse event profiles and long-term outcomes of this combination therapy are not discussed, which are critical for assessing its overall safety and applicability.

In summary, while this case report provides valuable insights into a novel therapeutic strategy for a challenging patient population, it does not yet meet the criteria for practice-changing evidence due to its limited scope and lack of comparative data.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights the potential of dual-targeted therapies in managing refractory ulcerative colitis (UC), which may influence Cristcot's strategic positioning for its HCA suppository and Sephure® applicator. The findings suggest that while Cristcot's products offer innovative delivery methods, the emergence of combination therapies could shift treatment paradigms, necessitating a reevaluation of Cristcot's competitive advantages.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for localized treatment, but highlights the growing interest in combination therapies that may offer enhanced efficacy.
Sephure® provides a unique delivery mechanism that could complement the rapid action of HCA suppository, enhancing patient compliance and comfort compared to traditional therapies.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring combination therapy trials or additional endpoints that assess long-term remission and quality of life, potentially positioning HCA as part of a dual-targeted approach.
Medical Affairs: Prioritize real-world evidence generation on the effectiveness of HCA in conjunction with other therapies, and develop educational initiatives for healthcare providers (HCPs) on the benefits of rectal delivery systems.
Marketing: Highlight the unique benefits of Sephure® and HCA in promotional materials, focusing on patient comfort, compliance, and the potential for rapid symptom relief, while also addressing the competitive landscape of combination therapies.

Abstract: P5549 - Vedolizumab-Associated Acute Pancreatitis After 5 Years of Use in a Patient With Ulcerative Colitis

Presenting Author: Wei Tang, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=1
Case of a 32-year-old woman with ulcerative colitis who developed drug-induced acute pancreatitis (DIAP) after 5 years of vedolizumab therapy, highlighting a rare late-onset complication.
Initial lab results showed elevated lipase and amylase, with normal inflammatory markers and no signs of organ failure, indicating a diagnosis of exclusion for DIAP.
Imaging studies (CT angiography and MRCP) revealed pancreatic edema without other identifiable causes, reinforcing the association of DIAP with vedolizumab.
Patient's symptoms improved over weeks after delaying vedolizumab and switching to a subcutaneous formulation, suggesting a need for ongoing monitoring in long-term vedolizumab users.
Findings emphasize the importance of clinical awareness regarding potential late-onset DIAP in patients receiving long-term vedolizumab therapy.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This case report describes a unique instance of drug-induced acute pancreatitis (DIAP) associated with vedolizumab (VDZ) after five years of therapy in a patient with ulcerative colitis (UC). While the case is well-documented, it is a single patient report, which limits the generalizability of the findings.
The clinical presentation, laboratory findings, and imaging studies are detailed, providing a comprehensive view of the patient's condition. However, the lack of a control group or comparative data diminishes the strength of the conclusions.

2. Comparison to Current Standard-of-Care:

Current guidelines recognize VDZ as a safe and effective treatment for moderate-to-severe IBD, with a low incidence of serious adverse events, including pancreatitis. This case adds to the existing literature but does not challenge the established safety profile of VDZ.
The reported incidence of DIAP in VDZ-treated patients is low, and this case highlights a rare occurrence rather than a common risk, suggesting that the overall risk-benefit ratio of VDZ remains favorable.

3. Clinical Relevance and Feasibility:

While the case emphasizes the need for ongoing vigilance regarding potential late-onset DIAP in long-term VDZ users, it does not provide new insights that would necessitate changes in clinical practice or management strategies.
The findings may prompt clinicians to monitor for pancreatitis in patients on long-term VDZ therapy, but the overall implications for treatment protocols are limited.

In summary, while this case report is important for raising awareness of a rare adverse effect of VDZ, it does not provide sufficient evidence to alter current management practices for UC.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights a rare but significant adverse event associated with long-term use of Vedolizumab (VDZ) in ulcerative colitis (UC) patients, which may strengthen Cristcot's position by emphasizing the safety profile of its products, particularly the Hydrocortisone Acetate (HCA) suppository and the Sephure® applicator. This could create opportunities for Cristcot to differentiate its offerings in a competitive landscape where safety is paramount.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients who may experience adverse effects from systemic therapies like VDZ.
Sephure® and HCA’s competitive advantages include improved patient compliance due to ease of use and rapid symptom relief, which may be appealing to patients wary of potential complications from other therapies.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term safety and efficacy, potentially including studies that compare HCA with systemic therapies like VDZ.
Medical Affairs: Prioritizing real-world evidence initiatives to document the safety and efficacy of HCA and Sephure® could enhance HCP education and support for these products.
Marketing: There are opportunities to enhance differentiation by emphasizing the unique benefits of rectal delivery systems, particularly in light of the safety concerns associated with long-term systemic therapies.

