Select Myelofibrosis Abstracts from EHA 2025

Prepared for

Abstract Number: S223

Presentation Title: PELABRESIB IN COMBINATION WITH RUXOLITINIB FOR JANUS KINASE INHIBITOR-NAIVE PATIENTS WITH MYELOFIBROSIS: 72-WEEK FOLLOW-UP WITH LONG-TERM EFFICACY OUTCOMES OF THE PHASE III MANIFEST-2 STUDY

Session: Innovative treatment approaches in MPN

Abstract Summary:

Number of Patients/Subjects=430
PELA+RUX demonstrated sustained improvements in splenic response, symptoms, SVR35/TSS50 dual response, bone marrow fibrosis, and anemia compared to PBO+RUX over 72 weeks.
Safety profile for Grade ≥3 treatment-emergent adverse events was similar across treatment arms, with Grade ≥3 anemia and thrombocytopenia more frequent in the PBO+RUX arm.
Survival outcomes showed a trend favoring PELA+RUX, with hazard ratios for progression-free survival, overall survival, and leukemia-free survival indicating potential benefits.
Overall findings suggest PELA+RUX provides meaningful clinical benefits over RUX alone, with evidence of ongoing disease modification and potential for improved survival in patients with myelofibrosis.

Summary of Study Impact on Navtemadlin (KRT-232):

The study of pelabresib (PELA) in combination with ruxolitinib (RUX) for JAK inhibitor-naive myelofibrosis patients does not directly compete with navtemadlin (KRT-232), which targets a different patient population (JAK inhibitor-refractory MF). However, it highlights the evolving treatment landscape and the potential for combination therapies in MF.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin, as it focuses on JAK inhibitor-naive patients, whereas navtemadlin is positioned for JAK inhibitor-refractory cases.
It reinforces the need for effective post-JAK inhibitor therapies, validating navtemadlin's role in this niche.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies with navtemadlin, similar to PELA+RUX, to enhance efficacy in JAK inhibitor-refractory patients.
Emphasizing navtemadlin's unique mechanism of action and efficacy in refractory cases could differentiate it from other treatments.

Medical Affairs Implications:

KOL engagement: Discuss the durability of response and management of cytopenias with navtemadlin, and its sequencing with JAK inhibitors.
Evidence gaps: Real-world data on navtemadlin's long-term outcomes and biomarker correlations would be valuable to clinicians.
Communication strategy: Highlight navtemadlin's efficacy in refractory MF and its potential as a single-agent therapy, contrasting with combination approaches in JAK inhibitor-naive settings.

Link to Abstract S223

Abstract Number: S218

Presentation Title: CLINICAL OUTCOMES IN PATIENTS WITH MYELOFIBROSIS TREATED WITH RUXOLITINIB AND ANEMIA SUPPORTING MEDICATIONS

Session: Assesment of risk and survival in MPN

Abstract Summary:

Number of Patients/Subjects=1384 with Hb<12, including 755 with Hb<10.
7.3% of patients initiated ESA or danazol within 3 months of enrollment, with 6.9% in the Hb<10 subset.
Spleen and symptom responses in patients receiving ESA/danazol with ruxolitinib were similar to the entire JUMP study population.
Mean hemoglobin levels increased steadily from a nadir at Week 4 to Week 48, with a 1.5% change from baseline in the Hb<12 cohort and 6.5% in the Hb<10 subset.
Ruxolitinib doses >25 mg daily were well tolerated, and most patients maintained hemoglobin levels within 1.0 g/dL of baseline, supporting the combination of ESA/danazol with ruxolitinib for anemia management in myelofibrosis.

Summary of Study Impact on Navtemadlin (KRT-232):

The study primarily focuses on the management of anemia in myelofibrosis patients treated with ruxolitinib and does not directly challenge or support navtemadlin’s positioning. However, it highlights the importance of managing anemia, a common issue in myelofibrosis, which could be relevant for navtemadlin’s clinical strategy.

Competitive Considerations:

The study does not introduce a new therapy that competes with navtemadlin but reinforces the role of supportive care in managing anemia alongside ruxolitinib.
It underscores the need for effective post-JAK inhibitor therapies, indirectly validating the potential role of navtemadlin in this space.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin’s efficacy in spleen volume and symptom score reduction, especially in JAK inhibitor-refractory settings.
Highlighting navtemadlin’s unique mechanism of action and its role in restoring p53 function could differentiate it from supportive care strategies.

Medical Affairs Implications:

KOL engagement: Discuss the potential of navtemadlin in addressing unmet needs in JAK inhibitor-refractory myelofibrosis, focusing on durability of response and combination strategies.
Evidence gaps: Real-world data on navtemadlin’s impact on anemia and its integration with existing therapies could be valuable.
Communication strategy: Emphasize navtemadlin’s efficacy in improving spleen volume and symptom scores, positioning it as a novel option in the treatment landscape.

Link to Abstract S218

Abstract Number: S219

Presentation Title: GENOMIC PROFILING FOR CLINICAL DECISION MAKING IN POST-POLYCYTHEMIA VERA AND POST-ESSENTIAL THROMBOCYTHEMIA MYELOFIBROSIS.

Session: Assesment of risk and survival in MPN

Abstract Summary:

Out of 644 secondary myelofibrosis (SMF) cases, 66.6% reported at least one myeloid neoplasm-associated gene variant (M-GV), with ASXL1 (29.7%) and TET2 (19.9%) being the most prevalent.
Median overall survival (OS) was significantly reduced in patients with at least two M-GVs, showing 7.2 years compared to 11.4 years for those with none or one M-GV (HR 1.71, p < 0.001).
Specific M-GVs such as ASXL1, EZH2, U2AF1, TP53, and SRSF2 were associated with significantly reduced median OS, with U2AF1 and SRSF2 showing the most pronounced impact.
Patients with a High-Risk genomic Profile 1 (HRP1), defined by having at least two M-GVs, had a significantly reduced 10-year blast phase-free survival (BP-FS) of approximately 75% compared to 90% for those with fewer M-GVs (p = 0.02).
Genomic profiling in SMF enhances risk stratification and clinical decision-making, identifying patients with poorer prognoses based on specific genetic mutations.

Summary of Study Impact on Navtemadlin (KRT-232):

The study primarily focuses on genomic profiling in secondary myelofibrosis (SMF) and its impact on risk stratification and prognosis. It does not directly challenge or support navtemadlin’s positioning but highlights the importance of genetic profiling in treatment decisions, which could indirectly influence navtemadlin’s application in personalized medicine.

Competitive Considerations:

The study does not introduce a new therapy that competes with navtemadlin but emphasizes the role of genetic profiling in treatment decisions, potentially validating navtemadlin’s role in a genetically informed therapeutic landscape.
It underscores the complexity of post-JAK inhibitor MF treatment, suggesting that therapies like navtemadlin could be positioned as part of a personalized treatment strategy based on genetic profiles.

Clinical or Market Strategy Implications:

Kartos may consider integrating genomic profiling into clinical trial designs to identify patient subgroups that could benefit most from navtemadlin, enhancing its market positioning.
Emphasizing navtemadlin’s efficacy in genetically defined subgroups could be a key differentiation lever, alongside its safety profile and potential disease-modifying effects.

Medical Affairs Implications:

KOL engagement: Discussions could focus on the integration of genomic profiling in treatment planning, the durability of navtemadlin’s response, and its sequencing with JAK inhibitors.
Evidence gaps: Real-world data on navtemadlin’s efficacy in genetically stratified populations and biomarker correlations would be valuable to clinicians.
Communication strategy: Narratives should highlight navtemadlin’s potential in personalized medicine, especially in patients with specific genetic profiles that indicate a poor prognosis.

Link to Abstract S219

Abstract Number: S220

Presentation Title: HEMATOLOGICAL IMPROVEMENT AND OTHER CLINICAL BENEFITS OF ELRITERCEPT AS MONOTHERAPY AND IN COMBINATION WITH RUXOLITINIB IN PARTICIPANTS WITH MYELOFIBROSIS (MF) FROM THE ONGOING PHASE 2 RESTORE TRIAL

Session: Innovative treatment approaches in MPN

Abstract Summary:

Elritercept, as monotherapy and in combination with ruxolitinib, was generally well-tolerated in participants with myelofibrosis, showing potential to treat multiple disease aspects.
52% of evaluable non-transfusion-dependent participants experienced a mean hemoglobin increase of ≥1.0g/dL over 12 weeks, with 21% achieving an increase of ≥1.5g/dL.
In transfusion-dependent participants, 39% achieved a 50% reduction in 12-week transfusion burden, and 24% achieved transfusion independence, with higher efficacy observed at doses ≥3mg/kg.
Spleen volume reduction of ≥10% was observed in 40% of participants, with 15% achieving a reduction of ≥35% by week 24; higher doses in combination therapy showed enhanced efficacy.
67% of participants experienced a reduction in total symptom score, with some achieving ≥50% improvement, indicating symptom relief potential.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on elritercept suggests potential competition for navtemadlin (KRT-232) in the treatment of myelofibrosis (MF), particularly in addressing anemia and cytopenias, which are significant concerns in MF management. However, navtemadlin's unique mechanism of action and demonstrated efficacy in JAK inhibitor-refractory MF may still position it favorably.

Competitive Considerations:

The study introduces elritercept as a potential competitor, especially in managing anemia and cytopenias in MF patients, which are not directly addressed by navtemadlin.
Elritercept's combination with ruxolitinib and its effects on anemia and spleen volume reduction could influence the post–JAK inhibitor MF treatment landscape, potentially offering a complementary or alternative approach to navtemadlin.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies with navtemadlin and other agents like elritercept to enhance efficacy, particularly in addressing cytopenias.
Emphasizing navtemadlin's efficacy in spleen volume reduction and symptom score improvement in JAK inhibitor-refractory MF could differentiate it from elritercept.

Medical Affairs Implications:

KOL engagement: Discussions could focus on the durability of response with navtemadlin, its role in sequencing with JAK inhibitors, and managing cytopenias.
Evidence gaps: Real-world data on navtemadlin's long-term efficacy and safety, as well as subgroup analyses, could be valuable to clinicians.
Communication strategy: Highlighting navtemadlin's unique mechanism and its efficacy in JAK inhibitor-refractory settings could strengthen its value proposition against other investigational agents.

Link to Abstract S220

Abstract Number: S221

Presentation Title: PRELIMINARY DATA FROM PHASE I/II STUDY OF NUVISERTIB, AN ORAL INVESTIGATIONAL SELECTIVE PIM1 INHIBITOR, SHOWED CLINICAL RESPONSE CORRELATING WITH CYTOKINE MODULATION IN PATIENTS WITH MYELOFIBROSIS

Session: Innovative treatment approaches in MPN

Abstract Summary:

Number of Patients/Subjects=77
Nuvisertib monotherapy was well tolerated with no dose-limiting toxicities (DLTs) observed.
Clinical activity included a ≥25% spleen volume reduction (SVR25) in 22.2% of patients and a ≥50% total symptom score reduction (TSS50) in 44.4% of patients treated with 720 mg BID for ≥12 weeks.
Symptom reduction strongly correlated with cytokine modulation, including decreased ENRAGE and MIP1β, and increased adiponectin (p<0.001).
Hematologic responses included a ≥1.0 g/dL hemoglobin increase in 24% of patients with baseline hemoglobin <10 g/dL and a ≥30×10⁹/L platelet increase in 26.7% of patients with baseline platelet count <100×10⁹/L.
43% of evaluable patients showed ≥1 grade reduction in bone marrow fibrosis, with most also showing SVR25, TSS50, hemoglobin, or platelet responses.
Data support further clinical development of nuvisertib in combination with JAK inhibitors ruxolitinib and momelotinib.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on nuvisertib presents a potential competitive challenge to navtemadlin (KRT-232) by introducing a novel mechanism of action through PIM1 inhibition, showing promising preliminary efficacy and safety in myelofibrosis (MF) patients. However, it also reinforces the need for alternative therapies in the post-JAK inhibitor setting, validating the therapeutic space navtemadlin targets.

Competitive Considerations:

The study introduces nuvisertib as a potential competitor, particularly due to its novel mechanism and preliminary efficacy in MF, which could challenge navtemadlin's positioning.
Nuvisertib's efficacy in reducing spleen volume and improving symptom scores, along with its safety profile, could influence the post-JAK inhibitor MF treatment landscape, highlighting the need for diverse therapeutic options.

Clinical or Market Strategy Implications:

Kartos may need to consider combination strategies or further differentiation of navtemadlin, possibly emphasizing its unique mechanism of restoring p53 function.
Emphasizing navtemadlin's efficacy in spleen volume reduction and symptom score improvement, as well as its role as a single agent, could be key differentiation levers.

Medical Affairs Implications:

KOL engagement: Discussions could focus on the durability of response, management of cytopenias, and sequencing strategies with JAK inhibitors.
Evidence gaps: Real-world data, subgroup analyses, and biomarker correlations could be valuable to clinicians, particularly in understanding patient selection and response predictors.
Communication strategy: Highlighting navtemadlin's unique mechanism and its efficacy in JAK inhibitor-refractory MF could strengthen its value proposition against emerging therapies like nuvisertib.

Link to Abstract S221

Abstract Number: S222

Presentation Title: ROPEGINTERFERON ALFA-2B FOR PRE-FIBROTIC PRIMARY MYELOFIBROSIS AND DIPSS LOW/INTERMEDIATE-RISK MYELOFIBROSIS

Session: Innovative treatment approaches in MPN

Abstract Summary:

Number of Patients/Subjects=71
Ropeginterferon alfa-2b demonstrated high response rates in hemoglobin (76.2%), white blood cell (79.4%), and platelet counts (100%) at Week 52.
Significant reductions in JAK2V617F and CALR variant allele frequencies were observed, with 44% and 43% reductions at Week 52, respectively.
Spleen size reduction was achieved in 53% of patients at Week 52, and a ≥50% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score was seen in 42.1% of patients.
Ropeg-IFN-α2b was well-tolerated, with common non-hematologic adverse events including transaminitis (49.2%) and malaise (42.2%), and no thrombohemorrhagic events or progression to blast-phase MF observed.
Ropeg-IFN-α2b induced clinical, hematologic, and molecular responses in pre-PMF and low/intermediate-1-risk MF patients.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on Ropeginterferon alfa-2b does not directly challenge navtemadlin’s positioning, as it targets a different patient population (pre-fibrotic and low/intermediate-risk MF) compared to navtemadlin’s focus on relapsed/refractory myelofibrosis post-JAK inhibitor failure. However, it highlights the evolving treatment landscape in myelofibrosis, emphasizing the need for diverse therapeutic strategies.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin, as Ropeg-IFN-α2b is aimed at earlier-stage MF patients.
It underscores the importance of developing treatments for various stages of MF, potentially validating navtemadlin’s role in later-stage, JAK inhibitor-refractory settings.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin’s efficacy in advanced MF settings and its potential in combination therapies, as explored in the POIESIS trial.
Highlighting navtemadlin’s unique mechanism of action and its efficacy in symptom and spleen volume reduction could differentiate it from other treatments.

Medical Affairs Implications:

KOL engagement: Focus on discussing navtemadlin’s role in advanced MF, particularly its efficacy post-JAK inhibitor failure and potential in combination therapies.
Evidence gaps: Real-world data on long-term outcomes and biomarker-driven responses could enhance navtemadlin’s clinical narrative.
Communication strategy: Emphasize navtemadlin’s efficacy in refractory MF and its potential as a combination therapy to strengthen its value proposition.

Abstract: S222

Title: ROPEGINTERFERON ALFA-2B FOR PRE-FIBROTIC PRIMARY MYELOFIBROSIS AND DIPSS LOW/INTERMEDIATE-RISK MYELOFIBROSIS

Type: Oral Presentation

Session title: Innovative treatment approaches in MPN

Background:
There is currently no consensus on the optimal treatment for primary myelofibrosis (PMF) in pre-/early fibrotic stage (pre-PMF) and DIPPS low/intermediate-1 risk MF. Ropeginterferon alfa 2b (Ropeg-IFN-α2b) is a next-generation monopegylated interferon alfa-2b developed specifically to treat myeloproliferative neoplasms (MPN).

Methods:
Key eligibility criteria included morphologically confirmed pre-PMF, and DIPSS low/intermediate-1 risk overt PMF, post-polycythemia vera MF (PPV-MF), and post-essential thrombocythemia MF (PET-MF) in patients requiring cytoreduction. The primary end-points were responses in hemoglobin (to between 10 g/dL and upper reference range), white blood cell (to < 10 x 10⁹/L) and platelet (to ≤ 400 x 10⁹/L) at 24 and 52 weeks. Secondary endpoints included safety (adverse events, AEs), reductions in variant allele frequencies (VAF) of driver and non-driver genes, spleen length by palpation, Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPNSAF-TSS), and bone marrow fibrosis. Patients received Ropeg-IFN-α2b at a dose of 250 mcg at Week 0, followed by 350 mcg at Week 2 and 500 mcg every 2 weeks from Week 4 onwards.

Results:
At the data cut-off of 30 June 2024, 71 patients (40 men and 31 women) with a median age of 60 (range: 31-86) years were enrolled. At a median follow up of 119 (10-131) weeks, responses in hemoglobin, white blood cell and platelet counts were 73.9%, 82.6% and 100% at Week 24; and 76.2%, 79.4% and 100% at Week 52, respectively. Reduction in JAK2V617F VAF was found in 16 of 47 evaluable patients (34%) at Week 24, and 20 of 41 evaluable patients (44%) at Week 52. Reduction in CALR VAF was found in 10 of 19 evaluable patients (53%) at Week 24, and 6 of 14 evaluable patients (43%) at Week 52. Reduction of spleen size was found in 9 of 19 patients (47%) at Week 24, and 9 of 17 patients (53%) at Week 52. Reduction in MPNSAF-TSS of ≥50% was found in 27 of 63 evaluable patients (42.9%) at Week 24, and 23 of 57 patients (42.1%) at Week 52. The most common non-hematologic AEs included transaminitis (grade 1-2, N=35, 49.2%); malaise (grade 1-2, N=29, 40.8%; grade 3-4, N=1, 1.4%), and hair loss (grade 1-2, N=24, 33.8%). The most common hematologic AEs were anemia (grade 1-2, N=15, 21.1%; grade 3-4, N=6, 8.5%), neutropenia (grade 1-2, N=15, 21.1%; grade 3-4, N=4, 5.6%) and thrombocytopenia (grade 1-2, N=8, 11.2%; grade 3-4, N=3, 4.2%). Thrombohemorrhagic events or progression to blast-phase MF was not observed during the study.

Summary/Conclusion:
Ropeg-IFN-α2b was well-tolerated and induced clinical, hematologic and molecular responses in patients with pre-PMF and low/intermediate-1-risk MF.

Keyword(s): Myeloproliferative disorder | Ropeg-Interferon | Myelofibrosis

Link to Abstract S222

Abstract Number: PF1306

Presentation Title: TRANSFUSION-RELATED COST AND TIME BURDEN OFFSETS IN PATIENTS WITH MYELOFIBROSIS TREATED WITH PACRITINIB COMPARED TO BEST AVAILABLE THERAPY BASED ON PERSIST-2 TRIAL

Session: Ethics and health economics

Abstract Summary:

Pacritinib (PAC) treatment resulted in a significant increase in transfusion independence (TI) among non-TI patients with myelofibrosis compared to best available therapy (BAT), achieving TI in 37% vs 7% of patients over a 24-week interval.
PAC led to a ≥50% reduction in transfusion burden in 49% of patients compared to 9% with BAT, with lower mean RBC transfusion rates (2.45 vs 3.54 per 30 days).
Annual transfusion-related costs with PAC were projected to be 19.5% lower than BAT, saving approximately $61K (~$252K vs ~$313K).
Annual transfusion-related time burden was reduced by 25.3% with PAC, saving approximately 172 hours (~508 hours vs ~680 hours) compared to BAT.
Cost and time savings with PAC were consistent regardless of the type of BAT used, including ruxolitinib or erythroid support therapies.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on pacritinib primarily addresses the economic and time burden of transfusions in myelofibrosis patients, focusing on anemia management. It does not directly challenge navtemadlin’s positioning, which targets spleen volume reduction and symptom score improvement in JAK inhibitor-refractory MF.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin, as it focuses on anemia and transfusion burden rather than spleen volume or symptom reduction.
Pacritinib’s benefits in anemia management may complement navtemadlin’s role, potentially positioning both drugs as part of a comprehensive treatment strategy post-JAK inhibitor failure.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies with pacritinib to address both anemia and spleen-related symptoms in MF patients.
Emphasizing navtemadlin’s efficacy in spleen volume and symptom score reduction could differentiate it from therapies focusing on anemia.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combination therapies that address both anemia and spleen-related symptoms, and the sequencing of navtemadlin with other treatments.
Evidence gaps: Real-world data on navtemadlin’s impact on anemia and transfusion needs could be valuable, as well as subgroup analyses on patients with concurrent anemia.
Communication strategy: Highlight navtemadlin’s unique benefits in spleen volume and symptom reduction, positioning it as a critical component of post-JAK inhibitor therapy.

Abstract: PF1306

Title: TRANSFUSION-RELATED COST AND TIME BURDEN OFFSETS IN PATIENTS WITH MYELOFIBROSIS TREATED WITH PACRITINIB COMPARED TO BEST AVAILABLE THERAPY BASED ON PERSIST-2 TRIAL

Type: Poster Presentation

Session title: Ethics and health economics

Background:
Anemia in patients with myelofibrosis (MF) is associated with a significant disease burden, especially in patients who require red blood cell (RBC) transfusions, as it negatively impacts quality of life and disease prognosis. In the PERSIST-2 trial, treatment with pacritinib (PAC), a JAK1 sparing inhibitor of JAK2/IRAK1/ACVR1, was associated with anemia benefit. A significant proportion of non-transfusion independent (non-TI) patients at baseline on PAC compared to best available treatment (BAT) achieved transfusion independence (TI) (37% vs 7%) in any 12 weeks over a 24-week interval and significantly more had a ≥50% reduction in transfusion burden (49% vs 9%) (Oh ST, et al. 2023) with lower RBC transfusion rates (Mean [2.45 vs 3.54/30-day]) (Data on file).

Aims:
This study aimed at estimating the projected differences in transfusion-related cost and time burden with PAC vs BAT.

Methods:
An economic evaluation based on transfusion-related data in patients treated with PAC or BAT (including ruxolitinib [RUX] and erythroid support [ES]) from the PERSIST-2 trial (NCT02055781). Transfusion status (TI and non-TI) at baseline and over any 12-week interval within the 24-week study period was defined based on the Gale criteria (i.e. presence or absence of RBC transfusions). RBC transfusion rates over 30-day periods, including all reported transfusions within the initial 24-week study period, were annualized and used as proxy for transfusion-related visits. Annual transfusion-related cost estimates by transfusion status were based on a previous MF burden of illness study which utilized IBM MarketScan data (Gerds AT, et al. 2022) and was adjusted to 2024 US dollars using the medical component of the Consumer Price Index. Transfusion-related time burden estimates were based on previously reported RBC transfusion visits in transfusion dependent patients with ϐ-thalassemia (Knoth RL, et al. 2022).

Results:
Annual transfusion-related cost with PAC was projected to be 19.5% lower, with a cost saving of ~$61K compared to BAT (~$252K vs ~$313K). Annual transfusion-related time burden with PAC vs BAT was lower by 25.3% with a time saving of ~172 hours (~508 hours vs ~680 hours). Among patients who were non-TI at baseline, projected annual cost and time savings for PAC vs BAT were ~$73K and ~204 hours, respectively. Results remained robust regardless of type of BAT (i.e. RUX or ES therapies).

Summary/Conclusion:
The reduction in transfusion rates associated with PAC treatment relative to BAT is projected to result in decreased transfusion-related medical cost and time burden for patients with MF and anemia.

Keyword(s): Transfusion | Myelofibrosis | Janus Kinase inhibitor

Link to Abstract PF1306

Abstract Number: PF1142

Presentation Title: DEVELOPMENT OF POLYMER-BASED NANOVECTORS FOR IN VIVO DELIVERY OF MRNA-THERAPEUTICS FOR PRIMARY MYELOFIBROSIS

Session: Gene therapy, cellular immunotherapy and vaccination - Biology & translational research

Abstract Summary:

Polymer-based nanovectors (NVs) using carboxyl-terminated low molecular weight polycaprolactone (cPCL) were developed for mRNA delivery in myelofibrosis treatment.
In vitro studies showed that these NVs, with diameters between 100 and 300 nm, did not induce cytotoxicity in hematopoietic stem/progenitor cells (HSC/HPC), with 15-18% uptake in GFP+ cells stable for 48 hours.
In vivo experiments in the Gata1^low mouse model demonstrated that 4% of blood cells were positive for NVs 3 hours post-injection, with distribution to the lung (6%), bone marrow (4%), and spleen (2%) after 24 hours, indicating favorable biocompatibility.
The NVs showed efficient interaction with HSC/HPC both in vitro and in vivo, suggesting their potential as a gene delivery system for myelofibrosis treatment.
Future studies will test NVs loaded with GATA1 mRNA, as gain-of-function of GATA1 has shown potential to rescue myelofibrosis in Gata1^low mice.

Summary of Study Impact on Navtemadlin (KRT-232):

The study introduces a novel mRNA delivery system for myelofibrosis, which does not directly compete with navtemadlin but represents a potential future therapeutic approach. It does not challenge navtemadlin’s current positioning but highlights the evolving landscape of myelofibrosis treatment.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin but suggests a novel therapeutic avenue that could complement or eventually compete with existing treatments.
It highlights the potential for mRNA-based therapies in the post–JAK inhibitor MF treatment landscape, which could diversify future treatment options.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies with emerging mRNA technologies or monitoring their development for potential partnerships.
Emphasizing navtemadlin’s current efficacy and safety profile in JAK inhibitor–refractory MF remains crucial, as mRNA therapies are still in early development stages.

Medical Affairs Implications:

KOL engagement: Discuss the durability of navtemadlin’s response and its role in sequencing with JAK inhibitors, while acknowledging emerging mRNA technologies.
Evidence gaps: Real-world data on navtemadlin’s long-term efficacy and safety, as well as biomarker correlations, would be valuable to clinicians.
Communication strategy: Highlight navtemadlin’s established efficacy in JAK inhibitor–refractory MF and its potential role in combination therapies.

Abstract: PF1142

Title: DEVELOPMENT OF POLYMER-BASED NANOVECTORS FOR IN VIVO DELIVERY OF MRNA-THERAPEUTICS FOR PRIMARY MYELOFIBROSIS

Type: Poster Presentation

Session title: Gene therapy, cellular immunotherapy and vaccination - Biology & translational research

Background:

Recently, messenger ribonucleic acid (mRNA)-based drugs have revealed their potential, accelerating scientific research to identify novel scientific and technological solutions that allow to expand the therapeutic targets that could be treated with mRNA-drugs. In this framework, mRNA technology relies on different nanoplatforms for intracellular delivery. The employment of nanotechnological solutions based on biocompatible and biodegradable polymers offer advantages in the generation of specific nanovectors (NVs) for mRNA protection and delivery. By properly modulating their physicochemical properties, polymer-based NVs exhibits unique cellular interactions that result in a fine control of cellular uptake and biodistribution (PMID: 36785927, 37919901, 26228769).

Aims:
Here, we adopted an innovative approach to formulate NVs-based delivery of mRNA for the in vivo delivery of mRNA-drugs for myelofibrosis, the most severe of the myeloproliferative neoplasms.

Methods:
Carboxyl-terminated low molecular weight polycaprolactone (cPCL) was precisely combined with polyplex in order to balance the cationic charge, thus resulting in stable. We evaluated the uptake and the biocompatibility in vitro and in vivo of the formulated red labelled-NVs in the Gata1^low mouse model of the disease. The transgenic mice harboured also the hCD34tTA/TET-O-H2BGFP reporter which labels the HSC/HPC compartments (PMDI: 24749072).

Results:
Preliminary results showed that in vitro culture of bone marrow cells, these polymer-based NVs, with a diameter comprised between 100 and 300 nm, do not induce HSC/HPC cytotoxicity. After 3 h upon treatment, ̴15-18% of the GFP+ cells in the culture showed consistent uptake of NVs, this percentage was stable until 48 h. Three-dimensional confocal microscopy observations indicated that the nanovectors had been internalized in GFP+ cells. To assess the role of the NVs in vivo, NVs were perfused in mice by intracardiac injection, followed by a boost after 24 h. After 3 h from the first injection, ̴ 4% of cells derived from the blood were strongly positive for NVs, in parallel, viability investigations revealed a favourable biocompatibility. After 24 h, nanoparticle positive cells were detected not only in the lung (~6%), but also in bone marrow (~ 4 %) and spleen (~2 %). In particular, they were present in ~ 4 % of the GFP+ bone marrow cells.

Summary/Conclusion:

In conclusion, the developed cPCL-based NVs for the delivery of mRNA revealed as safe and positively interacted with HSC/HPC both in vitro and in vivo experiments, suggesting that they are poised as an efficient in vivo gene delivery system for the treatment of myelofibrosis. Since preliminary genetic data indicate that gain-of-function of GATA1 rescues myelofibrosis in Gata1^low mice (PMID: 34707640), in the near future we will test NVs loaded with GATA1 mRNA on this myelofibrosis model.

Acknowledgements: TecnoMed Puglia; EU funding PNRR Projects n. CN00000041 CN3 RNA; LSH-TA PNC-E3-2022-23683269; Project “Biotecnologia, Bioinformatica e Sviluppo farmaceutico” POS 2014-2020, Tract 4, Azione 4.1- Cod. T4-AN-01; National Cancer Institute (P01-CA108671) and Associazione Italiana Ricerca Cancro (AIRC IG23525).

Keyword(s): Nanoparticle | Myelofibrosis

Link to Abstract PF1142

Abstract Number: PS2295

Presentation Title: ECONOMIC BURDEN OF CYTOPENIA IN PATIENTS WITH MYELOFIBROSIS: ANALYSIS OF A US NATIONAL ADMINISTRATIVE CLAIMS DATABASE

Session: Ethics and health economics

Abstract Summary:

Number of Patients/Subjects=1,532
70% of patients with myelofibrosis (MF) were cytopenic at diagnosis, and these patients were more likely to be older than 65 years and had a higher baseline Charlson comorbidity score compared to non-cytopenic patients (p<0.001).
All-cause healthcare resource utilization (HCRU) and costs were significantly higher for cytopenic MF patients compared to non-cytopenic patients during both baseline and follow-up periods, with a 53% higher total healthcare cost in the follow-up period ($12,826 vs $8,360 PPPM, p<0.001).
Cytopenic MF patients had a 72% higher number of MF-related ambulatory visits and a 200% higher number of MF-related hospitalizations compared to non-cytopenic patients, although they had 15% fewer pharmacy fills (p<0.001).
The study highlights the need for therapeutic options that effectively manage cytopenia to reduce the overall disease burden and optimize benefits for patients and the healthcare system.

Summary of Study Impact on Navtemadlin (KRT-232):

The study highlights the economic and healthcare resource burden of cytopenic myelofibrosis, emphasizing the need for effective treatments. While it does not directly challenge navtemadlin, it underscores the importance of addressing cytopenia in MF, which could influence navtemadlin's positioning if it demonstrates efficacy in this subgroup.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin but highlights a significant unmet need in cytopenic MF, potentially validating navtemadlin's role if it can address this need.
It emphasizes the broader post–JAK inhibitor MF treatment landscape's need for therapies that manage cytopenia, which could be a differentiating factor for navtemadlin.

Clinical or Market Strategy Implications:

Kartos may consider focusing on cytopenic MF in future trials or marketing strategies, highlighting navtemadlin's potential benefits in this subgroup.
Emphasizing navtemadlin's efficacy in reducing spleen volume and symptom scores, particularly in cytopenic patients, could be a key differentiation lever.

Medical Affairs Implications:

KOL engagement: Discuss the potential benefits of navtemadlin in managing cytopenia, durability of response, and sequencing with JAK inhibitors.
Evidence gaps: Real-world data on navtemadlin's impact on cytopenic MF, subgroup analyses, and biomarker correlations would be valuable.
Communication strategy: Highlight navtemadlin's unique value proposition in addressing both MF symptoms and cytopenia compared to other investigational agents.

Link to Abstract PS2295

Abstract Number: PS1813

Presentation Title: GLUTAMATE OVERLOAD IN THE MYELOFIBROSIS MICROENVIRONMENT RESHAPES MESENCHYMAL STROMAL CELLS' EPIGENETIC ARCHITECTURE TOWARD SENESCENCE.

Session: Myeloproliferative neoplasms - Biology & translational research

Abstract Summary:

Increased glutamate concentration in the sera of myelofibrosis patients was identified, impacting mesenchymal stromal cells (MSCs) by altering their metabolic and epigenetic profiles.
Glutamate treatment in healthy MSCs led to fumarate accumulation due to reduced fumarate dehydrogenase activity, resulting in increased reactive oxygen species production and DNA damage.
Fumarate accumulation promoted heterochromatin formation and cellular senescence, evidenced by increased β-Galactosidase activity and upregulation of senescence-associated secretory phenotype (SASP) genes.
Both glutamate and fumarate exposure enhanced collagen deposition in MSCs, contributing to the fibrotic microenvironment characteristic of primary myelofibrosis.
These findings suggest that glutamate overload in the myelofibrosis microenvironment drives inflammation, SASP activation, and fibrosis, shaping the pathological landscape of the disease.

Summary of Study Impact on Navtemadlin (KRT-232):

The study does not directly impact navtemadlin’s positioning as it focuses on the role of glutamate in the myelofibrosis microenvironment rather than on therapeutic interventions. However, it provides insights into the disease pathology that could inform future therapeutic strategies.

Competitive Considerations:

The study does not introduce a competing therapy but rather enhances understanding of the myelofibrosis microenvironment, which could indirectly validate the need for targeted therapies like navtemadlin.
It highlights the complexity of the post–JAK inhibitor MF treatment landscape, emphasizing the need for multifaceted approaches.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies that address both the tumor microenvironment and direct tumor cell inhibition.
Emphasizing navtemadlin’s efficacy in restoring p53 function could differentiate it from therapies targeting the microenvironment.

Medical Affairs Implications:

KOL engagement: Discuss the role of the microenvironment in MF and how navtemadlin’s mechanism complements this understanding.
Evidence gaps: Real-world data on navtemadlin’s impact on the microenvironment could be valuable.
Communication strategy: Highlight navtemadlin’s unique mechanism of action and its potential synergy with therapies targeting the microenvironment.

Abstract: PS1813

Title: GLUTAMATE OVERLOAD IN THE MYELOFIBROSIS MICROENVIRONMENT RESHAPES MESENCHYMAL STROMAL CELLS' EPIGENETIC ARCHITECTURE TOWARD SENESCENCE.

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Biology & translational research

Background:
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by defective hematopoiesis. The expansion of malignant clones is modulated by their interactions with the tumor microenvironment (TME), which is defined by extensive fibrosis and inflammation. Within TME, mesenchymal stromal cells (MSCs) are reprogrammed towards cellular senescence, defined to the senescence-associated secretory phenotype (SASP). It amplifies the inflammatory state within the PMF-TME, further enriched with metabolites which might contribute to the onset of MSC phenotype.

Aims:
The study aims to explore metabolomic alterations in MF-TME, with a particular focus on the impact of glutamate (Glu) on MSCs, as it was among the most upregulated metabolites in the sera of MF patients.

Methods:
We used HPLC approach to investigate the metabolomic profile of patients’ peripheral blood samples. We simulated Glu accumulation using an in vitro model of healthy MSCs. Furthermore, MSCs were also isolated from MF patients’ and compared to healthy controls. Mass spectrometry analysis was used to define the proteomic profile of MSCs following Glu supplementation. The MSC phenotype was characterized through metabolomic profiling, qPCR, flow cytometry, Western blot analysis, immunofluorescence assay, Azan-Mallory staining, and β-galactosidase activity assessment.

Results:
HPLC analysis revealed an increased Glu concentration in patients’ sera. Following Glu treatment in healthy MSCs, mass spectrometry analysis identified the TCA cycle as one of the most impacted pathways in the in vitro model, leading to intracellular fumarate accumulation. This was linked to reduced fumarate dehydrogenase activity. By supplementing either Glu or fumarate to healthy MSCs we detected an increased reactive oxygen species production, triggering DNA damage. Moreover, fumarate accumulation altered the epigenetic landscape of MSCs, promoting heterochromatin formation. These findings were confirmed in primary MSCs. Notably, supplementation with either Glu or fumarate induced cellular senescence, as evidenced by increased β-Galactosidase activity and upregulation of SASP-associated genes. Furthermore, both Glu and fumarate exposure enhanced collagen deposition in MSCs, highlighting their contribution to the fibrotic microenvironment characteristic of the PMF-TME.

Summary/Conclusion:
Glutamate buildup in PMF affects mesenchymal stromal cell metabolism, resulting in fumarate accumulation, oxidative stress, and cellular senescence. These alterations drive inflammation, SASP activation, and fibrosis, ultimately shaping the pathological microenvironment characteristic of PMF.

Keyword(s): Mesenchymal cells | Myelofibrosis | Epigenetic

Link to Abstract PS1813

Abstract Number: PS1809

Presentation Title: IDENTIFICATION AND VALIDATION OF A NOVEL FERROPTOSIS-RELATED GENE SIGNATURE FOR PREDICTION OF THE PROGNOSIS IN PRIMARY MYELOFIBROSIS : BASED ON SINGLE-CELL ANALYSIS AND MACHINE LEARNING

Session: Myeloproliferative neoplasms - Biology & translational research

Abstract Summary:

Five hub genes (NRAS, KRAS, PIK3CA, CHMP6, ELOVL5) were identified as key ferroptosis-related genes (FRGs) for predicting the progression risk of primary myelofibrosis (PMF).
A predictive model using these genes demonstrated high accuracy, with an area under the curve (AUC) of 1.000 in the training cohort and 0.872 in the validation cohort.
Single-cell RNA sequencing confirmed higher expression of these hub genes in PMF-sAML compared to stable PMF, and clinical samples showed upregulated mRNA levels in the PMF progressive group.
KEGG analysis linked these genes to pathways involved in longevity regulation and EGFR tyrosine kinase inhibitor resistance, suggesting potential therapeutic targets.
The study found a positive correlation between the hub genes and immune cell infiltrations, including monocytes, M0 and M2 macrophages, and T cell gamma delta.

Summary of Study Impact on Navtemadlin (KRT-232):

The study does not directly impact navtemadlin’s positioning as it focuses on a novel gene signature for predicting PMF progression rather than treatment efficacy. However, it highlights potential new therapeutic targets that could complement existing treatments like navtemadlin.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin but suggests new avenues for therapeutic development that could eventually complement or compete with existing treatments.
It emphasizes the need for novel approaches in the post-JAK inhibitor MF treatment landscape, potentially validating the importance of innovative therapies like navtemadlin.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies with agents targeting the identified ferroptosis-related genes to enhance treatment efficacy.
Emphasizing navtemadlin’s unique mechanism of action and its efficacy in JAK inhibitor-refractory MF could differentiate it from emerging therapies.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combining navtemadlin with therapies targeting ferroptosis-related pathways to improve outcomes.
Evidence gaps: Real-world data on navtemadlin’s long-term efficacy and safety, as well as its performance in combination therapies, would be valuable.
Communication strategy: Highlight navtemadlin’s role in addressing unmet needs in JAK inhibitor-refractory MF and its potential synergy with novel therapeutic targets.