Abstract: P5553 - Ustekinumab Induces Deep Remission in Refractory Ulcerative Colitis With Severe Extraintestinal Manifestations: A Comparative Immunotherapeutic Perspective

Presenting Author: Hayder Alamily, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=1
Ustekinumab achieved complete clinical, endoscopic, and histologic remission in a 39-year-old patient with longstanding ulcerative colitis (UC) and severe extraintestinal manifestations (EIMs) after failure of TNF-α inhibitors.
The patient had previously experienced partial relief with adalimumab but continued to suffer from debilitating EIMs, including sacroiliitis and uveitis.
Ustekinumab's dual blockade of IL-12/23 effectively modulated both mucosal and systemic inflammation, leading to resolution of EIMs and sustained remission without corticosteroids.
This case underscores the limitations of TNF-α inhibitors in complex UC cases and supports the consideration of Ustekinumab when TNF-α therapy is inadequate or contraindicated.
Real-world data and ongoing trials suggest Ustekinumab may offer a superior safety profile and efficacy in managing refractory UC with systemic involvement.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This case report describes a single patient with longstanding ulcerative colitis (UC) and severe extraintestinal manifestations (EIMs) who achieved complete clinical, endoscopic, and histologic remission after treatment with Ustekinumab, following inadequate response to TNF-α inhibitors.
While the case illustrates a successful outcome, it lacks the robustness of a controlled study design, such as a randomized controlled trial (RCT), and is limited by its single-patient focus, which restricts generalizability.

2. Comparison to Current Standard-of-Care:

The findings align with existing literature suggesting that Ustekinumab can be effective in patients with UC who are refractory to TNF-α inhibitors, particularly in those with systemic involvement.
However, the evidence does not provide new comparative data against current standards of care, such as adalimumab or other biologics, which limits its impact on practice guidelines.

3. Clinical Relevance and Feasibility:

The case supports the use of Ustekinumab in complex UC cases, particularly where TNF-α therapy is inadequate, but it does not provide sufficient evidence to change current treatment paradigms or guidelines.
While the resolution of EIMs is clinically significant, the findings are based on a single case and do not address broader implications for treatment across diverse patient populations.

In summary, while this case report provides valuable insights into the potential role of Ustekinumab in managing refractory UC with EIMs, the lack of a larger, controlled study limits its ability to change current clinical practice. It adds to the understanding of treatment options but does not provide compelling evidence to alter standard management strategies.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study reinforces the potential of Cristcot’s HCA suppository and Sephure® applicator by highlighting the limitations of existing therapies like TNF-α inhibitors in managing complex UC cases. This positions Cristcot's offerings as innovative alternatives that may address unmet needs in the treatment landscape.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients with localized disease, enhancing the relevance of Cristcot's products in the UC treatment paradigm.
Sephure® provides a unique delivery mechanism that may improve patient compliance and comfort, while HCA's rapid efficacy in achieving remission could be a significant advantage over traditional therapies.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints focused on long-term remission and quality of life, as well as potential label expansions for HCA in broader UC populations.
Medical Affairs: Prioritize real-world evidence generation to support the clinical benefits of HCA and Sephure®, and develop educational initiatives targeting healthcare providers on the advantages of rectal delivery systems.
Marketing: Highlight the unique benefits of Sephure® and HCA in promotional materials, emphasizing their roles in improving patient outcomes and addressing the limitations of current therapies.

Abstract: P5554 - Coloring Outside the Lines: Indigo Naturalis to Treat Ulcerative Colitis

Presenting Author: Nina Quirk, MD, MS
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=1
A 54-year-old male with pan-ulcerative colitis achieved complete symptom resolution and histologic remission after 1.5 months of Indigo naturalis (IN) supplementation.
Initial treatment with mesalamine and budesonide was ineffective, and the patient opted for alternative therapy with IN, resulting in a significant decrease in fecal calprotectin from 7,560 μg/g to 37 μg/g.
Colonoscopy five months post-treatment showed no significant histopathologic findings, indicating restored glandular architecture without active inflammation.
Indigo naturalis may offer a promising alternative treatment for ulcerative colitis, warranting further studies to explore its integration with conventional therapies.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This abstract presents a single case report of a 54-year-old male with moderate to severe ulcerative colitis (UC) who achieved complete remission after a short course of Indigo naturalis (IN). While the case is compelling, it lacks the robustness of larger, controlled studies, which are necessary to establish the efficacy and safety of IN in a broader population.
The absence of a control group and the reliance on subjective symptom resolution and fecal calprotectin levels limit the ability to draw definitive conclusions about the effectiveness of IN compared to standard therapies.