Link to Abstract PS1809

Abstract Number: PS1808

Presentation Title: CLINICAL AND GENE EXPRESSION PATTERNS ASSOCIATED WITH DISEASE PROGRESSION IN PATIENTS WITH LOW-RISK MYELOFIBROSIS ENROLLED IN THE MYELOFIBROSIS AND ESSENTIAL THROMBOCYTHEMIA OBSERVATIONAL STUDY (MOST)

Session: Myeloproliferative neoplasms - Biology & translational research

Abstract Summary:

Number of Patients/Subjects=158
61% of patients with low-risk myelofibrosis progressed to intermediate-/high-risk over a median follow-up of ~54 months.
Baseline WBC >11×10⁹/L was significantly associated with increased progression risk (OR 2.60, P=0.019), remaining significant in multivariate analysis (OR 2.51, P=0.043).
RNA-seq identified 104 upregulated genes, including CD34 and MMP8, and 20 downregulated genes in patients with progression. G2M checkpoint and MYC pathways were significantly upregulated in these patients.
MYC pathway genes were upregulated independent of treatment status, suggesting potential mechanisms of treatment resistance. JAK/STAT signaling markers, IL6ST and IL2RA, were upregulated in all patients with progression.

Summary of Study Impact on Navtemadlin (KRT-232):

The study primarily focuses on identifying progression markers in low-risk myelofibrosis (MF) and does not directly impact navtemadlin’s positioning. However, it provides insights into disease progression that could inform future therapeutic strategies.

Competitive Considerations:

The study does not introduce a new therapy that competes with navtemadlin but highlights potential biomarkers and pathways involved in MF progression, which could be relevant for navtemadlin’s development.
It underscores the complexity of MF progression, potentially validating the need for novel treatments like navtemadlin in post-JAK inhibitor settings.

Clinical or Market Strategy Implications:

Kartos may consider integrating these progression markers into their clinical trial designs to better stratify patients and assess navtemadlin’s efficacy in specific subgroups.
Emphasizing navtemadlin’s efficacy in JAK inhibitor-refractory MF and its potential role in modifying disease progression could be key differentiation levers.

Medical Affairs Implications:

KOL engagement: Discuss the potential of navtemadlin in addressing progression pathways identified in the study, such as MYC and cell cycle genes.
Evidence gaps: Real-world data on navtemadlin’s impact on progression markers and its efficacy in different genetic backgrounds could be valuable.
Communication strategy: Highlight navtemadlin’s unique mechanism of action and its role in the treatment landscape for JAK inhibitor-refractory MF.

Link to Abstract PS1808

Abstract Number: PS1807

Presentation Title: TUMOUR NEUTROPHIL DYSFUNCTION IN PRIMARY MYELOFIBROSIS: MITOCHONDRIAL IMPAIRMENT, OXIDATIVE STRESS, AND REDUCED ASCORBIC ACID PRODUCTION SHAPE THE BONE MARROW MICROENVIRONMENT

Session: Myeloproliferative neoplasms - Biology & translational research

Abstract Summary:

PMNs in primary myelofibrosis (PMF) exhibit increased mitochondrial ROS production, elevated mitochondrial mass, and depolarized membranes, indicating significant metabolic dysfunction.
Hyperactivation of SYK and STAT5, along with increased NLRP3 expression, suggests sustained inflammasome activation and chronic oxidative/nitrosative stress in PMNs.
Metabolomic analysis shows severe depletion of antioxidants like ascorbic acid and glutathione, with increased malondialdehyde and nitrite/nitrate levels, exacerbating oxidative stress.
Conditioned media from PMNs enhances NETs formation and induces a pro-inflammatory phenotype in mesenchymal stromal cells (MSCs), increasing cytokine expression.
Ruxolitinib (RUXO) treatment reduces NETs formation and shifts MSCs toward an anti-inflammatory phenotype, indicating potential therapeutic benefits of targeting oxidative stress and metabolic dysfunction in PMF.

Summary of Study Impact on Navtemadlin (KRT-232):

The study primarily focuses on the pathophysiology of primary myelofibrosis (PMF) and the role of neutrophil dysfunction, rather than directly addressing navtemadlin (KRT-232). However, it indirectly supports the potential for combination therapies in PMF, which could include navtemadlin, by highlighting the benefits of targeting oxidative stress and metabolic dysfunction alongside JAK inhibitors like ruxolitinib.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin but suggests a complementary approach to treatment by addressing oxidative stress and metabolic dysfunction in PMF.
It reinforces the need for combination therapies in the post–JAK inhibitor MF treatment landscape, potentially validating navtemadlin's role in such strategies.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination trials of navtemadlin with antioxidants or other agents targeting metabolic dysfunction to enhance therapeutic outcomes.
Emphasizing navtemadlin's efficacy in combination with JAK inhibitors and its unique mechanism of restoring p53 function could differentiate it in the market.

Medical Affairs Implications:

KOL engagement: Discuss the potential for navtemadlin to be part of combination strategies that address both JAK pathway inhibition and oxidative stress management.
Evidence gaps: Real-world data on navtemadlin's efficacy in combination with other agents, and biomarker studies correlating oxidative stress markers with treatment response, would be valuable.
Communication strategy: Highlight navtemadlin's role in combination therapies and its potential to improve outcomes in JAK inhibitor-refractory MF patients.

Link to Abstract PS1807

Abstract Number: PS1794

Presentation Title: UNRAVELING THE MYELOFIBROTIC BONE MARROW NICHE: STROMAL AND IMMUNE INTERACTIONS AS POTENTIAL THERAPEUTIC TARGETS

Session: Myeloproliferative neoplasms - Biology & translational research

Abstract Summary:

SPP1+ macrophages, cDC2, and adipo-CAR cells showed the highest number of differentially upregulated genes in myelofibrosis (MF) compared to healthy controls, with significant increases in interferon response genes.
Adipo-CAR cells exhibited overexpression of Wnt-related genes and downregulation of adipogenesis, indicating altered differentiation in MF and significant up-regulation of ECM-related genes.
Megakaryocyte progenitors were identified as primary interaction partners of adipo-CAR cells, engaging in receptor-ligand interactions along the TGF-β-SMAD3 axis, confirmed by multiplex imaging.
Immunohistochemistry revealed increased TGF-β expression in collagen-expressing regions, particularly in clustered megakaryocytes and enlarged stromal cells, highlighting the importance of stromal interactions in MF.
The study identifies critical stromal and immunological components in MF, suggesting new avenues for stromal-targeted therapies to enhance current treatment strategies.

Summary of Study Impact on Navtemadlin (KRT-232):

The study does not directly challenge or support navtemadlin’s positioning but highlights potential new therapeutic targets in the myelofibrosis (MF) bone marrow niche, which could complement existing treatments like navtemadlin.

Competitive Considerations:

The study introduces potential new therapeutic targets (stromal and immune interactions) that could eventually lead to therapies complementing or competing with navtemadlin.
It suggests a broader understanding of MF pathophysiology, which could lead to novel treatment strategies post-JAK inhibitor failure, potentially affecting the landscape navtemadlin operates in.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies with stromal-targeted therapies to enhance navtemadlin’s efficacy.
Emphasizing navtemadlin’s unique mechanism of restoring p53 function could differentiate it from emerging stromal-targeted approaches.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combining navtemadlin with stromal-targeted therapies and the implications of stromal-immune interactions in MF.
Evidence gaps: Real-world data on navtemadlin’s long-term efficacy and safety, especially in combination with other therapies, would be valuable.
Communication strategy: Highlight navtemadlin’s role in addressing unmet needs in JAK inhibitor-refractory MF and its potential synergy with new therapeutic targets.

Abstract: PS1794

Title: UNRAVELING THE MYELOFIBROTIC BONE MARROW NICHE: STROMAL AND IMMUNE INTERACTIONS AS POTENTIAL THERAPEUTIC TARGETS

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Biology & translational research

Background:
MPNs are caused by mutually exclusive HSC driver mutations (CALR, JAK2, and MPL), which result in excessive myeloid cell production. A subset of MPN patients develops myelofibrosis (MF), which can occur primarily or consecutively to a pre-existing MPN. MF, which is associated with a poor prognosis, is defined by extracellular matrix fibers accumulation in the bone marrow and ultimately, resulting in the failure to produce blood cells. Allo-HSCT up to now remains the sole disease-modifying treatment. While MSCs (CAR cells) promote fibrosis in mouse models, their significance in human MF is uncertain. Current treatments focus on the malignant clones, but there is a lack of specialized anti-fibrotic methods, owing to inadequate evidence on stromal heterogeneity and reprogramming in MF.

Aims:
In this project, we aimed at elucidating the cellular complexity of the MF bone marrow niche with a focus on the regulation of the mutated hematopoietic stem cell by the immune cells and the non-hematopoietic stromal compartment.

Methods:
We employed scRNAseq to systematically define the reprogramming of the hematopoietic niche in MF. Specifically, we processed fresh trephine biopsies from healthy and MF individuals presenting with a high fibrosis grade (grade 2-3). We developed an isolation strategy to enrich for MF-driving hematopoietic stem cells, immune cells as well as mesenchymal stromal cells. Our dataset captured a total of 127,652 cells across all conditions (n=19 biopsies), spanning hematopoietic stem and progenitor cells, as well as the major immune and non-immune components of the human bone marrow niche.

Results:
SPP1+ macrophages, cDC2, and adipo-CAR cells were the three cell types exhibiting the highest number of differentially upregulated genes in MF relative to healthy controls. These cell types exhibited notable increase of interferon (IFN-ɑ and -Ɣ) response genes, with adipo-CAR cells demonstrating considerable overexpression of Wnt-related genes alongside downregulation of adipogenesis, which aligns with their altered differentiation in MF. Consequently, adipo-CAR cells represented the stromal fractions exhibiting the most pronounced up-regulation of ECM-related genes. Megakaryocyte progenitors were predicted to be the main interaction partners of adipo-CAR cells in the MF microenvironment, primarily engaging in receptor-ligand interactions along the TGF-β-SMAD3 axis. The physical interaction between megakaryocytes and activated stromal cells was confirmed using multiplex imaging (CODEX phenocycler), demonstrating the relevance of this MF-driving crosstalk in the MF niche. Immunohistochemistry further revealed that TGF-β expression was significantly increased in collagen-expressing regions, particularly in clustered megakaryocytes and interlaced, enlarged stromal cells. Lastly, genotyping of transcripts, along with the analysis of mitochondrial variations, revealed mutant-specific interactions with the hematopoietic niche in MF.

Summary/Conclusion:
Our research thus identifies critical stromal and immunological components in MF. We found (mutant-specific) niche interactions by combining single-cell and spatial analysis. This opens up new ways for stromal-targeted therapies to improve current treatments.

Keyword(s): Bone marrow fibrosis | Bone marrow niche

Link to Abstract PS1794

Abstract Number: PS1795

Presentation Title: SINGLE CELL MULTIOMIC ANALYSIS UNCOVERS MOLECULAR AND CLONAL EVENTS ASSOCIATED WITH RUXOLITINIB TREATMENT RESPONSE IN MYELOFIBROSIS

Session: Myeloproliferative neoplasms - Biology & translational research

Abstract Summary:

Number of Patients/Subjects=12
Ruxolitinib responders showed a reduction in circulating CD34+ cells, while non-responders had increased CD34+ and monocyte frequencies post-treatment.
Driver mutation variant allele frequency (VAF) decreased in granulocytes of responders, indicating effective treatment response.
Non-responders had prior epigenetic mutations (e.g., TET2, ASXL1) before acquiring the MPN driver mutation, leading to clonal expansion despite treatment.
Single-cell multiomic analysis revealed distinct clonal dynamics, with non-responders showing increased mutation burden in CD34+ HSPCs and CD14+ monocytes, whereas responders had an expansion of wild-type monocytes.

Summary of Study Impact on Navtemadlin (KRT-232):

The study provides insights into the molecular and clonal dynamics associated with ruxolitinib resistance in myelofibrosis, which indirectly supports navtemadlin’s positioning as a potential treatment option for JAK inhibitor-refractory MF. The findings highlight the complexity of MF treatment and the need for alternative therapies like navtemadlin.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin but rather underscores the limitations of current JAK inhibitors, reinforcing the need for alternative treatments.
It highlights the challenges in the post-JAK inhibitor MF treatment landscape, validating the role of navtemadlin as a promising option for patients who do not respond to ruxolitinib.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin’s efficacy in JAK inhibitor-refractory patients and explore combination strategies with ruxolitinib for suboptimal responders.
Focus on differentiation levers such as navtemadlin’s unique mechanism of restoring p53 function and its efficacy in reducing spleen volume and symptom scores.

Medical Affairs Implications:

KOL engagement: Discuss the durability of response and potential sequencing with JAK inhibitors, highlighting navtemadlin’s role in overcoming resistance.
Evidence gaps: Real-world data on navtemadlin’s efficacy in various subgroups and biomarker correlations would be valuable to clinicians.
Communication strategy: Emphasize navtemadlin’s efficacy in JAK inhibitor-refractory MF and its potential as a single-agent therapy, differentiating it from other investigational agents.

Abstract: PS1795

Title: SINGLE CELL MULTIOMIC ANALYSIS UNCOVERS MOLECULAR AND CLONAL EVENTS ASSOCIATED WITH RUXOLITINIB TREATMENT RESPONSE IN MYELOFIBROSIS

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Biology & translational research

Background:
Myelofibrosis (MF) originates from the acquisition of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs) that affect JAK2, MPL or CALR genes and induce the constitutive activation of JAK/STAT signaling. The JAK inhibitor Ruxolitinib (Ruxo) is effective in reducing splenomegaly and constitutional symptoms but is not able to completely eradicate the neoplastic clone in MF patients, indeed loss of response is observed due to disease progression and symptoms worsening.

Aims:
The aim of this study is to unveil molecular and cellular determinants of Ruxo resistance in MF patients.

Methods:
To describe clonal dynamics associated with Ruxo response we performed single cell (SC) genomics coupled with SC proteomics by means of Tapestri platform (Mission Bio) in 12 MF patients before and during Ruxo treatment. Circulating CD34+ HSPCs were isolated from cryopreserved peripheral blood mononuclear cells (MNC), mixed in a 1:1 ratio with MNCs and stained with Human Heme oncology cocktail including 42 oligonucleotide conjugated antibodies recognizing HSPCs and lineage markers (Biolegend). SC genomic library included a 299-amplicon custom panel covering 29 of the most frequently mutated genes in myeloid neoplasms.

Results:

Of the patients included in the study, 7 were classified as Ruxo responders and 5 as non-responders according to symptoms, splenic response and disease progression. We observed that the frequency of circulating CD34+ cells was higher in non-responder patients after treatment, while it was reduced in responders. Additionally, driver mutation variant allele frequency (VAF) decreased upon treatment only in granulocytes from responder patients. According to bulk genomic analysis all patients displayed a driver mutation together with at least one additional mutation in 8 patients, with the most frequently mutated genes being epigenetic remodelers (TET2 and ASXL1).
SC multiomic analysis defined mutation acquisition order and clonal architecture in immunophenotypically defined hematopoietic cell populations. CD34+ HSPCs were reduced in responder patients after Ruxo treatment while non-responders displayed increased monocytes frequency. As for non-responders, the acquisition of an MPN driver mutation was preceded by hits in epigenetic modifier genes (TET2 or ASXL1). In these patients, the malignant clone which dominated hematopoiesis before treatment further expanded during time in both CD34+ and CD34- cell compartments. On the contrary, in responder patients, driver mutation was the first molecular hit and non-mutated cells expanded over time, albeit differences in the clonal dynamics of CD34+ and CD34- cells were observed. In particular, because of JAK inhibition, the frequency of malignant cells with the highest number of mutations increased in non-responder patients in CD34+ HSPCs and even more dramatically in CD14+ monocytes. Conversely, in responder patients Ruxo was effective in eliminating cells displaying the driver mutation alone, and consequently an expansion of WT monocytes was observed.

Summary/Conclusion:
Our results demonstrate that circulating CD34+ cells are reduced after Ruxo treatment in responder patients. SC multiomic analysis revealed that epigenetic mutations occurring before driver hit compromise Ruxo efficacy in MF. Finally, clonal dynamics differ between CD34+ HSPCs and CD34- differentiated cells and highly mutated monocytes expand after treatment in non-responder patients.

The research leading to these results has received funding from the European Union – NextGenerationEU through the Italian Ministry of University and Research under PNRR − M4C2-I1.3 Project PE_00000019 “HEAL ITALIA” to Rossella Manfredini and Sebastiano Rontauroli (CUP E93C22001860006, University of Modena and Reggio Emilia, Modena, Italy). The views and opinions expressed are those of the authors only and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the European Commission can be held responsible for them.

Keyword(s): Myelofibrosis | Genomics | Ruxolitinib | Proteomics

Link to Abstract PS1795

Abstract Number: PS1797

Presentation Title: CHARACTERIZATION OF CD9 AS A NOVEL MARKER FOR DISEASE-PROPAGATING STEM CELLS IN MYELOFIBROSIS

Session: Myeloproliferative neoplasms - Biology & translational research

Abstract Summary:

Number of Patients/Subjects=48 MF patients and 25 healthy donors analyzed; RNA-seq performed on HSCs from 13 MF patients and 5 healthy donors; flow cytometry validation in 30 MF and 15 HDs; single-cell genomic/proteomic analysis in 8 MF patients.
CD9 identified as a surface marker selectively enriched on MF HSCs, confirmed by RNA-seq and flow cytometry; CD9+ HSCs showed higher frequency in MF versus healthy donors.
Single-cell analysis demonstrated enrichment of driver mutations (JAK2, CALR, MPL) within CD9+ HSCs compared with CD9- subpopulations.
In vitro, MF CD9+ HSCs retained CD34 expression during multilineage differentiation, indicating greater primitiveness and clonogenic potential than CD9- HSCs.
In vivo, NSGS mice transplanted with MF CD9+ HSCs exhibited superior engraftment across peripheral blood, bone marrow, and spleen compared to CD9- HSCs, supporting CD9 as a marker of disease-propagating stem cells in MF.

Summary of Study Impact on Navtemadlin (KRT-232):

The study does not directly impact navtemadlin’s positioning as it focuses on identifying CD9 as a marker for disease-propagating stem cells in myelofibrosis, rather than on therapeutic interventions. However, it provides insights into the biology of MF that could inform future therapeutic strategies, potentially complementing navtemadlin’s mechanism of action.

Competitive Considerations:

The study does not introduce a competing therapy but highlights a potential target for future therapeutic development, which could eventually complement or compete with navtemadlin.
It underscores the complexity of MF and the need for therapies that target disease-propagating cells, reinforcing the importance of navtemadlin’s role in the post–JAK inhibitor MF treatment landscape.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies that target both MDM2 and CD9+ stem cells to enhance treatment efficacy.
Emphasizing navtemadlin’s efficacy in reducing spleen volume and symptom scores could differentiate it from potential future therapies targeting CD9+ cells.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combining navtemadlin with therapies targeting CD9+ cells to address disease propagation and improve outcomes.
Evidence gaps: Investigate the role of CD9+ cells in treatment resistance and explore biomarkers that could predict response to navtemadlin.
Communication strategy: Highlight navtemadlin’s unique position as a single agent with significant efficacy in JAK inhibitor–refractory MF, while acknowledging ongoing research into disease-propagating cells.

Abstract: PS1797

Title: CHARACTERIZATION OF CD9 AS A NOVEL MARKER FOR DISEASE-PROPAGATING STEM CELLS IN MYELOFIBROSIS

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Biology & translational research

Background:
Myeloproliferative neoplasms are a group of clonal hematopoietic disorders among which myelofibrosis (MF) is the most aggressive, as it is characterized by severe bone marrow fibrosis and a median survival of 5 years from diagnosis. MF arises from the expansion of a single hematopoietic stem cell (HSC), which, following the acquisition of somatic driver mutation in JAK2, MPL or CALR genes, and later co-occuring additional mutations, acquires selective advantage over wild-type HSCs. Current therapies, including JAK inhibitors Ruxolitinib and Fedratinib, are unable to induce molecular remission and eliminate MF HSCs.

Aims:
To identify MF HSCs whose expansion gives rise to the neoplastic clone and characterize them in vitro and in vivo

Methods:
Peripheral blood samples from 48 MF patients, harboring either JAK2, CALR or MPL driver mutations, and 25 healthy donors (HD) were collected. HSCs from 13 MF patients and 5 HDs were analyzed by RNA-sequencing to identify new putative surface markers mainly expressed by MF HSCs. Data were then validated by multicolor flow cytometry on 30 MF patients and 15 HDs. To evaluate whether HSCs expressing CD9 were enriched for the malignant clone we performed single cell genomic analysis coupled with single cells proteomics in 8 MF patients using Tapestri platform (Mission Bio). To investigate whether CD9+ or CD9- HSCs derived from HDs and MF patients were functionally different, CD9+ and CD9- HSCs from MF patients and HDs were FACS sorted and characterized for their clonogenic potential and differentiation ability in vitro. Patient Derived-Xenograft (PDX) mice were established by transplanting CD9+ or CD9- HSCs in sub-lethally irradiated NSGS immunodeficient mice to test their repopulating ability and disease potential.

Results:
RNA-sequencing data performed on MF and HD HSCs evidenced increased expression of several surface receptors among which CD9 was selected for further validation. Increased frequency of CD9+ HSCs was confirmed by flow cytometry in MF patients. Additionally, single cell analysis demonstrated that MF HSC subpopulations positive for CD9 were enriched in cells harboring the driver mutation compared to their marker-negative counterparts. In vitro assays prove that, unlike HDs, FACS-purified HSCs from MF patients retained CD34 expression in a multilineage differentiation assay and displayed greater primitiveness compared to CD9- HSCs. Preliminary results show that NSGS mice transplanted with MF FACS-purified CD9+ HSCs proved higher engraftment compared to CD9- HSCs in different hematopoietic tissues, including peripheral blood, bone marrow and spleen.

Summary/Conclusion:
HSCs from MF patients, regardless of the driver mutation carried by the patients, are enriched in CD9+ cells which display increased in vitro clonogenic potential and superior ability to propagate the disease in vivo in immunodeficient mouse model, suggesting the possible role of CD9 as marker for disease-propagating stem cell in MF.

Keyword(s): Mouse model | Myeloproliferative disorder | Hematopoietic stem cell

Link to Abstract PS1797

Abstract Number: PS1819

Presentation Title: T CELL MATURATION SHIFT TOWARD A SENESCENT PROFILE AND ENHANCED INHIBITORY SIGNALING VIAREGULATORY T CELLS ARE ASSOCIATED WITH ADVANCED MYELOFIBROSIS

Session: Myeloproliferative neoplasms - Biology & translational research

Abstract Summary:

Increased frequency of Tγδ cells in MF patients compared to controls (p=0.0003), with a trend of increased CD8+ cells in advanced MF stages.
MF patients exhibit a shift in T cell maturation, with decreased immature (SCM, p=0.01; CM, p=0.02) and increased senescent (EMRA, p=0.0004) CD4+ cells, and similar trends in CD8+ cells (CM decrease, p=0.04; EMRA increase, p<0.0001).
Advanced MF correlates with increased Treg cells, particularly in cytopenic vs. proliferative MF (p=0.022), suggesting immune evasion mechanisms.
MF patients show decreased NKG2D expression in CD8+ cells (p<0.0001) and trends towards increased CTLA-4 and TIGIT expression in advanced stages, indicating a less activated T cell profile.
Findings suggest that T cell maturation and activation changes are linked to MF progression, highlighting potential therapeutic targets in the leukemic microenvironment.

Summary of Study Impact on Navtemadlin (KRT-232):

The study provides insights into the immune microenvironment of myelofibrosis (MF), particularly the role of T cells in disease progression. While it does not directly impact navtemadlin’s positioning, it highlights potential areas for combination therapies targeting immune modulation.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin but suggests potential for therapies targeting the immune microenvironment in MF.
It reinforces the complexity of post–JAK inhibitor MF treatment, indicating a need for multifaceted approaches.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies with immune-modulating agents to enhance navtemadlin’s efficacy.
Emphasizing navtemadlin’s unique mechanism of restoring p53 function could differentiate it from potential immune-targeting therapies.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combining navtemadlin with immune-modulating therapies and the implications of T cell senescence in MF.
Evidence gaps: Real-world data on navtemadlin’s impact on immune profiles and its combination with other agents could be valuable.
Communication strategy: Highlight navtemadlin’s role in addressing unmet needs in JAK inhibitor-refractory MF and its potential in combination regimens.

Link to Abstract PS1819

Abstract Number: PS1805

Presentation Title: INCB057643, A BROMODOMAIN AND EXTRA-TERMINAL PROTEIN INHIBITOR, HAS NOVEL ROLES IN MYELOID CELL REGULATION AND IMMUNOSUPPRESSIVE TUMOUR ENVIRONMENT REMODELLING IN MYELOFIBROSIS

Session: Myeloproliferative neoplasms - Biology & translational research

Abstract Summary:

INCB057643 inhibited pathogenic megakaryopoiesis by reducing megakaryocyte differentiation and proinflammatory cytokine levels, including IL-8 and ENA-78, with ENA-78 production specific to mutant cells.
RNAseq of clinical samples demonstrated dose-dependent effects of INCB057643 on gene expression, particularly affecting epigenetic genes and those involved in platelet biogenesis.
INCB057643 selectively inhibited myeloid cells by downregulating immunosuppressive receptors and proinflammatory cytokines, leading to tumour microenvironment remodelling and reduced inflammation.
DGE analysis showed decreased expression of functional and immunosuppressive protumourigenic genes in myeloid cells, while T- or B-cell gene expression was unchanged or elevated.
INCB057643 reduced hallmark MYC target signatures, aligning with its potential to mitigate MPN progression by modulating MYC expression.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on INCB057643 does not directly challenge navtemadlin’s positioning but highlights a different therapeutic approach in myelofibrosis (MF) by targeting epigenetic regulation and the tumor microenvironment. Navtemadlin’s role in restoring p53 function remains distinct, focusing on TP53 wild-type malignancies.

Competitive Considerations:

The study introduces a potential complementary therapy rather than direct competition, as INCB057643 targets BET proteins and the tumor microenvironment, while navtemadlin focuses on MDM2 inhibition and p53 restoration.
It broadens the post–JAK inhibitor MF treatment landscape by offering a novel mechanism of action, potentially used in combination with other therapies like navtemadlin.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies with BET inhibitors like INCB057643 to enhance therapeutic outcomes in MF.
Emphasizing navtemadlin’s unique mechanism of action and efficacy in JAK inhibitor-refractory MF could differentiate it from other emerging therapies.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combination therapies and the distinct mechanisms of action between navtemadlin and BET inhibitors.
Evidence gaps: Real-world data on navtemadlin’s long-term efficacy and safety, as well as biomarker-driven patient selection, would be valuable.
Communication strategy: Highlight navtemadlin’s efficacy in spleen volume and symptom score reduction, positioning it as a key player in the post–JAK inhibitor setting.

Link to Abstract PS1805

Abstract Number: PF824

Presentation Title: MECHANISMS OF FIBROCYTE INDUCTION IN LYMPHOID MALIGNANCIES: THE ROLE OF CCL22 AND TIMP-1 IN SECONDARY MYELOFIBROSIS

Session: Myeloproliferative neoplasms - Biology & translational research

Abstract Summary:

IM-9 cell line supernatant significantly enhanced fibrocyte differentiation compared to other cell lines, indicating its potential role in secondary myelofibrosis (MF) induction.
RNA sequencing and assays revealed that IM-9 had higher expression and secretion of CCL22 and TIMP-1, which were also elevated in serum from lymphoid malignancy patients with secondary MF.
Higher MF grade (MF-2) correlated with reduced hemoglobin levels and increased serum CCL22 and TIMP-1, suggesting these factors' involvement in disease severity.
Neutralizing antibodies against CCL22 and TIMP-1 significantly reduced fibrocyte induction by IM-9, indicating their partial role in fibrocyte differentiation, though complete inhibition was not achieved.
Targeting CCL22 and TIMP-1 may offer a potential therapeutic strategy for managing secondary MF in lymphoid malignancies, with the CCL22-CCR4 pathway being a possible target.

Summary of Study Impact on Navtemadlin (KRT-232):

The study does not directly impact navtemadlin’s positioning as it focuses on secondary myelofibrosis (MF) in lymphoid malignancies, whereas navtemadlin targets relapsed/refractory MF post-JAK inhibitor failure. However, it highlights potential new therapeutic targets (CCL22 and TIMP-1) that could complement navtemadlin’s mechanism.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin but suggests alternative pathways (CCL22 and TIMP-1) that could be explored for combination therapies.
It broadens the understanding of MF pathogenesis, potentially influencing the post-JAK inhibitor MF treatment landscape by identifying new targets.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies with agents targeting CCL22 and TIMP-1 to enhance efficacy in MF treatment.
Emphasizing navtemadlin’s unique mechanism of restoring p53 function and its efficacy in JAK inhibitor-refractory MF could differentiate it from emerging therapies targeting different pathways.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combination therapies and the role of navtemadlin in the broader MF treatment paradigm, including its efficacy and safety profile.
Evidence gaps: Real-world data on navtemadlin’s long-term efficacy and safety, as well as its performance in various MF subtypes, would be valuable.
Communication strategy: Highlight navtemadlin’s role as a first-in-class MDM2 inhibitor with significant efficacy in JAK inhibitor-refractory MF, while acknowledging the potential of new targets like CCL22 and TIMP-1 for future combination strategies.

Link to Abstract PF824

Abstract Number: PF819

Presentation Title: JAK2 V617F VAF AND PRESENCE OF COPY NEUTRAL-LOH AT CHROMOSOME 9P (CHR9P) PREDICTS TRANSFORMATION TO MYELOFIBROSIS (MF) IN PATIENTS WITH POLYCYTHEMIA VERA (PV) ENROLLED IN REVEAL

Session: Myeloproliferative neoplasms - Biology & translational research

Abstract Summary:

JAK2 V617F variant allele frequency (VAF) at enrollment is predictive of transformation to myelofibrosis (MF) in patients with polycythemia vera (PV) (P=0.014).
Copy neutral loss of heterozygosity (CN-LOH) at chromosome 9p is significantly associated with JAK2 V617F VAF and is predictive of transformation to MF (P=0.034).
A JAK2 V617F VAF threshold of ≥0.75 provides the highest positive predictive value and area under the curve for predicting transformation.
CN-LOH or a copy number gain at chr9p is 100% predictive of a VAF >0.5, but the reverse is not necessarily true.
Copy number gain at chr9p is associated with the absence of transformation (P=0.045), suggesting different underlying mechanisms in MPN transformation.

Summary of Study Impact on Navtemadlin (KRT-232):

The study does not directly impact navtemadlin’s positioning as it focuses on predictive markers for transformation to myelofibrosis in polycythemia vera patients, rather than treatment efficacy or safety in myelofibrosis.

Competitive Considerations:

The study does not introduce a competing therapy to navtemadlin but provides insights into disease progression markers, which could indirectly affect treatment strategies.
It highlights the importance of genomic markers in understanding disease progression, which could influence the broader post–JAK inhibitor MF treatment landscape by emphasizing personalized medicine approaches.

Clinical or Market Strategy Implications:

Kartos may consider integrating genomic markers like JAK2 V617F VAF and CN-LOH into clinical trial designs to better stratify patients and potentially enhance treatment outcomes.
Emphasizing navtemadlin’s efficacy in JAK inhibitor–refractory MF and its potential role in combination therapies could be key differentiation levers.

Medical Affairs Implications:

KOL engagement: Discuss the role of genomic markers in treatment sequencing and the potential for navtemadlin to be part of a personalized treatment approach.
Evidence gaps: Real-world data on navtemadlin’s efficacy in patients with specific genomic profiles could be valuable.
Communication strategy: Highlight navtemadlin’s unique mechanism of action and its efficacy in refractory settings, positioning it as a critical option in the treatment landscape.

Link to Abstract PF819

Abstract Number: PF816

Presentation Title: IMMUNE-MEGAKARYOCYTES ARE RESPONSIBLE FOR THE PATHOLOGICAL INTERLEUKIN-8 DEPENDENT EMPERIPOLESIS WITH NEUTROPHILS ASSOCIATED WITH MYELOFIBROSIS IN GATA1LOW MICE

Session: Myeloproliferative neoplasms - Biology & translational research

Abstract Summary:

In the myelofibrosis Gata1^low mouse model, megakaryocytes (MK) are enriched for an immune subpopulation responsible for CXCL1-dependent pathological emperipolesis, leading to MK death and pro-inflammatory cytokine release.
Four types of MK-neutrophil interactions were observed, with Type 3 interactions (long, slow emperipolesis leading to MK death) predominantly occurring in Gata1^low cultures, especially in the 37-48 hour time window.
Type 3 interactions were significantly reduced in Gata1^low cultures treated with Reparixin, indicating these interactions are supported by CXCL1 released by malignant MK.
RNAseq of Gata1^low MK revealed an activated CXCR1/CXCR2 signature and pathways related to neutrophil activation, immunity, and chemotaxis, confirming the role of immune MK in pathological interactions.
CD53-positive MK were involved in Type 3 interactions, while CD53-negative cells were not, suggesting the immune subpopulation's critical role in these pathological processes.

Summary of Study Impact on Navtemadlin (KRT-232):

The study does not directly impact navtemadlin’s positioning as it focuses on the mechanistic insights of myelofibrosis pathology rather than therapeutic interventions. However, it provides valuable biological insights that could inform future therapeutic strategies, including those involving navtemadlin.

Competitive Considerations:

The study does not introduce a competing therapy but enhances understanding of myelofibrosis pathology, potentially validating the need for targeted therapies like navtemadlin.
It highlights the complexity of post-JAK inhibitor MF treatment, underscoring the need for novel agents that address underlying disease mechanisms.

Clinical or Market Strategy Implications:

Kartos may consider integrating these mechanistic insights into their clinical trial designs to explore combination strategies or new endpoints that address the inflammatory microenvironment in MF.
Emphasizing navtemadlin’s efficacy in restoring p53 function and its potential role in modulating the inflammatory milieu could differentiate it from other treatments.

Medical Affairs Implications:

KOL engagement: Discuss the role of inflammation and immune interactions in MF and how navtemadlin might modulate these pathways.
Evidence gaps: Real-world data on navtemadlin’s impact on inflammatory markers or cytokine profiles in MF could be valuable.
Communication strategy: Highlight navtemadlin’s unique mechanism of action and its potential to address both tumor and microenvironmental factors in MF.

Link to Abstract PF816

Abstract Number: PF815

Presentation Title: TRANSCRIPTIONAL REPROGRAMMING OF SPLENIC ENDOTHELIAL CELLS IN MYELOFIBROSIS

Session: Myeloproliferative neoplasms - Biology & translational research

Abstract Summary:

Differential gene expression analysis identified a splenic littoral endothelial cell (EC) signature with 417 genes upregulated in EC regions of interest (ROIs) in healthy controls, including the master regulator NR5A1.
The splenic EC signature was validated against large single-cell RNA-seq datasets, confirming its specificity for splenic EC identification.
In myelofibrosis (MF) samples, 942 transcripts were upregulated and 1662 downregulated in EC ROIs, indicating a shift from native endothelial identity to a stress-associated state.
Key genes involved in EC stress response and supporting extramedullary hematopoiesis (EMH) in MF included NOS2, NOX4, FOXC1, CXC3CL1, PDGFB, and CSF3, along with inflammatory genes such as IL6 and complement factors C3 and C5.
The study highlights the transcriptional reprogramming of splenic ECs in MF, with a focus on the attenuation of NR5A1 expression, suggesting a potential target for future research on EMH and littoral EC identity.

Summary of Study Impact on Navtemadlin (KRT-232):

The study does not directly impact navtemadlin’s positioning as it focuses on the transcriptional reprogramming of splenic endothelial cells in myelofibrosis, rather than on therapeutic interventions. However, it provides insights into the disease biology that could inform future therapeutic strategies.

Competitive Considerations:

The study does not introduce a competing therapy but enhances understanding of MF pathophysiology, potentially validating the need for targeted therapies like navtemadlin.
It highlights the complexity of MF, suggesting that therapies addressing endothelial cell reprogramming could complement existing treatments, including post–JAK inhibitor options.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies that target both the hematopoietic and endothelial components of MF.
Emphasizing navtemadlin’s efficacy in restoring p53 function could differentiate it from therapies focusing on endothelial reprogramming.

Medical Affairs Implications:

KOL engagement: Discuss the potential for navtemadlin to be part of combination therapies addressing both hematopoietic and endothelial dysfunctions.
Evidence gaps: Real-world data on navtemadlin’s impact on extramedullary hematopoiesis and endothelial cell function could be valuable.
Communication strategy: Highlight navtemadlin’s unique mechanism of action and its role in the broader context of MF treatment, including its potential synergy with therapies targeting endothelial reprogramming.

Link to Abstract PF815

Abstract Number: PF820

Presentation Title: DECODING THE SUCNR1/HIF-1α /TNF-α AXIS: HOW MONOCYTES FUEL MYELOFIBROSIS IN MYELOPROLIFERATIVE NEOPLASMS

Session: Myeloproliferative neoplasms - Biology & translational research

Abstract Summary:

Monocytes are significantly elevated in MPN patients, especially in those with prePMF, compared to controls, contributing to disease progression.
In vitro, monocytes from MPN subtypes enhance fibroblast growth, proliferation, and collagen fiber metabolic activity, with prePMF showing the strongest effects.
Pro-inflammatory cytokines, particularly TNF-α and IL-6, are significantly increased in the prePMF group, promoting fibroblast proliferation and metabolic changes.
TNF-α inhibitors effectively suppress fibroblast proliferation and metabolic activity induced by monocytes, suggesting a potential therapeutic approach.
The SUCNR1/HIF-1α/TNF-α axis is implicated in monocyte activation and myelofibrosis progression, highlighting its role in the inflammatory cascade in MPN patients.

Summary of Study Impact on Navtemadlin (KRT-232):

The study does not directly challenge navtemadlin’s positioning but provides insights into the inflammatory pathways involved in myelofibrosis, which could complement navtemadlin’s mechanism of action by targeting different aspects of the disease.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin but highlights the potential of targeting inflammatory pathways, such as the SUCNR1/HIF-1α/TNF-α axis, which could be explored in combination with navtemadlin.
It reinforces the complexity of post–JAK inhibitor MF treatment, suggesting that a multi-targeted approach could be beneficial.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination therapies that include TNF-α inhibitors or other anti-inflammatory agents alongside navtemadlin.
Emphasizing navtemadlin’s unique mechanism of restoring p53 function could differentiate it from therapies targeting inflammatory pathways.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combination strategies and the role of inflammation in MF progression.
Evidence gaps: Real-world data on navtemadlin’s efficacy in combination with anti-inflammatory agents could be valuable.
Communication strategy: Highlight navtemadlin’s efficacy in JAK inhibitor-refractory MF and its potential role in combination therapies targeting inflammation.