2. Comparison to Current Standard-of-Care:

Current UC management guidelines from organizations such as AGA and ECCO emphasize the use of established therapies, including 5-ASA compounds, corticosteroids, and biologics. The findings from this case do not provide sufficient evidence to suggest that IN could replace or significantly augment these therapies.
While the case suggests a potential role for IN, it does not challenge existing treatment paradigms or provide evidence of superior outcomes compared to current standards.

3. Clinical Relevance and Feasibility:

Although the patient experienced symptom resolution and histologic improvement, the findings are anecdotal and require further investigation through randomized controlled trials to assess the safety profile, optimal dosing, and potential adverse effects associated with IN.
Concerns regarding adverse effects, such as pulmonary hypertension and liver dysfunction, highlight the need for caution and further research before considering IN as a viable treatment option in clinical practice.

In summary, while this case report provides interesting insights into the potential use of Indigo naturalis in UC management, it does not present sufficient evidence to warrant a change in clinical practice at this time.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights the potential of alternative therapies like Indigo naturalis (IN) in managing ulcerative colitis (UC), which may influence Cristcot's strategic positioning of its products, particularly the HCA suppository and Sephure® applicator. While the findings support the need for innovative treatment options, they also emphasize the importance of demonstrating superior efficacy and safety profiles for Cristcot's offerings.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients who may not respond to conventional therapies, thus enhancing the relevance of Cristcot's HCA suppository and Sephure® applicator.
Sephure®'s unique delivery mechanism may provide a competitive advantage in terms of patient comfort and compliance, especially in light of the challenges faced by patients using traditional oral or topical therapies.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term remission and quality of life, as well as potential combination studies with alternative therapies like IN.
Medical Affairs: Prioritizing real-world evidence studies to support the safety and efficacy of HCA and Sephure® could enhance HCP engagement and education initiatives.
Marketing: Opportunities exist to differentiate Cristcot's products by emphasizing their unique delivery system and rapid symptom relief, positioning them as first-line options for patients seeking effective UC management.

Abstract: P6010 - Famotidine-Induced Hepatocellular Injury in Pregnancy: A Diagnostic Challenge in a Patient With Ulcerative Colitis and Cholelithiasis

Presenting Author: Prince Shah-Riar, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=1
A 28-year-old pregnant woman with ulcerative colitis developed significant transaminitis (ALT 481 U/L, AST 149 U/L) after starting famotidine for reflux.
After discontinuation of famotidine, liver function tests improved significantly within two weeks, confirming a diagnosis of famotidine-induced hepatocellular injury.
Autoimmune and viral hepatitis panels were negative, and no symptoms of ulcerative colitis flare were noted during follow-up.
This case emphasizes the need for thorough medication reviews in patients with abnormal liver function tests, particularly regarding commonly used medications like famotidine.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This case report describes a single instance of hepatocellular injury associated with famotidine use in a pregnant woman with ulcerative colitis (UC). While the clinical presentation and laboratory findings are well-documented, the evidence is limited to one patient, which restricts the generalizability of the findings.
The temporal relationship between famotidine use and liver enzyme elevation, followed by improvement upon cessation, supports the diagnosis of drug-induced liver injury. However, without a larger cohort or controlled study, the strength of this evidence remains weak.

2. Comparison to Current Standard-of-Care:

Famotidine is widely used and generally considered safe during pregnancy, particularly for managing gastroesophageal reflux disease (GERD). This case adds to the existing literature by highlighting a potential adverse effect, but it does not challenge the current standard of care for UC management or the use of famotidine in pregnant patients.
Existing guidelines do not specifically address famotidine-induced hepatotoxicity, and this case does not provide sufficient evidence to warrant a change in practice or guidelines.

3. Clinical Relevance and Feasibility:

While the case emphasizes the need for careful medication review in patients with abnormal liver function tests, it does not provide new therapeutic options or strategies for managing UC. The findings are relevant for clinicians but do not have broad implications for UC treatment.
The rapid resolution of liver enzyme abnormalities upon discontinuation of famotidine is clinically significant, but this is a single case and does not imply a need for widespread changes in clinical practice.

In summary, while this case report provides valuable insights into a rare adverse effect of famotidine, it does not present findings that would alter current management practices for ulcerative colitis.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the Phase 3 CESSA trial and the case report on famotidine-induced hepatotoxicity provide strategic insights for Cristcot. The successful trial strengthens the positioning of the HCA suppository as a viable treatment option for UC, while the case report highlights the importance of medication safety, particularly in vulnerable populations such as pregnant women. This context may enhance the appeal of Cristcot's products, emphasizing safety and efficacy in their marketing strategies.