Link to Abstract PF820

Abstract Number: PF822

Presentation Title: THROMBOCYTOPENIA IN MYELOFIBROSIS (MF) IS CHARACTERIZED BY INFLAMMATORY MEGAKARYOCYTES WITH REDUCED G6B EXPRESSION THROMBOCYTOPENIA IN MYELOFIBROSIS IS CHARACTERIZED BY INFLAMMATORY MEGAKARYOCYTES WITH REDUCED G6B EXPRESSION

Session: Myeloproliferative neoplasms - Biology & translational research

Abstract Summary:

Thrombocytopenia in myelofibrosis (MF) is linked to inflammatory megakaryocytes (MKs) with reduced G6B expression, contributing to impaired MK maturation.
Patients with MF and thrombocytopenia (MPN-MF-T) exhibit higher levels of TNFα and YKL40 compared to those without thrombocytopenia (MPN-MF-NT), indicating a cytokine-driven mechanism.
Ex-vivo studies show that rYKL40 or rTNFα addition to MK cultures blocks MK maturation and reduces G6B expression, highlighting the role of these cytokines in disease pathology.
AVID200 therapy, a TGFβ1/3 trap, increases platelet numbers in MPN-MF-T patients refractory to ruxolitinib, suggesting therapeutic potential by modulating cytokine levels.
Data suggest a regulatory loop between YKL40 and TGFβ, with implications for targeted therapies in MF-associated thrombocytopenia.

Summary of Study Impact on Navtemadlin (KRT-232):

The study primarily focuses on the pathophysiology of thrombocytopenia in myelofibrosis (MF) and does not directly address navtemadlin (KRT-232). However, it provides insights into the inflammatory mechanisms and cytokine interactions that could be relevant for understanding the broader disease context in which navtemadlin operates. The findings do not challenge navtemadlin’s positioning but highlight potential areas for further research, particularly in understanding the interplay of cytokines in MF.

Competitive Considerations:

The study does not introduce a competing therapy but rather enhances the understanding of MF pathophysiology, which could indirectly support navtemadlin’s role by providing a deeper context for its mechanism of action.
It underscores the complexity of post-JAK inhibitor MF treatment, suggesting that therapies targeting specific pathways, like navtemadlin, may need to consider cytokine interactions.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies that address cytokine-mediated pathways, potentially enhancing navtemadlin’s efficacy.
Emphasizing navtemadlin’s unique mechanism of restoring p53 function could differentiate it from therapies focusing solely on cytokine modulation.

Medical Affairs Implications:

KOL engagement: Discuss the potential for navtemadlin to be used in combination with therapies targeting cytokine pathways, and its role in managing cytopenias.
Evidence gaps: Real-world data on navtemadlin’s impact on cytokine levels and its efficacy in patients with varying cytokine profiles could be valuable.
Communication strategy: Highlight navtemadlin’s efficacy in JAK inhibitor-refractory MF and its potential synergy with cytokine-targeting agents.

Link to Abstract PF822

Abstract Number: PF826

Presentation Title: CD44 CONTRIBUTES TO EXTRAMEDULLARY HEMATOPOIESIS IN MYELOFIBROSIS PATIENTS BY REGULATING THE INTERPLAY BETWEEN MONOCYTE AND HEMATOPOIETIC STEM AND PROGENITOR CELLS

Session: Myeloproliferative neoplasms - Biology & translational research

Abstract Summary:

CD44 is crucial in promoting the migration of monocytes and hematopoietic stem and progenitor cells (HSPCs) in myelofibrosis (MF), contributing to extramedullary hematopoiesis (EMH) and splenomegaly.
Inhibition of CD44 significantly reduces monocyte migration in vitro, with CD44 ligands osteopontin (OPN) and hyaluronic acid (HA) being elevated in MF patients and their inhibition also dampening monocyte migration.
Migration of MF HSPCs is enhanced compared to healthy donor cells and is significantly reduced by anti-CD44 antibodies in vitro, suggesting a potential therapeutic target.
MF monocytes produce CD44 ligands, OPN and HA, which may facilitate HSPCs mobilization from the bone marrow to the spleen, indicating a mechanism for EMH.
Findings support the development of novel therapeutic strategies combining CD44 and JAK inhibition to counteract disease progression in MF patients.

Summary of Study Impact on Navtemadlin (KRT-232):

The study does not directly challenge navtemadlin’s positioning but highlights a novel therapeutic target (CD44) that could complement existing treatments, including navtemadlin, in myelofibrosis management.

Competitive Considerations:

The study introduces a potential new therapeutic target (CD44) that could be developed into a complementary or competitive therapy, but it does not currently present a direct competitor to navtemadlin.
It suggests a broader understanding of MF pathophysiology, potentially enriching the post–JAK inhibitor treatment landscape with combination strategies.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies involving CD44 inhibitors and navtemadlin to enhance treatment efficacy in MF.
Emphasizing navtemadlin’s efficacy in spleen volume reduction and symptom score improvement could differentiate it from emerging therapies targeting CD44.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combination therapies and the role of CD44 in MF pathogenesis alongside navtemadlin’s benefits.
Evidence gaps: Investigate real-world data on navtemadlin’s long-term efficacy and safety, and explore biomarker correlations with treatment response.
Communication strategy: Highlight navtemadlin’s unique mechanism of restoring p53 function and its proven efficacy in JAK inhibitor–refractory MF.

Link to Abstract PF826

Abstract Number: PS1854

Presentation Title: AN EXPLORATORY ANALYSIS OF SYMPTOMATIC BENEFIT IN PATIENTS TREATED WITH GECACITINIB: A FOCUS ON THOSE INTOLERANT OR REFRACTORY/RELAPSED TO RUXOLITINIB

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

In ZGJAK006, 50% of patients had a baseline Total Symptom Score (TSS) ≥10, with a median TSS of 9.5 in the overall population and 16.0 in the symptomatic population.
In ZGJAK017, 79.4% of patients had a baseline TSS ≥10, with a median TSS of 19.5 in the overall population and 24.0 in the symptomatic population.
Fatigue and abdominal discomfort were the most severe symptoms at baseline in both studies, with significant improvement observed in individual symptoms, particularly night sweats, by week 24.
20.5% of patients in ZGJAK006 and 11.8% in ZGJAK017 achieved dual spleen volume reduction (SVR35) and TSS50 response at week 24, with higher rates at any study time (40.9% and 32.4%, respectively).
Patients intolerant or refractory/relapsed to ruxolitinib experienced symptomatic improvement and dual response of SVR35 and TSS50 after treatment with gecacitinib.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on gecacitinib suggests potential competition for navtemadlin in the post–JAK inhibitor myelofibrosis (MF) treatment landscape. However, navtemadlin's demonstrated efficacy in the BOREAS trial, particularly in spleen volume reduction and symptom score improvement, reinforces its value proposition as a single-agent therapy in JAK inhibitor–refractory MF.

Competitive Considerations:

The study introduces gecacitinib as a potential competitor, showing symptomatic improvement and dual response in patients intolerant or refractory to ruxolitinib.
Navtemadlin's efficacy in achieving significant SVR35 and TSS50 responses positions it strongly in the post–JAK inhibitor MF treatment landscape, potentially offering a more robust single-agent option compared to gecacitinib.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin's superior efficacy in clinical trials and exploring combination strategies, such as with ruxolitinib, to enhance its market positioning.
Highlighting navtemadlin's efficacy, safety profile, and potential disease-modifying effects could differentiate it from other therapies like gecacitinib.

Medical Affairs Implications:

KOL engagement: Focus on discussing the durability of response, management of cytopenias, and sequencing strategies with JAK inhibitors.
Evidence gaps: Real-world data, subgroup analyses, and biomarker correlations could further validate navtemadlin's clinical benefits and resonate with clinicians.
Communication strategy: Emphasize navtemadlin's unique value proposition, particularly its efficacy as a single-agent therapy in JAK inhibitor–refractory MF, compared to other investigational agents.

Link to Abstract PS1854

Abstract Number: PS1820

Presentation Title: IDENTIFICATION OF ULTRA HIGH-RISK GENOTYPES FOR PROGRESSION TO BLAST PHASE DISEASE REDEFINES MOLECULAR-BASED STRATIFICATION OF MYELOFIBROSIS

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Co-occurring mutations in SRSF2-IDH2, ASXL1-SRSF2, and ASXL1-EZH2 are significantly associated with progression to blast phase in myelofibrosis, indicating biological cooperativity driving disease progression.
Myelofibrosis patients with dual SRSF2 and IDH2 mutations have significantly shorter leukemia-free survival compared to those with single mutations, highlighting the high risk of leukemic transformation.
ASXL1 mutations worsen leukemia-free survival only when co-occurring with SRSF2 or EZH2 mutations, suggesting specific mutation interactions are critical for risk assessment.
High-risk mutation pairs do not affect survival post-allogeneic stem cell transplantation, indicating the importance of early identification and prioritization for transplantation in eligible patients.
Findings suggest a need to revise current molecular risk stratification in myelofibrosis to incorporate these high-risk mutation patterns for better clinical management.

Summary of Study Impact on Navtemadlin (KRT-232):

The study primarily focuses on genetic risk stratification in myelofibrosis (MF) and does not directly address navtemadlin (KRT-232). However, it indirectly supports navtemadlin's positioning by highlighting the need for effective treatments in high-risk MF patients, particularly those with specific genetic mutations that predispose them to leukemic transformation.

Competitive Considerations:

The study does not introduce a new therapy that competes with navtemadlin but emphasizes the importance of targeted treatments for genetically high-risk MF patients.
It reinforces the need for effective post-JAK inhibitor therapies, potentially validating navtemadlin's role in the treatment landscape for MF, especially in genetically high-risk populations.

Clinical or Market Strategy Implications:

Kartos Therapeutics might consider incorporating genetic stratification into their clinical trial designs to better target high-risk MF populations.
Emphasizing navtemadlin's efficacy in genetically high-risk patients could be a key differentiation lever, alongside its efficacy and safety profile.

Medical Affairs Implications:

KOL engagement: Discussions could focus on the durability of response in high-risk genetic subgroups and the potential sequencing with JAK inhibitors.
Evidence gaps: Real-world data on navtemadlin's efficacy in patients with high-risk genetic mutations could be valuable, as well as subgroup analyses correlating genetic profiles with treatment outcomes.
Communication strategy: Highlighting navtemadlin's potential benefits in genetically high-risk MF patients could strengthen its value proposition compared to other investigational agents.

Abstract: PS1820

Title: IDENTIFICATION OF ULTRA HIGH-RISK GENOTYPES FOR PROGRESSION TO BLAST PHASE DISEASE REDEFINES MOLECULAR-BASED STRATIFICATION OF MYELOFIBROSIS

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background:
Transformation of chronic-phase myeloproliferative neoplasms (MPNs) to accelerated or blast phase disease (MPN-AP/BP) is a critical complication of MPNs and a largely fatal event. Biological insights into this process remain limited. Risk assessment for progression to MPN-AP/BP has been centered on the impact of single gene mutations. However, the prognostic significance of these mutations, such as ASXL1, remains a subject of debate, making clinical action based on mutational data challenging.

Aims:
We sought to determine if there were specific patterns of mutations in patients with MPN-AP/BP and whether there was a biological basis for such patterns. We further sought to determine if these mutation patterns, when identified in chronic phase MPN, had an implication for the likelihood of Leukemic Transformation (LT) in patients.

Methods:
We performed targeted sequencing of 588 genes (mean depth 709x) in a cohort of 187 samples from 161 individual MPN-AP/BP patients, including 26 patients with paired pre- and post-transformation samples.

Results:
We identified a statistically significant association between co-occurring mutations in SRSF2-IDH2, ASXL1-SRSF2, and ASXL1-EZH2 (Fig 1A). These co-mutation patterns were not observed in analysis of multiple published chronic-phase MPN datasets, suggesting an underlying biological cooperativity which drives disease progression. Indeed, prior studies have demonstrated a mechanistic interplay between SRSF2 and IDH2 (Yoshimi et al.), as well as ASXL1 and SRSF2 (Sui et al.) mutations in myeloid malignancies. To assess whether this also applies to ASXL1 and EZH2 mutations, we generated Mx-Cre-Asxl1fl/fl and Mx-Cre-Asxl1fl/fl-Ezh2fl/fl mice. Mx-Cre-Asxl1fl/fl-Ezh2fl/fl had a significantly shorter overall survival than Mx-Cre-Asxl1fl/fl mice and developed a lethal myeloid neoplasm, whereas Mx-Cre-Asxl1fl/fl mice remained largely unaffected, supporting a cooperative effect of these mutations.
Importantly, analysis of two large Myelofibrosis (MF) databases from the Mayo Clinic (N=405) and the University of Florence (N=518), revealed that MF patients with dual SRSF2 and IDH2 mutations had a significantly shorter leukemia-free survival (LFS) than patients with single mutations in either gene (p<0.001 Fig 1B). Further, ASXL1 mutations were found to impart a worsened LFS only in the context of co-occurring SRSF2 mutations or co-occurring EZH2 mutations (p<0.01, Fig 1C). Analysis of outcomes of MF patients treated with allogeneic stem cell transplantation (SCT), using the North American Myelofibrosis Transplant Outcome (NAMTO) database (N =498), demonstrated that those patients with co-occurring mutations in SRSF2-IDH2, ASXL1-SRSF2, and ASXL1-EZH2 showed no difference in survival versus the cohort as a whole, suggesting that these mutation pairs do not impact transplant outcomes.

Summary/Conclusion:
Our data suggest that MF patients with concurrent mutations in SRSF2-IDH2 are at highest risk for LT, followed by ASXL1 with concurrent SRSF2 or EZH2 mutations, and that these associations appear to be based on biological cooperativity. By contrast, EZH2 or IDH2 mutations without these co-occurring mutations appear to have a relatively low risk of LT (Fig 1D). These data argue for revision of current molecular risk stratification in MF. Finally, high-risk paired mutations do not appear to impact survival of MF patients after SCT, suggesting that early identification of such patients and prioritization for SCT in those eligible are crucial to improve outcomes.

Keyword(s): Myeloproliferative disorder | Acute leukemia

Link to Abstract PS1820

Abstract Number: PS1821

Presentation Title: A STUDY TO EVALUATE SINGLE-AGENT SELINEXOR VERSUS PHYSICIAN'S CHOICE IN PARTICIPANTS WITH PREVIOUSLY TREATED MYELOFIBROSIS

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=24
Selinexor (SEL) monotherapy achieved a spleen volume reduction of ≥35% (SVR35) in 33% of patients compared to 13% with physician's choice (PC), and ≥25% reduction (SVR25) in 67% vs 38%.
Symptom improvement (TSS50) was observed in 29% of SEL patients compared to 0% in PC, with a mean TSS change of -5.9 vs 0.0.
SEL stabilized hemoglobin levels and reduced transfusion needs, with a decrease in proinflammatory cytokines, suggesting disease modification.
SEL was generally well tolerated, with no treatment-emergent discontinuations, supporting its potential in combination with ruxolitinib (RUX) for JAKi-naïve myelofibrosis, as explored in the ongoing Ph3 SENTRY trial.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on selinexor (SEL) does not directly challenge navtemadlin’s positioning but highlights a potential complementary mechanism in the treatment of myelofibrosis (MF). SEL's efficacy in previously JAK inhibitor-exposed MF patients suggests a role in combination therapies, which could be synergistic with navtemadlin.

Competitive Considerations:

The study introduces SEL as a potential competitor in the MF space, particularly in combination with ruxolitinib, but it also validates the need for novel mechanisms like navtemadlin’s MDM2 inhibition.
SEL's results in post-JAK inhibitor MF patients reinforce the need for effective therapies in this challenging setting, supporting navtemadlin’s role.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination trials with SEL or similar agents to enhance efficacy in MF treatment.
Emphasizing navtemadlin’s unique mechanism and its efficacy in JAK inhibitor-refractory MF could differentiate it from SEL.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combination therapies and the durability of response with navtemadlin.
Evidence gaps: Real-world data on navtemadlin’s long-term efficacy and safety, as well as biomarker-driven patient selection, would be valuable.
Communication strategy: Highlight navtemadlin’s efficacy in JAK inhibitor-refractory MF and its potential in combination regimens.

Link to Abstract PS1821

Abstract Number: PS1822

Presentation Title: SAFETY AND EFFICACY OF BROMODOMAIN AND EXTRA-TERMINAL (BET) INHIBITOR INCB057643 IN PATIENTS (PTS) WITH RELAPSED OR REFRACTORY MYELOFIBROSIS (MF) AND OTHER ADVANCED MYELOID NEOPLASMS: A PHASE 1 STUDY

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects: 76 in monotherapy, 28 in combination therapy.
INCB057643 monotherapy or combination with ruxolitinib was generally well tolerated, with no treatment-related fatal events.
Thrombocytopenia was the most common treatment-emergent adverse event, occurring in 41% of patients.
Week 24 spleen volume response (SVR35) was achieved by 4/23 monotherapy patients and 5/21 combination therapy patients.
Week 24 symptom response (TSS50) was achieved by 8/21 monotherapy patients and 10/19 combination therapy patients.
Durable anemia response was observed in 10/37 monotherapy patients and 6/25 combination therapy patients.
Ongoing dose expansion for 6- and 10-mg monotherapy and 4- and 8-mg combination therapy groups; a phase 3 study in advanced post-JAKi MF patients is being initiated.

Summary of Study Impact on Navtemadlin (KRT-232):

The study of INCB057643, a BET inhibitor, presents a potential competitive landscape for navtemadlin (KRT-232) in the treatment of relapsed/refractory myelofibrosis (MF). While the study shows promising results in terms of safety and efficacy, it does not directly challenge navtemadlin's positioning but highlights the evolving treatment options in post-JAK inhibitor MF.

Competitive Considerations:

The study introduces INCB057643 as a potential competitor, especially in combination with ruxolitinib, for patients with suboptimal response to JAK inhibitors.
It suggests a growing interest in alternative mechanisms of action, such as BET inhibition, in the post-JAK inhibitor MF treatment landscape.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies with navtemadlin and other agents like ruxolitinib to enhance efficacy.
Emphasizing navtemadlin's unique mechanism of restoring p53 function and its efficacy in spleen volume and symptom score reduction could differentiate it from BET inhibitors.

Medical Affairs Implications:

KOL engagement: Discuss the durability of response and management of cytopenias, comparing navtemadlin's profile with emerging therapies.
Evidence gaps: Real-world data and subgroup analyses focusing on biomarkers and long-term outcomes could strengthen navtemadlin's clinical narrative.
Communication strategy: Highlight navtemadlin's efficacy in JAK inhibitor-refractory MF and its potential in combination therapies to reinforce its value proposition.

Abstract: PS1822

Title: SAFETY AND EFFICACY OF BROMODOMAIN AND EXTRA-TERMINAL (BET) INHIBITOR INCB057643 IN PATIENTS (PTS) WITH RELAPSED OR REFRACTORY MYELOFIBROSIS (MF) AND OTHER ADVANCED MYELOID NEOPLASMS: A PHASE 1 STUDY

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background:
BET proteins are epigenetic readers that regulate expression of oncoproteins involved in hematologic malignancies, including MF. The oral, small-molecule BET inhibitor INCB057643 had favorable tolerability and encouraging clinical activity in pts with advanced MF in a previous phase 1/2 trial.

Methods:
This ongoing phase 1, open-label 3+3 dose-escalation/expansion study (NCT04279847) is evaluating INCB057643 monotherapy (part 1; 4 mg→12 mg once daily [qd]) in adults with relapsed or refractory MF, essential thrombocythemia, myelodysplastic syndrome (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndrome; or combination therapy (part 2; 4 mg qd→part 1 maximum tolerated dose) with ruxolitinib (RUX) in adults with MF and suboptimal response to RUX or who were Janus kinase inhibitor (JAKi) naive. Primary endpoint is safety/tolerability. Secondary endpoints include spleen volume response (≥35% reduction from baseline [BL; SVR35] at Week [Wk] 24), symptom response (≥50% reduction from BL in MPN-Symptom Assessment Form total symptom score [TSS50] at Wk 24), and anemia response (sustained hemoglobin increase ≥1.5 g/dL from BL [if transfusion (TF) independent at BL] or TF independence [if dependent at BL] for ≥12 wk).

Results:
As of the data cut, 18 pts were treated in monotherapy dose escalation, 30 in monotherapy dose expansion, 23 in combination therapy dose escalation, and 5 in combination therapy dose expansion. All patients with MF in combination therapy were suboptimal responders to RUX; no patients with MF who were JAKi naive were enrolled at the time of data cutoff. Median (range) INCB057643 exposure was 196 (15-944) days (d) in monotherapy dose escalation, 131 (14-473) d in monotherapy dose expansion, 284 (85-692) d in combination therapy dose escalation, and 81 (55-115) d in combination therapy dose expansion.

The most common treatment (tx)-emergent adverse event (TEAE) was thrombocytopenia (TCP; 41%). Grade ≥3 TEAEs occurred in 51%. Serious TEAEs occurred in 29%; 4 (5%) were tx related. No fatal events were deemed tx related. Ten TEAEs led to discontinuation. 2 dose-limiting toxicities occurred with monotherapy (12 mg, TCP, hyperbilirubinemia) and 1 with combination therapy (6 mg, TCP). 3 pts had acute myeloid leukemia transformation (4-mg monotherapy MDS/MPN, 10-mg monotherapy MDS, 4-mg combination therapy MF).

Among evaluable MF pts receiving monotherapy at any dose, Wk 24 SVR35 was achieved by 4/23 pts (4/9 receiving ≥10 mg) and Wk 24 TSS50 was achieved by 8/21 pts (5/9 receiving ≥10 mg). In pts treated with any combination therapy dose, Wk 24 SVR35 was achieved by 5/21 pts and Wk 24 TSS50 was achieved by 10/19 pts. Best responses in spleen volume and TSS50 are shown in the Figure. Durable anemia response occurred in 10/37 evaluable monotherapy pts (2 TF-dependent at BL) and 6/25 combination therapy pts.

Summary/Conclusion:
INCB057643 monotherapy or combination therapy with RUX was generally well tolerated, with no tx-related fatal events. Improvements in anemia, spleen size, and symptom burden were observed with monotherapy and combination therapy. Dose expansion is ongoing for 6- and 10-mg monotherapy and 4- and 8-mg combination therapy groups (add-on and JAKi naive). A phase 3 study of INCB057643 monotherapy in advanced post-JAKi MF pts is being initiated.

Keyword(s): Myeloproliferative disorder | Myelofibrosis

Link to Abstract PS1822

Abstract Number: PS1825

Presentation Title: DYNAMIC ELEVATIONS OF EARLY-STAGE MYELOID-DERIVED SUPPRESSOR CELLS PREDICT LEUKEMIC TRANSFORMATION IN MYELOFIBROSIS PATIENTS TREATED WITH RUXOTILNIB: A REAL-WORLD, PROSPECTIVE, LONGITUDINAL STUDY

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Patients with leukemic transformation (LT) had a significantly higher proportion of high early-stage myeloid-derived suppressor cells (e-MDSCs) compared to those without LT (100% vs 49.21%, p = 0.008).
e-MDSC levels were significantly correlated with white blood cell counts, peripheral blood blasts, lactate dehydrogenase levels, and MIPSS70 scores, indicating a strong association with disease severity.
High-risk MIPSS70 patients had significantly higher e-MDSC levels compared to low- and intermediate-risk groups, suggesting e-MDSCs as a potential marker for risk stratification.
During ruxolitinib treatment, 87.50% of patients with LT experienced an increase in e-MDSC levels, compared to 20.83% in patients without LT, indicating a potential predictive role for e-MDSCs in treatment response.
High e-MDSCs increased the risk for LT by 7.74-fold, and dynamically increasing e-MDSCs were associated with a significantly higher incidence of LT, highlighting their potential as surrogate markers for disease progression in MF patients.

Summary of Study Impact on Navtemadlin (KRT-232):

The study does not directly challenge navtemadlin’s positioning but provides insights into leukemic transformation in myelofibrosis patients treated with ruxolitinib. It highlights the potential of e-MDSCs as a biomarker for disease progression, which could complement navtemadlin’s therapeutic strategy.

Competitive Considerations:

The study does not introduce a competing therapy but rather enhances understanding of disease progression in MF, potentially validating the need for effective post-JAK inhibitor treatments like navtemadlin.
It underscores the complexity of MF treatment post-JAK inhibitor failure, reinforcing the need for novel agents such as navtemadlin in the treatment landscape.

Clinical or Market Strategy Implications:

Kartos may consider integrating e-MDSC monitoring in clinical trials to better stratify patients and assess treatment efficacy.
Emphasizing navtemadlin’s efficacy in reducing spleen volume and symptom scores could differentiate it from other treatments, especially in JAK inhibitor-refractory settings.

Medical Affairs Implications:

KOL engagement: Discuss the role of e-MDSCs in disease progression and how navtemadlin could be positioned as a treatment option post-JAK inhibitor failure.
Evidence gaps: Real-world data on navtemadlin’s impact on leukemic transformation and its correlation with e-MDSC levels could be valuable.
Communication strategy: Highlight navtemadlin’s unique mechanism of action and its potential role in altering disease progression in MF.

Abstract: PS1825

Title: DYNAMIC ELEVATIONS OF EARLY-STAGE MYELOID-DERIVED SUPPRESSOR CELLS PREDICT LEUKEMIC TRANSFORMATION IN MYELOFIBROSIS PATIENTS TREATED WITH RUXOTILNIB: A REAL-WORLD, PROSPECTIVE, LONGITUDINAL STUDY

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background:
Myelofibrosis (MF) is the most aggressive subtype of myeloproliferative neoplasms (MPN) and has a high tendency to progress to acute myeloid leukemia (AML). Myeloid-derived suppressor cells (MDSCs) are immature cells that proliferate in the circulation of cancer patients. They regulate the immune system, contributing to tumor initiation and progression, while also promote neoangiogenesis. Early-stage MDSCs (e-MDSC) (Lin-HLADR-CD33+CD66b-) are potential precursors for other MDSC subsets, and their expansion has emerged as a marker of advanced malignancy in multiple myeloma. However, the implications of e-MDSC expansion in MF have not been explored.

Aims:
In this prospective study, we hypothesize that elevated e-MDSC is associated with leukemic transformation (LT) and we aim to explore whether dynamic elevations of e-MDSCs during ruxolitinib treatment correlate with leukemia-free survival (LFS).

Methods:
We included patients diagnosed with MF who were regularly followed up at our center and had complete medical records. Patients who did not undergo flow cytometry for circulating MDSC subset tests or next-generation sequencing for MIPSS70 scoring were excluded. A total of 73 patients were enrolled in this study. Of these, 56 patients received ruxolitinib treatment, and 32 of these ruxolitinib-treated patients underwent dynamic MDSC testing (Fig. A). MDSC data were prospectively collected every 6 months. Leukemia-free survival (LFS) was estimated using the Kaplan-Meier (K-M) method. High e-MDSCs were defined as ≥5% and elevating Δe-MDSCs was defined as an increase ≥ 1% in the subsequent measurement compared to the first one.

Results:
Patients with LT had a significantly higher proportion of high e-MDSCs (100% vs 49.21%, p = 0.008) (Fig. B). Correlation analysis indicated that e-MDSC levels were significantly associated with WBC counts (r = 0.58), PBB (r = 0.33), LDH levels (r = 0.43), and were positively correlated with MIPSS70 scores (r = 0.48) (p < 0.05 for all) (Fig. C). MIPSS70 risk stratification showed that high-risk patients had significantly higher e-MDSC levels compared to low- (median: 9.09 vs 3.77, p = 0.047) and intermediate-risk groups (meidan: 9.09 vs 3.55, p = 0.048) (Fig. D). During ruxolitinib treatment, 87.50% of patients with LT experienced an increase in e-MDSC levels, whereas the percentage in patients without LT is 20.83% (Fig. E). The risk for LT increased by 3.96-fold in patients with high e-MDSCs (HR = 4.96, 95% CI: 1.36 - 18.08). The K-M method demonstrated that patients with high e-MDSCs had a significantly higher incidence of LT (log-rank p = 0.015) (Fig. F). Notably, the risk for LT increased by 7.74-fold in patients with high e-MDSCs (HR = 8.84, 95% CI: 2.08 - 37.60). The K-M method demonstrated that patients with elevating Δe-MDSC had a significantly higher incidence of LT (log-rank p = 0.003) (Fig. G).

Summary/Conclusion:
This real-world, prospective, and longitudinal study demonstrates that high and dynamically increasing e-MDSCs correlate with LT in MF patients. Most importantly, our findings highlight that e-MDSCs could be a dynamic surrogate marker for progression in MF patients treated with ruxolitinib, thereby aiding in the evaluation of treatment efficacy and disease status.

This research was funded by the Key R&D Program of Zhejiang (No. 2022C03137) and the Zhejiang Medical Association Clinical Medical Research special fund project (No. 2022ZYC-D09). ^†Correspondence to: Prof Jian Huang, E-mail: househuang@zju.edu.cn

Keyword(s): Ruxolitinib | Leukemic transformation | Myelofibrosis

Link to Abstract PS1825

Abstract Number: PS1827

Presentation Title: REAL-WORLD EFFECTIVENSS OF PACRITINIB IN PATIENTS WITH MYELOFIBROSIS WHO HAVE THROMBOCYTOPENIA AND ANEMIA

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Among 179 PAC-treated patients with myelofibrosis and bicytopenia, 21% had bicytopenia at index, with a median follow-up of 8 months.
Median hemoglobin improved from 7.2 g/dL at index to 8.6 g/dL by day 270, while median platelet count improved from 49.5 x10⁹/L at index to 73.5 x10⁹/L by day 270.
For patients with severe bicytopenia, median hemoglobin improved from 7.2 g/dL at index to 8.4 g/dL by day 270, and median platelet count improved from 26 x10⁹/L at index to 56 x10⁹/L by day 270.
Overall survival probability at 12 months was 65.8% for patients with bicytopenia and 65.5% for those with severe bicytopenia.
Real-world data support PAC's clinical utility in improving hematologic outcomes and survival in myelofibrosis patients with bicytopenia, addressing unmet needs in this poor prognosis subgroup.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on pacritinib (PAC) does not directly challenge navtemadlin’s positioning but highlights an alternative treatment for myelofibrosis (MF) patients with specific hematologic challenges, such as bicytopenia. Navtemadlin’s efficacy in JAK inhibitor-refractory MF remains distinct, focusing on spleen volume and symptom score reduction.

Competitive Considerations:

The study introduces PAC as a therapy for MF patients with anemia and thrombocytopenia, but it does not directly compete with navtemadlin, which targets a different patient population (JAK inhibitor-refractory MF).
PAC’s role in the MF treatment landscape is complementary, addressing a niche of patients with bicytopenia, while navtemadlin focuses on post-JAK inhibitor scenarios.

Clinical or Market Strategy Implications:

Kartos may not need to adjust its clinical trial strategy significantly but should consider exploring navtemadlin’s efficacy in broader MF populations, including those with hematologic challenges.
Emphasizing navtemadlin’s efficacy in spleen volume and symptom score reduction, particularly in JAK inhibitor-refractory cases, can differentiate it from PAC.

Medical Affairs Implications:

KOL engagement: Discuss the durability of navtemadlin’s response and its role in sequencing with JAK inhibitors, contrasting with PAC’s hematologic benefits.
Evidence gaps: Real-world data on navtemadlin’s long-term outcomes and subgroup analyses could enhance its clinical narrative.
Communication strategy: Highlight navtemadlin’s unique mechanism and efficacy in JAK inhibitor-refractory MF, positioning it as a critical option in the treatment continuum.

Abstract: PS1827

Title: REAL-WORLD EFFECTIVENSS OF PACRITINIB IN PATIENTS WITH MYELOFIBROSIS WHO HAVE THROMBOCYTOPENIA AND ANEMIA

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background:
Anemia and thrombocytopenia (bicytopenia) in patients (pts) with myelofibrosis (MF) is a therapeutic challenge due to treatment-related myelosuppression from JAK1/2 inhibitors. Pacritinib (PAC) is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that can be administered at full dose with clinically significant spleen volume reduction, symptom benefit, and reduced transfusions in pts with bicytopenia.

Aims:
To evaluate hematologic outcomes and survival in real-world clinical practice, among PAC-treated pts with MF presenting with bicytopenia.

Methods:
The Integra-PrecisionQ database of de-identified electronic health data (~80% community oncology practices) was used for this retrospective study of pts with MF and bicytopenia who initiated treatment with PAC anytime between 6/01/2022 and 6/30/2024. Pts were included if they had hemoglobin (Hb) <8.0 g/dL and platelet counts (PLT) <100 x10⁹/L at the time of PAC initiation (index). Hb and PLT are reported overall and for a subset of pts with severe bicytopenia (Hb <8.0 g/dL and PLT <50 x10⁹/L). Overall survival (OS) was assessed from index to the earliest of: death, end of data availability, or end of study period (9/2024), and 12-month survival probabilities were estimated using the Kaplan Meier method. Continuous variables were summarized using medians and interquartile range (IQR), and categorical variables were described using counts and percentages.

Results:
Among 179 PAC-treated pts with MF and Hb and PLT data at index and follow-up, 21% had bicytopenia at index (n=38). A majority of the pts with bicytopenia were male (63.2%) with a median (IQR) age at MF diagnosis of 74 years (67-80), and 50% of pts received PAC in the first-line setting with a median of 3.9 months (0.1, 16.6) from MF diagnosis to index. The median follow-up from index was 8 months (4-15) overall, and the median duration of treatment with PAC was 5 months among pts (n=17) with ≥9 months of follow-up. Median Hb (IQR) was 7.2 g/dL (6.9-7.6) at index and improved by almost 1 g/dL by day 90 (8.1 g/dL; 7.5-8.8) and continued to improve through day 270 (8.6 g/dL; 7.9-9.3) (Figure). Median PLT count (IQR) was 49.5 x10⁹/L (27-71) at index, and remained stable through day 90 (42 x10⁹/L; 21-74) with improvements observed at day 270 (73.5 x10⁹/L; 42-95). For pts with severe bicytopenia at index (n=19), median Hb levels were stable from index (7.2 g/dL; 6.5-7.5) through day 90 (7.7 g/dL; 7.1-8.8) and improved by day 270 (8.4 g/dL; 7.8-9.3). Median PLT counts were stable from index (26 x10⁹/L; 18.5-35) through day 90 (21 x10⁹/L; 15-39.5) and improved at day 270 (56 x10⁹/L; 20-84) (Figure). Through the end of the observation period 65.8% (25/38) of pts with bicytopenia, and 63.2% (12/19) for those with severe bicytopenia were still alive. OS probability at 12 months was 65.8% (95% CI: 47.2-79.1) and 65.5% (95% CI: 38.3-83.0) for those with bicytopenia and severe bicytopenia respectively.

Summary/Conclusion:
Real-world data in pts with MF and bicytopenia demonstrate hematologic improvement or stability following treatment with PAC. Overall survival and 12-month survival probability in this subgroup of pts known to have a poor prognosis were comparable with previously publication OS among the overall PAC-treated cohort. These results from real world clinical practice support prior data of PAC’s clinical utility in addressing unmet needs of pts with MF who have bicytopenias.

Keyword(s): Real world data | Thrombocytopenia | Myelofibrosis | Anemia

Link to Abstract PS1827

Abstract Number: PS1828

Presentation Title: EXPLORATORY ANALYSIS OF GECACITINIB IN RUXOLITINIB-INTOLERANT MYELOFIBROSIS PATIENTS: IMPACT OF BASELINE ANEMIA AND PRIOR RUXOLITINIB TREATMENT DURATION ON RESPONSE TO GECACITINIB

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

SVR35 rates at week 24 were similar across anemia severity subgroups, with 45.5% in mild/moderate anemia and 40.9% in severe anemia, aligning with the overall rate of 43.2%.
Both anemia subgroups showed mean hemoglobin increases, with mild/moderate anemia group increasing by 11.1 g/L and severe anemia group by 14.3 g/L, with 50% achieving hemoglobin improvement in each group.
Anemia improvement was observed in 45.5% of mild/moderate anemia patients and 54.5% of severe anemia patients, with reduced median RBC transfusion rates in both groups.
Patients with shorter prior RUX treatment duration achieved a numerically higher SVR35 rate at week 24, regardless of baseline hemoglobin levels.
Gecacitinib demonstrated a dual therapeutic effect in RUX-intolerant patients, improving anemia and reducing spleen volume, with 25% of the FAS population meeting the composite endpoint of concurrent anemia improvement and SVR35 at week 24.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on gecacitinib (GCA) does not directly challenge navtemadlin’s positioning but highlights a potential complementary approach in treating myelofibrosis, particularly for patients intolerant to ruxolitinib. GCA's dual inhibition of JAK and ACVR1 offers a different mechanism that could be considered in combination strategies.

Competitive Considerations:

The study introduces GCA as a potential competitor in the post–JAK inhibitor MF treatment landscape, particularly for patients intolerant to ruxolitinib, but it does not directly compete with navtemadlin, which targets JAK inhibitor-refractory cases.
GCA's efficacy in improving anemia and reducing spleen volume may validate the need for alternative or complementary therapies in MF, potentially supporting navtemadlin's role in combination regimens.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination trials with GCA or similar agents to enhance efficacy in MF, especially for patients with anemia or those intolerant to ruxolitinib.
Emphasizing navtemadlin's unique mechanism of restoring p53 function and its efficacy in JAK inhibitor-refractory MF could differentiate it from GCA.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combination therapies, durability of response, and management of cytopenias in MF treatment.
Evidence gaps: Real-world data on navtemadlin's long-term efficacy and safety, as well as biomarker-driven patient selection, could be valuable.
Communication strategy: Highlight navtemadlin's efficacy in refractory cases and its potential role in combination therapies to strengthen its value proposition.

Abstract: PS1828

Title: EXPLORATORY ANALYSIS OF GECACITINIB IN RUXOLITINIB-INTOLERANT MYELOFIBROSIS PATIENTS: IMPACT OF BASELINE ANEMIA AND PRIOR RUXOLITINIB TREATMENT DURATION ON RESPONSE TO GECACITINIB

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background:
Gecacitinib (GCA), a dual inhibitor of JAK and ACVR1, has shown clinically significant and lasting improvements in anemia, splenomegaly, and symptoms for patients with myelofibrosis who were intolerant to ruxolitinib (RUX). The majority of these patients had experienced new or worsening anemia while on RUX. However, the response to GCA among subgroups with varying baseline hemoglobin (HGB) levels and different durations of prior RUX treatment remains unclear.

Aims:
We performed an exploratory post-hoc subgroup analysis to support the interpretation of the benefits related to spleen enlargement and anemia experienced by RUX-intolerant patients across various subgroups from the ZGJAK006 study (NCT04217993).

Methods:
ZGJAK006 was a single-arm, open-label, multicenter study that enrolled patients who were intolerant to RUX but not refractory or relapsed, and had baseline HGB below lower limit of normal (LLN).

The analyzed subgroups were:

1) Baseline anemic status according to HGB levels (severe: <80 g/L; mild/moderate: 80 g/L- LLN)

2) Duration of prior treatment with RUX

The endpoints included splenic response (spleen volume decreased by ≥35% from baseline, i.e. SVR35) at week 24, and improvement of anemia (defined as patients who were transfusion dependent at baseline became transfusion-independent, patients who were transfusion-independent with HGB ≤100 g/L at baseline had ≥20 g/L increase in HGB, or patients with at least 50% reduction in red blood cell [RBC] transfusion frequency or units compared to baseline) by week 24.