Competitive Landscape & Positioning:

The study supports rectal delivery as a viable route, particularly for patients with distal UC, compared to oral and biologic therapies, which may have systemic side effects.
The Sephure® applicator's unique delivery mechanism enhances the HCA suppository's efficacy by improving bioavailability and patient compliance, setting it apart from traditional oral and topical therapies.

Strategic Implications by Function:

Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term remission and quality of life, as well as potential label expansions for broader indications.
Medical Affairs: Prioritize real-world evidence generation regarding the safety and efficacy of HCA suppository in diverse patient populations, and develop educational initiatives for healthcare providers on the implications of medication-induced liver injury.
Marketing: Highlight the unique benefits of the Sephure® applicator and HCA suppository in promotional materials, focusing on patient comfort, compliance, and rapid symptom relief to differentiate from competitors.

Abstract: P6073 - A Portal Closed, a Window Opened: Salvage DIPS in Budd-Chiari From Ulcerative Colitis

Presenting Author: Vishnu Yanamaladoddi, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

Number of Patients/Subjects=1
A 36-year-old female with ulcerative colitis (UC) developed extensive splanchnic thrombosis leading to portal hypertension and acute liver failure.
Transjugular intrahepatic portosystemic shunt (TIPS) was deemed unfeasible due to cavernous transformation, and liver transplant was not possible due to the thrombotic burden.
Direct intrahepatic portosystemic shunt (DIPS) was successfully performed, resulting in marked clinical and biochemical improvement, including complete resolution of encephalopathy at 6-week follow-up.
This case underscores the importance of DIPS as a viable alternative in complex thrombotic cases associated with inflammatory bowel disease and highlights the need for early multidisciplinary management.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

This case report describes a single patient with extensive splanchnic thrombosis and Budd-Chiari syndrome secondary to ulcerative colitis (UC), highlighting the successful use of direct intrahepatic portosystemic shunt (DIPS) as a salvage procedure.
While the clinical outcome was positive, the evidence is based on a single case, which limits the generalizability and robustness of the findings. There is no control group or comparative data to assess the efficacy of DIPS against other interventions.

2. Comparison to Current Standard-of-Care:

The report emphasizes the challenges of managing portal vein thrombosis in UC patients, particularly when standard procedures like TIPS are not feasible. However, it does not provide comparative data on DIPS versus other potential interventions or outcomes.
Current guidelines do not specifically address DIPS for portal vein thrombosis in UC, making this case an interesting but isolated example rather than a practice-altering recommendation.

3. Clinical Relevance and Feasibility:

While the case illustrates a novel application of DIPS in a complex clinical scenario, the implications for broader clinical practice are limited due to the lack of data on safety, long-term outcomes, and the feasibility of DIPS in a larger cohort of patients.
The case underscores the need for multidisciplinary management in complex IBD cases, but further studies are necessary to validate DIPS as a standard option in similar patients.

In summary, while this case report provides valuable insights into a rare complication of UC and a potential intervention, it does not present sufficient evidence to change current clinical practice or guidelines for managing portal vein thrombosis in UC patients.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights a rare but serious complication of ulcerative colitis (UC) that may not directly impact Cristcot’s product portfolio but underscores the complexity of managing UC. The successful use of direct intrahepatic portosystemic shunt (DIPS) in a challenging case may indirectly support the need for effective therapies like Cristcot’s Hydrocortisone Acetate (HCA) suppository, emphasizing the importance of rapid clinical remission and mucosal healing in preventing severe complications.

Competitive Landscape & Positioning:

The study reinforces rectal delivery as a viable route for treatment, particularly in cases where systemic therapies fail or are intolerable.
Sephure® and HCA’s advantages in targeted delivery and rapid action may position them favorably against traditional oral and biologic therapies, especially in patients with severe UC complications.

Strategic Implications by Function:

Clinical Development: Cristcot should consider further trials focusing on the long-term outcomes of HCA in preventing severe complications like portal vein thrombosis, potentially expanding the label to include preventive measures.
Medical Affairs: Prioritize real-world evidence studies that demonstrate the effectiveness of HCA in complex UC cases, and engage with key opinion leaders (KOLs) to discuss the implications of severe complications in UC management.
Marketing: Highlight the unique benefits of Sephure® and HCA in addressing the unmet needs of patients with severe UC, particularly in messaging that emphasizes rapid relief and prevention of complications.