Results:
The SVR35 rates at week 24 were comparable across anemia severity subgroups, with 45.5% in mild/moderate anemia group, and 40.9% in severe anemia group, mirroring the overall FAS population rate of 43.2%. Both anemia subgroups demonstrated mean hemoglobin elevation while maintaining stable mean platelet counts (Figure 1). In mild/moderate anemia group, mean HGB increased by 11.1 g/L from baseline to week 24, with 50.0% showing HGB improvement. Similarly, severe anemia group exhibited a mean HGB increase of 14.3 g/L, with 50% achieving HGB improvement. Overall, anemia improvement was observed in 45.5% of mild/moderate anemia patients and 54.5% of severe anemia patients. The median rates of RBC transfusion through week 24 were 0 units/4-week (vs 0 units/4-week at baseline) in mild/moderate group and 0.4 units/4-week (vs 1.2 units/4-week at baseline) in severe anemia group.

Patients were stratified using two approaches: primary categorization based on the median duration of prior RUX treatment, and secondary classification according to quartiles of prior RUX duration. Notably, patients with shorter duration of prior treatment achieved a numerically higher SVR35 rate at week 24, regardless of baseline HGB levels (Table 1).

Among patients with HGB ≤100 g/L or transfusion dependence at baseline (n=40), those who achieved anemia improvement showed a numerically higher SVR35 rate at week 24 compared to non-responders (50.0% vs. 33.3%, respectively). In the FAS population (n=44), 25.0% of patients met the composite endpoint of concurrent anemia improvement and SVR35 at week 24.

Summary/Conclusion:
In RUX-intolerant patients with anemia, GCA treatment resulted in comparable splenic benefits across anemia subgroups and led to a reduced transfusion rate. Notably, patients with shorter durations of prior RUX exhibited a numerically higher SVR35 rate at week 24. Furthermore, GCA demonstrated a dual therapeutic effect, improving anemia and reducing spleen volume.

Keyword(s): Janus Kinase inhibitor | Myelofibrosis | Anemia | Myeloproliferative disorder

Link to Abstract PS1828

Abstract Number: PS1829

Presentation Title: IMPACT OF DUAL SPLEEN RESPONSE AND TRANSFUSION INDEPENDENCE ON SURVIVAL IN JAK INHIBITOR-NAIVE PATIENTS WITH MYELOFIBROSIS AND ANEMIA TREATED WITH MOMELOTINIB: A SUBGROUP ANALYSIS OF SIMPLIFY-1

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects: 180 (86 in momelotinib arm, 94 in ruxolitinib arm).
Momelotinib and ruxolitinib showed similar spleen volume reduction (SVR35) rates overall (31% vs 33%) in patients with baseline hemoglobin <10 g/dL.
Momelotinib achieved higher dual response rates (SVR35+transfusion independence [TI]) compared to ruxolitinib (27% vs 7%), with significant benefits across all subgroups.
Transfusion independence (TI) was the strongest predictor of overall survival (OS) with momelotinib, with hazard ratios of 0.19 for TI alone and 0.40 for SVR35+TI, indicating improved long-term outcomes.
Momelotinib's dual benefits for spleen reduction and anemia management suggest prioritizing TI in anemic myelofibrosis patients to optimize survival outcomes.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on momelotinib does not directly challenge navtemadlin’s positioning, as it focuses on JAK inhibitor-naive patients with anemia, while navtemadlin targets JAK inhibitor-refractory myelofibrosis. However, it highlights the importance of transfusion independence (TI) as a predictor of overall survival, which could influence endpoints in navtemadlin trials.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin, as it targets a different patient population (JAK inhibitor-naive vs. JAK inhibitor-refractory).
It reinforces the need for effective post-JAK inhibitor therapies, validating navtemadlin’s role in the treatment landscape for refractory MF.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing transfusion independence as a key endpoint in future trials or marketing strategies for navtemadlin.
Highlighting navtemadlin’s efficacy in spleen volume reduction and symptom score improvement could differentiate it from therapies like momelotinib.

Medical Affairs Implications:

KOL engagement: Discuss the durability of response and potential sequencing with JAK inhibitors, focusing on navtemadlin’s unique positioning in refractory cases.
Evidence gaps: Real-world data on navtemadlin’s impact on transfusion independence and overall survival in refractory MF could be valuable.
Communication strategy: Emphasize navtemadlin’s efficacy in JAK inhibitor-refractory MF and its potential role in combination therapies, such as with ruxolitinib.

Abstract: PS1829

Title: IMPACT OF DUAL SPLEEN RESPONSE AND TRANSFUSION INDEPENDENCE ON SURVIVAL IN JAK INHIBITOR-NAIVE PATIENTS WITH MYELOFIBROSIS AND ANEMIA TREATED WITH MOMELOTINIB: A SUBGROUP ANALYSIS OF SIMPLIFY-1

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background:
Splenomegaly is a hallmark of myelofibrosis (MF), often co-occurring with anemia (hemoglobin [Hb] <10 g/dL). Approximately 40% of patients are anemic at diagnosis, and the majority develop anemia during their disease course. Such patients may require prioritization of anemia management alongside traditional treatment goals such as spleen volume reduction (SVR) and symptom control. In the phase 3 SIMPLIFY-1 trial, momelotinib was noninferior to ruxolitinib for SVR ≥35% (SVR35; 27% vs 29%; P=.011) and nominally superior for transfusion independence (TI [no transfusions or Hb <8 g/dL in the previous 12 weeks]; 67% vs 49%; P<.001) at week 24 (Mesa, J Clin Oncol, 2017). The impact of SVR35 and TI on predicting long-term outcomes such as overall survival (OS) in patients with MF and anemia has not been characterized to date.

Aims:
We assessed SVR35 rates with momelotinib vs ruxolitinib across patient subgroups in the anemic subpopulation of SIMPLIFY-1 and evaluated the impact of both SVR35 and TI on OS with momelotinib.

Methods:
These post hoc analyses were conducted in the subset of patients with baseline anemia (Hb <10 g/dL) in SIMPLIFY-1, a randomized trial of momelotinib (n=215) vs ruxolitinib (n=217) in JAK inhibitor-naive patients with intermediate- or high-risk MF. SVR35, TI, and dual responses (SVR35+TI) at week 24 were reported across subgroups defined by key baseline characteristics. OS was assessed via the Kaplan-Meier method in a landmark analysis based on response vs nonresponse with momelotinib at week 24. The crossover trial design precluded evaluation of OS in the ruxolitinib arm, as all patients received momelotinib after week 24.

Results:
A total of 86 patients in the momelotinib arm and 94 in the ruxolitinib arm had baseline Hb <10 g/dL and were included in these analyses. At week 24, the SVR35 rate was similar with momelotinib vs ruxolitinib overall (27/86 [31%] vs 31/94 [33%]; difference, −0.02 [95% CI, −0.15 to 0.12]) and across most subgroups, including those defined by age, sex, baseline spleen volume, IPSS prognostic risk, and MF subtype. SVR35 rates were notably higher with momelotinib in the baseline platelets <100×10⁹/L subgroup (6/13 [46%] vs 0/13), and with ruxolitinib in the baseline platelets >200×10⁹/L subgroup (8/37 [22%] vs 23/47 [49%]).

The overall SVR35 rate with momelotinib (31%) was largely maintained when considering patients who were also TI at week 24 (SVR35+TI rate, 23/86 [27%]), but few patients achieved dual responses with ruxolitinib (SVR35+TI rate, 7/94 [7%]; difference vs momelotinib, 0.19 [95% CI, 0.07-0.31]); SVR35+TI rates were higher with momelotinib across all subgroups. OS was prolonged in patients achieving TI ± SVR35 at week 24 with momelotinib vs those who achieved neither endpoint (TI: n=17, HR=0.19 [95% CI, 0.06-0.65]; SVR35+TI: n= 23, HR=0.40 [95% CI, 0.18-0.89]) (Figure) and was similar in patients achieving TI alone or SVR35+TI.

Summary/Conclusion:
In this trial population of JAK inhibitor-naive patients with baseline Hb <10 g/dL, momelotinib provided comparable SVR to ruxolitinib across most patient subgroups. Most patients achieved dual SVR35+TI responses with momelotinib, illustrating its combined benefits for spleen reduction and anemia in MF, while similar SVR35 rates with ruxolitinib often resulted in transfusion need. TI emerged as the strongest predictor of OS with momelotinib, suggesting that this endpoint should be prioritized in anemic patients with MF to optimize long-term outcomes.

Keyword(s): Anemia | Survival prediction | Myelofibrosis | Janus Kinase inhibitor

Link to Abstract PS1829

Abstract Number: PS1831

Presentation Title: RETROSPECTIVE ANALYSIS OF EFFICACY AND SAFETY OUTCOMES IN PATIENTS WITH PRIMARY AND SECONDARY MYELOFIBROSIS TREATED WITH RUXOLITINIB: JUMP STUDY

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Ruxolitinib (RUX) demonstrated similar efficacy in spleen response, fatigue improvement, and survival outcomes across patients with primary myelofibrosis (PMF) and secondary myelofibrosis (SMF), including post-polycythemia vera (PV) and post-essential thrombocythemia (ET) types.
Patients with SMF showed comparable spleen response rates and best responses to RUX as those with PMF, with minimal differences observed when further differentiating by SMF type.
Mean improvements in FACIT-fatigue scores from baseline to Week 48 were similar between PMF and SMF, though slightly lower for post-ET patients.
Adverse event profiles were largely similar between PMF and SMF patients, with a notable >5% increase in any grade asthenia and a >5% decrease in Grade 3/4 anemia in post-ET and SMF/post-PV patients compared to PMF patients.
The study supports RUX as a viable treatment option for SMF, regardless of SMF type, similar to its use in PMF.

Summary of Study Impact on Navtemadlin (KRT-232):

The study primarily focuses on the efficacy and safety of ruxolitinib in primary and secondary myelofibrosis, showing comparable outcomes across these groups. It does not directly challenge or support navtemadlin’s positioning but highlights the ongoing relevance of JAK inhibitors in MF treatment, which could indirectly affect navtemadlin's market strategy.

Competitive Considerations:

The study does not introduce a new therapy that competes directly with navtemadlin but reinforces the role of JAK inhibitors like ruxolitinib in MF treatment.
It underscores the need for effective post-JAK inhibitor therapies, validating navtemadlin’s role in the treatment landscape for JAK inhibitor-refractory MF.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin’s efficacy in JAK inhibitor-refractory cases, as the study supports the continued use of JAK inhibitors in earlier lines of treatment.
Differentiation levers such as navtemadlin’s unique mechanism of action and its efficacy in refractory cases should be highlighted.

Medical Affairs Implications:

KOL engagement: Discuss the durability of response and sequencing strategies with JAK inhibitors, focusing on navtemadlin’s role post-JAK inhibitor failure.
Evidence gaps: Real-world data on navtemadlin’s efficacy in specific subgroups or biomarker-driven approaches could be valuable.
Communication strategy: Emphasize navtemadlin’s efficacy in refractory settings and its potential in combination therapies, as explored in the POIESIS trial.

Link to Abstract PS1831

Abstract Number: PS1832

Presentation Title: A PHASE 1/2A TRIAL OF PXS-5505, A NOVEL PAN-LYSYL OXIDASE INHIBITOR, IN PATIENTS WITH ADVANCED MYELOFIBROSIS

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

In the Add-on phase (AOP) of the study, PXS-5505 200 mg BID was administered alongside ruxolitinib (RUX) for 52 weeks to assess safety, tolerability, and impact on disease-related parameters in patients with advanced myelofibrosis (MF).
Of the 13 patients who completed 12 weeks of treatment, 11 showed improvements in total symptom score (TSS), with 5 achieving a 50% reduction at this early timepoint.
Longer therapy duration led to further improvements, with 4 out of 5 patients achieving a TSS50 response at Week 38, and 2 out of 5 achieving a 25% reduction in spleen volume.
The study enrolled 16 patients in the AOP, with a median previous RUX treatment duration of 38 months and a median baseline TSS of 23.
Data from this study phase will inform clinical and regulatory discussions on the further development of PXS-5505 in MF, focusing on its safety profile and potential efficacy indicators when used with RUX.

Summary of Study Impact on Navtemadlin (KRT-232):

The study of PXS-5505 does not directly challenge navtemadlin’s positioning but introduces a potential complementary approach in the treatment of myelofibrosis (MF). The focus on a different mechanism of action (anti-fibrotic) suggests that PXS-5505 could be used in combination with other therapies, including navtemadlin, rather than as a direct competitor.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin, as PXS-5505 targets lysyl oxidase for an anti-fibrotic effect, whereas navtemadlin is an MDM2 inhibitor restoring p53 function.
PXS-5505 could enhance the post–JAK inhibitor MF treatment landscape by offering a novel mechanism that may be used alongside existing therapies, potentially including navtemadlin.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies with PXS-5505 to enhance efficacy in MF, particularly in patients with fibrosis-driven symptoms.
Emphasizing navtemadlin’s unique mechanism and efficacy in JAK inhibitor–refractory MF could differentiate it from PXS-5505, which focuses on fibrosis reduction.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combination therapies, including navtemadlin and PXS-5505, to address different aspects of MF pathology.
Evidence gaps: Real-world data on combination efficacy and safety, as well as biomarker-driven patient selection, would be valuable.
Communication strategy: Highlight navtemadlin’s efficacy in symptom and spleen volume reduction, positioning it as a key player in the post–JAK inhibitor setting.

Link to Abstract PS1832

Abstract Number: PS1834

Presentation Title: DEVELOPMENT AND VALIDATIONTION OF A MODEL FOR PREDICTING LEUKEMIC TRANSFORMATION IN MYELOFIBROSIS PATIENTS A MULTI-CENTER RETROSPECTIVE STUDY

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=616
Multivariate logistic regression identified independent risk factors for leukemic transformation in MF patients, including history of radiotherapy and chemotherapy, cardiovascular risk factors, elevated peripheral blood blast percentage, increased white blood cell count, reduced hemoglobin levels, and higher red cell distribution width (RDW).
The developed nomogram demonstrated high predictive accuracy with an AUC of 0.90 for the training cohort and 0.83 for the validation cohort, indicating strong predictive performance.
Calibration curves showed strong agreement with the ideal curve, confirming that the model's predictions closely aligned with actual outcomes.
Decision curve analysis indicated that the nomogram provided a net benefit across a wide range of threshold probabilities, suggesting practical value for clinicians in real-world settings.
The nomogram offers an effective tool for early identification of MF patients at risk of leukemic transformation, potentially guiding timely monitoring and interventions to improve patient outcomes.

Summary of Study Impact on Navtemadlin (KRT-232):

The study does not directly impact navtemadlin’s positioning as it focuses on predicting leukemic transformation in myelofibrosis (MF) rather than treatment efficacy. However, it indirectly supports navtemadlin by highlighting the need for effective treatments in high-risk MF patients.

Competitive Considerations:

The study does not introduce a competing therapy but emphasizes the importance of managing high-risk MF patients, potentially validating navtemadlin’s role in this context.
It underscores the need for effective post–JAK inhibitor treatments, reinforcing navtemadlin’s potential value in the MF treatment landscape.

Clinical or Market Strategy Implications:

Kartos may consider integrating predictive tools like the nomogram into clinical trials to identify high-risk patients who might benefit most from navtemadlin.
Emphasizing navtemadlin’s efficacy in reducing spleen volume and symptom scores could differentiate it as a valuable option for high-risk MF patients.

Medical Affairs Implications:

KOL engagement: Discuss the potential of navtemadlin in high-risk MF patients identified by predictive models, focusing on durability of response and sequencing with JAK inhibitors.
Evidence gaps: Real-world data on navtemadlin’s efficacy in high-risk populations and biomarker correlations could be valuable.
Communication strategy: Highlight navtemadlin’s role in addressing unmet needs in high-risk MF patients, leveraging its efficacy and safety profile.

Link to Abstract PS1834

Abstract Number: PS1852

Presentation Title: ANEMIA RESPONSE IN PATIENTS WITH MYELOFIBROSIS TREATED WITH LUSPATERCEPT: A REAL-WORLD COHORT STUDY

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=15
67% of patients were transfusion-dependent before luspatercept; 20% achieved 12-week transfusion independence.
53% experienced an increase in hemoglobin of ≥1.5 g/dL for 12 weeks or ≥50% decrease in transfusion requirement if transfusion-dependent.
No correlation was found between response and epoetin levels, MIPSS70+ risk score, or primary vs secondary MF.
Median overall survival was longer for responders (175 months) compared to non-responders (83 months), though not statistically significant (p=0.33).
Response rates are promising, but further dose optimization and predictive response metrics are needed for better tailoring luspatercept use in MF-related anemia.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on luspatercept primarily addresses anemia in myelofibrosis (MF) patients, a different therapeutic target than navtemadlin, which focuses on spleen volume reduction and symptom score improvement in JAK inhibitor-refractory MF. Therefore, the study does not directly challenge navtemadlin’s positioning but highlights a complementary treatment area.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin, as it targets anemia rather than spleen volume or symptom reduction.
It reinforces the need for comprehensive treatment strategies in MF, potentially positioning navtemadlin as part of a broader therapeutic regimen post-JAK inhibitor failure.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies with anemia-targeting agents like luspatercept to enhance overall patient outcomes in MF.
Emphasizing navtemadlin’s efficacy in spleen volume and symptom reduction could differentiate it from anemia-focused treatments.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combination therapies and the role of navtemadlin in comprehensive MF management, including its impact on spleen volume and symptoms.
Evidence gaps: Real-world data on navtemadlin’s long-term efficacy and safety, especially in combination with other agents, would be valuable.
Communication strategy: Highlight navtemadlin’s unique benefits in JAK inhibitor-refractory MF, focusing on its role in reducing spleen volume and improving symptoms.

Link to Abstract PS1852

Abstract Number: PS1837

Presentation Title: FACTORS ASSOCIATED WITH GRAFT FAILURE AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN PATIENTS WITH MYELOFIBROSIS: A MULTICENTER RETROSPECTIVE STUDY

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=189
Graft failure occurred in 29 patients, with a higher incidence in unrelated donor HSCT (44.4%) compared to haploidentical (15.9%) and HLA-matched sibling donor (4.9%) HSCT (P<0.001).
Massive splenomegaly significantly increased graft failure risk (22.2% vs. 7.7% with no splenomegaly), with an odds ratio of 6.448 (95% CI: 1.476-28.162, P=0.013).
Multivariate analysis identified donor source (OR=11.147, 95% CI: 2.448-50.447, P=0.002) and splenomegaly as significant risk factors for graft failure.
1-year outcomes post-transplantation: overall survival 66.1%, disease-free survival 62.1%, relapse 10.34%, non-relapse mortality 29.8%, acute GVHD 44%, chronic GVHD 25%.
Management of splenomegaly may improve transplantation outcomes, highlighting its potential as a therapeutic target in reducing graft failure risk.

Abstract: PS1837

Title: FACTORS ASSOCIATED WITH GRAFT FAILURE AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN PATIENTS WITH MYELOFIBROSIS: A MULTICENTER RETROSPECTIVE STUDY

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Summary of Study Impact on Navtemadlin (KRT-232):

The study on graft failure in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelofibrosis (MF) does not directly impact navtemadlin’s positioning. However, it highlights the challenges in MF treatment, reinforcing the need for effective therapies like navtemadlin, especially post-JAK inhibitor failure.

Competitive Considerations:

The study does not introduce a competing therapy to navtemadlin but underscores the complexity of MF treatment, validating the need for alternative approaches like navtemadlin.
It highlights the limitations of allo-HSCT, particularly in patients with massive splenomegaly, suggesting a continued need for effective pharmacological interventions in the post-JAK inhibitor MF landscape.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin’s role in managing MF patients who are not candidates for or have failed allo-HSCT.
Focus on differentiation through efficacy in spleen volume reduction and symptom score improvement, as well as potential combination strategies with ruxolitinib.

Medical Affairs Implications:

KOL engagement: Discuss navtemadlin’s potential in reducing splenomegaly and improving outcomes in JAK inhibitor-refractory MF patients.
Evidence gaps: Explore real-world data on navtemadlin’s efficacy in patients with massive splenomegaly and its impact on transplantation outcomes.
Communication strategy: Highlight navtemadlin’s unique mechanism and efficacy in the context of limited post-JAK inhibitor options, contrasting with the challenges of allo-HSCT.

Abstract: PS1837

Title: FACTORS ASSOCIATED WITH GRAFT FAILURE AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN PATIENTS WITH MYELOFIBROSIS: A MULTICENTER RETROSPECTIVE STUDY

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background:
Graft failure (GF) is a significant barrier for success allogeneic stem cell transplantation (allo-HSCT) in patients with myelofibrosis (MF). However, studies focus on GF in MF patients were lacking.

Aims:
Our current study aims to investigate the incidence, risk factors and prognosis of GF in allo-HSCT for MF.

Methods:
Clinical data from MF patients who underwent allo-HSCT across 31 hematology centers in China between December 2008 and December 2024 were retrospectively analyzed. Graft failure was defined according to the EBMT consensus (Primary GF is defined by an ANC<0.5×10⁹/l by day +28 following stem cell infusion, Hb <80 g/L and platelets <20×10⁹/L; Secondary GF is deﬁned as the presence of an ANC<0.5×10⁹/L occurring after initial engraftment and not related to relapse, infection or drug toxicity.). Splenomegaly was categorized as no spenomegaly, mild (Splenomegaly no more than 15 cm by palpation or 22 cm of longitudinal diameter according to ultrasound scan evaluation.), massive (Splenomegaly exceeding 15 cm by palpation or 22 cm of longitudinal diameter according to ultrasound scan evaluation). The primary endpoint was graft failure. The secondary endpoints include 1-year overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse, and non-relapse mortality (NRM).

Results:
A total of 189 patients were reviewed. Among the 189 patients, 127 were diagnosed with primary myelofibrosis (PMF), 18 with post-essential thrombocythemia/polycythemia vera MF (post-ET/PV MF), and 44 with MF with acute myeloid leukemia (MF-AML). 59 patients received HLA-matched sibling donor (MSD) HSCT, 114 underwent haploidentical HSCT, and 16 received unrelated donor HSCT. Graft failure occurred in 29 patients (21 primary, 8 secondary). The incidence of graft failure varied significantly by donor source (MSD: 4.9%, haploidentical: 15.9%, unrelated: 44.4%; P<0.001, chi-square test). Massive splenomegaly was associated with increased graft failure incidence (no splenomegaly: 7.7%, mild splenomegaly: 12.7%, massive splenomegaly: 22.2%; ). In multivariate analysis, splenomegaly (OR = 6.448, 95% CI: 1.476-28.162, P = 0.013) and donor source (OR = 11.147, 95% CI: 2.448-50.447, P = 0.002) were linked to graft failure. Other variables (pre-transplant WBC, hemoglobin, platelets, MF grading, HCT-CI, DSA, graft MNC, CD34+ count) showed no association. Of 29 graft failure cases, 6 had secondary transplantation (2 survived with engraftment); 23 received treatments like MSC infusion, DLI, or immunosuppression, with 7 recovering hematopoiesis and surviving.
After a median follow-up of 353 days, 1-year outcomes were: OS, 66.1%; DFS, 62.1%; relapse, 10.34%; NRM, 29.8%; acute GVHD, 44%; chronic GVHD, 25%. Multivariate analysis indicated pre-transplant splenomegaly trended toward lower DFS (no splenomegaly: 73.1%; mild: 64.9%; massive: 56.7%; P = 0.127), but was not significant. Other variables (donor source, leukocyte count, hemoglobin, platelets, marrow fibrosis, HCT-CI, DSA, MNC, CD34+ count) showed no link to OS, relapse, or NRM.

Summary/Conclusion:
Allogeneic stem cell transplantation provides a curative promise for patient with MF. However, graft failure remains significant challenges in allo-HSCT, particularly in haploidentical HSCT and those with massive pre-transplant splenomegaly. This study suggests that management of splenomegaly might be a potential method for improving transplantation outcomes.

Keyword(s): Myelofibrosis | Allogeneic hematopoietic stem cell transplant | Engraftment | Splenomegaly

Link to Abstract PS1837

Abstract Number: PS1839

Presentation Title: INDIRECT TREATMENT COMPARISON OF GECACITINIB VS RUXOLITINIB IN MYELOFIBROSIS

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Gecacitinib demonstrated higher odds ratios (ORs) for spleen volume reduction ≥35% (SVR35) compared to ruxolitinib, with a significant advantage observed in the SIMPLIFY-I study arm (OR = 4.63, 95% CI, 2.09-10.24; P = 0.0002).
For total symptom score reduction ≥50% (TSS50), gecacitinib showed statistically significant improvements over ruxolitinib in both COMFORT-I (OR = 3.19, 95% CI, 1.34-7.59; P = 0.0091) and SIMPLIFY-I (OR = 3.63, 95% CI, 1.70-7.79; P = 0.0010).
Gecacitinib was associated with a statistically lower risk of anemia, decreased neutrophil count, and adverse events (AEs) leading to discontinuation compared to ruxolitinib, with significant differences in anemia and neutrophil count reduction.
The risk of grade 3/4 thrombocytopenia was lower with gecacitinib compared to the ruxolitinib arm of COMFORT-I, but not in SIMPLIFY-I.
Overall, gecacitinib may offer efficacy and safety advantages over ruxolitinib, but direct head-to-head studies are needed for confirmation.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on gecacitinib does not directly challenge navtemadlin’s positioning, as it focuses on JAK inhibitor-naïve patients, whereas navtemadlin targets JAK inhibitor-refractory myelofibrosis. However, it highlights the evolving landscape of MF treatments, emphasizing the need for effective post-JAK inhibitor therapies like navtemadlin.

Competitive Considerations:

The study introduces gecacitinib as a potential competitor in the JAK inhibitor-naïve space, but it does not directly compete with navtemadlin, which is positioned for JAK inhibitor-refractory cases.
It underscores the necessity for effective treatments in the post-JAK inhibitor setting, reinforcing navtemadlin’s role in this niche.

Clinical or Market Strategy Implications:

Kartos may not need to adjust its strategy significantly but should monitor developments in the JAK inhibitor-naïve market.
Emphasizing navtemadlin’s efficacy in JAK inhibitor-refractory MF and its unique mechanism of restoring p53 function could be key differentiators.

Medical Affairs Implications:

KOL engagement: Focus on discussing navtemadlin’s durability of response and its role in sequencing after JAK inhibitors.
Evidence gaps: Real-world data on navtemadlin’s long-term efficacy and safety, as well as biomarker correlations, would be valuable.
Communication strategy: Highlight navtemadlin’s unique positioning in the post-JAK inhibitor space and its potential in combination therapies.

Link to Abstract PS1839

Abstract Number: PS1841

Presentation Title: RELATIONSHIP BETWEEN HEMOGLOBIN AND QUALITY OF LIFE IN NON-TRANSFUSION-DEPENDENT PATIENTS WITH MYELOFIBROSIS TREATED WITH LUSPATERCEPT

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=36
Achieving a hemoglobin (Hb) level of ≥10 g/dL or an increase of ≥1.5 g/dL in non-transfusion-dependent myelofibrosis patients treated with luspatercept was significantly associated with improvements in anemia-related quality of life (QoL), particularly in anemia and fatigue symptoms.
Regression models showed that changes in Hb were significant predictors of changes in the Functional Assessment of Cancer Therapy - Anemia (FACT-An) Anemia Subscale (AnS) and Fatigue Subscale (FS) scores, with all coefficients exceeding clinically important difference thresholds.
Among patients with a mean Hb increase ≥1.5 g/dL and evaluable QoL assessments, 83% experienced meaningful improvements in AnS, and 66% in FS, overlapping with the clinical response period.
This analysis confirms a significant and clinically meaningful relationship between Hb increase and anemia-related QoL improvement in this patient population.

Abstract: PS1841

Title: RELATIONSHIP BETWEEN HEMOGLOBIN AND QUALITY OF LIFE IN NON-TRANSFUSION-DEPENDENT PATIENTS WITH MYELOFIBROSIS TREATED WITH LUSPATERCEPT

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Summary of Study Impact on Navtemadlin (KRT-232):

The study on luspatercept does not directly challenge navtemadlin’s positioning but highlights the importance of addressing anemia and quality of life in myelofibrosis treatment, which could complement navtemadlin’s efficacy in spleen volume and symptom score reduction.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin but emphasizes the need for comprehensive treatment strategies in MF, potentially validating navtemadlin’s role in combination therapies.
It underscores the multifaceted needs in post–JAK inhibitor MF treatment, suggesting that therapies improving anemia and QoL could be complementary to navtemadlin’s benefits.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies with agents like luspatercept to address anemia and enhance overall patient outcomes.
Emphasizing navtemadlin’s efficacy in spleen volume reduction and symptom improvement, alongside potential combination benefits, could differentiate it in the market.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combination therapies to address both spleen-related symptoms and anemia, enhancing overall patient management.
Evidence gaps: Real-world data on navtemadlin’s impact on anemia and QoL, as well as subgroup analyses, could be valuable.
Communication strategy: Highlight navtemadlin’s unique position as a single agent with significant efficacy in JAK inhibitor–refractory MF, while exploring synergies with anemia-targeting agents.

Abstract: PS1841

Title: RELATIONSHIP BETWEEN HEMOGLOBIN AND QUALITY OF LIFE IN NON-TRANSFUSION-DEPENDENT PATIENTS WITH MYELOFIBROSIS TREATED WITH LUSPATERCEPT

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background:
Anemia is a common complication in myelofibrosis (MF) and associated with fatigue and reduced quality of life (QoL). The phase 2 ACE-536-MF-001 (MF-001) study demonstrated that luspatercept improves hemoglobin (Hb) in non-transfusion-dependent (NTD) patients (pts) with MF. Over the entire treatment period, 36.1% of NTD pts achieved a mean Hb increase from baseline ≥1.5 g/dL. However, the relationship between Hb increase and QoL in NTD pts with MF is still unclear.

Aims:
This post-hoc analysis aims to explore the relationship between Hb level and anemia-related QoL in NTD MF pts treated with luspatercept, and to evaluate the effectiveness of the Hb target (≥10 g/dL or an increase of ≥1.5 g/dL) in improving anemia-related QoL.

Methods:
Pts in Cohorts 1 (no concomitant ruxolitinib [rux]) and 3A (on a stable dose of rux for ≥112 days prior to enrolment) of MF-001 were selected and pooled for this analysis. NTD was defined as no red blood cell units administered 84 days before the first luspatercept dose. The Functional Assessment of Cancer Therapy - Anemia (FACT-An) questionnaire was administered every other cycle (Q6W). The FACT-An Anemia Subscale (AnS) and Fatigue Subscale (FS) were prioritized for this analysis. Hb values within three days of a FACT-An assessment date were included. Linear mixed-effects regression models were estimated to quantify the relationship between change from baseline (CFB) in FACT-An subscales (the dependent variable) and Hb (the time-varying independent variable). Two models were fitted varying the parameterization of Hb: CFB (≥1.5 g/dL vs. <1.5 g/dL) and absolute post-baseline Hb (≥10 g/dL vs. <10 g/dL). Baseline covariates (age, FACT-An subscale score, sex) and visit (discrete) were also included in all models. Additionally, proportions of pts achieving both a mean Hb increase ≥1.5 g/dL over the entire treatment period and meaningful improvement in the AnS (CFB ≥4 points) or FS (CFB ≥3 points) were reported.

Results:
The 36 pts in the NTD cohort had a median age of 68.5 years, median baseline Hb values of 8.6 g/dL, and mean baseline AnS and FS scores of 58.3 (scale range: 0 [worst] - 80 [best]) and 37.3 (scale range: 0 [worst] - 52 [best]), respectively. At baseline and Day 169, 35/36 (97.2%) and 17/27 (63.0%) of pts on treatment, respectively, had non-missing FACT-An scores. Regression model coefficients (Table) indicated that both CFB in Hb and absolute post-baseline Hb were significant (p <0.05) predictors of CFB in AnS and FS scores. Furthermore, all coefficients exceeded pre-specified clinically important difference (CID) thresholds. Among the 6 pts who achieved a mean Hb increase ≥1.5 g/dL over the entire treatment period and had an evaluable QoL assessment, defined as non-missing baseline score below population norms, 5 (83%) experienced at least one meaningful improvement in AnS that overlapped with the clinical response period. Similarly, 4/6 pts (66%) had at least one meaningful improvement in FS overlapping with the clinical response period.

Summary/Conclusion:
In pts with NTD MF treated with luspatercept, achieving a Hb level of ≥10 g/dL or increase of ≥1.5 g/dL was associated with a meaningful improvement in patient-reported anemia and fatigue symptoms. Most pts with a Hb response and evaluable QoL also experienced an improvement in anemia-related QoL. This analysis demonstrated a significant and clinically meaningful relationship between Hb increase and anemia-related QoL improvement in this population.

Keyword(s): Patient reported outcomes | Myelofibrosis | Hemoglobin | Quality of life

Link to Abstract PS1841

Abstract Number: PS1842

Presentation Title: REAL-WORLD TREATMENT PATTERNS AND CLINICAL OUTCOMES IN PATIENTS WITH MYELOFIBROSIS TREATED WITH PACRITINIB (PAC) WITH PLATELETS ≥50 X109/L AT PAC INITIATION: INTERIM RESULTS FROM THE MY-PAC STUDY

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=35
Pacritinib (PAC) treatment in myelofibrosis patients with platelet counts ≥50 x10⁹/L resulted in a 66.7% reduction in spleen size category by Day 180, with no worsening of spleen size observed.
Platelet counts improved with a median increase of 15% from baseline through Day 180, and 17.4% of patients with thrombocytopenia achieved a significant platelet response.
Hemoglobin levels increased by a median of 10% from baseline through Day 180, with 28.6% of patients with baseline hemoglobin <10 g/dL achieving an increase of >1.0 g/dL.
Overall survival was high, with 88.6% of patients alive at the end of the study period and a 180-day survival probability of 91.4% from PAC initiation.
PAC demonstrated benefits in real-world settings, showing stability or reduction in spleen size and improvements in platelet counts and hemoglobin levels in patients with platelet counts ≥50 x10⁹/L.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on pacritinib (PAC) does not directly challenge navtemadlin’s positioning but highlights an alternative treatment option for myelofibrosis (MF) patients, particularly those with thrombocytopenia. Navtemadlin’s efficacy in JAK inhibitor-refractory MF remains distinct, especially given its unique mechanism of restoring p53 function.

Competitive Considerations:

The study introduces PAC as a viable option for MF patients with thrombocytopenia, but it does not directly compete with navtemadlin, which targets a different patient population (JAK inhibitor-refractory MF).
PAC’s approval and real-world data reinforce the need for diverse treatment strategies in MF, potentially validating navtemadlin’s role in the broader post-JAK inhibitor landscape.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin’s efficacy in JAK inhibitor-refractory MF and exploring combination strategies, such as with ruxolitinib, to enhance its market positioning.
Navtemadlin’s differentiation should focus on its unique mechanism of action, efficacy in refractory cases, and potential combination benefits.

Medical Affairs Implications:

KOL engagement: Discussions should focus on navtemadlin’s durability of response, management of cytopenias, and sequencing with JAK inhibitors.
Evidence gaps: Real-world data, subgroup analyses, and biomarker correlations could further support navtemadlin’s clinical utility.
Communication strategy: Emphasize navtemadlin’s novel mechanism and efficacy in refractory MF to differentiate it from other agents like PAC.

Link to Abstract PS1842

Abstract Number: PS1844

Presentation Title: THE ECONOMIC BURDEN OF MYELOFIBROSIS TREATED WITH RUXOLITINIB IN FRANCE

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=1,235
Ruxolitinib was used as first-line treatment for 33.7% of patients with Myelofibrosis (MF) in the study, with a median follow-up of 23 months.
During follow-up, 78.5% of patients were hospitalized overnight at least once, with a median duration of 10.5 days per patient per year.
Mean total direct medical costs per patient per year were €126,696, with ruxolitinib acquisition costs accounting for approximately 25% of total costs.
Direct medical expenditure for MF is three times higher than that for chronic renal insufficiency, highlighting the significant economic burden of MF treatment.

Summary of Study Impact on Navtemadlin (KRT-232):

The study primarily focuses on the economic burden of myelofibrosis treatment with ruxolitinib in France, highlighting the high direct medical costs associated with the disease. It does not directly challenge or support navtemadlin’s positioning but underscores the need for effective post-JAK inhibitor therapies, potentially reinforcing navtemadlin’s value proposition as a novel treatment option.

Competitive Considerations:

The study does not introduce a new competing therapy but highlights the economic burden of current treatments, suggesting a need for more cost-effective and efficacious options like navtemadlin.
It emphasizes the limitations of current JAK inhibitor therapies, potentially validating the need for alternatives in the post-JAK inhibitor MF treatment landscape.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin’s potential to reduce healthcare costs by improving efficacy and reducing the need for additional treatments like blood transfusions.
Highlighting navtemadlin’s efficacy in JAK inhibitor-refractory MF could differentiate it from existing therapies, focusing on its unique mechanism and potential cost savings.

Medical Affairs Implications:

KOL engagement: Discuss the potential of navtemadlin to reduce the economic burden by decreasing hospitalizations and transfusion needs.
Evidence gaps: Real-world data on navtemadlin’s impact on healthcare resource utilization and cost-effectiveness would be valuable.
Communication strategy: Emphasize navtemadlin’s role in addressing unmet needs in MF treatment, particularly in reducing the economic burden and improving patient outcomes.

Abstract: PS1844

Title: THE ECONOMIC BURDEN OF MYELOFIBROSIS TREATED WITH RUXOLITINIB IN FRANCE

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background:
Myelofibrosis (MF) is a myeloproliferative neoplasm characterised by development of progressive bone marrow fibrosis which compromises the production of red blood cells, platelets and granulocytes, ultimately leading to the need for regular blood transfusions. The development of Janus kinase inhibitors represented the first targeted pharmacological treatment of MF to provide sustained symptomatic improvement. The first of these, ruxolitinib, was marketed in France in 2012.

Aims:
To estimate the direct medical costs of patients with MF receiving Janus kinase inhibitors as first line treatment in France.

Methods:
This retrospective observational study was performed within the French national health insurance database (Système National des Données de Santé; SNDS). All adult patients with a confirmed diagnosis of MF between 01/01/2013 and 31/12/2021 were eligible. Patients were followed up for ≥12 months until 31/12/22, or death. All reimbursed healthcare in the hospital and community setting during the follow-up period, both in the private and public sectors, was documented. Costs were standardised to December 2022 using the Consumer Price Index. The cost analysis was performed from the public health insurance perspective.

Results:
A total of 3,667 individuals with MF were identified in the SNDS database, of whom 1,235 (33.7%) received a JAKi (ruxolitinib in all cases) as first-line treatment, and constitute the analysis population for the economic analysis. The median follow-up duration was 23 months [IQR: 11 - 43]. During follow-up, 970 patients (78.5%) were hospitalised overnight (whatever the reason) at least once, for a total median duration of 10.5 days per patient per year [IQR: 1.1 - 36.2]. 604 patients (48.9%) patients were hospitalised at least once in an intensive care unit and 745 (60.3%) made an emergency visit. 867 patients (70.2%) underwent blood transfusion at least once and 99 (8.0%) received haematopoietic stem cell transplantation. 1,090 patients (88.3%) consulted a hospital-based specialist and 1,203 patients (97.4%) underwent laboratory tests. 203 patients (16.4%) patients received hydroxyurea at least once, 698 (56.5%) an erythropoietin-stimulating agent and 613 (49.6%) glucocorticoids.

Mean total direct medical costs per patient per year (± SD) were €126,696 ± 83,568. The breakdown of mean total direct medical costs by cost component is presented in the Figure. ICU stays accounted for €2,616 ± 19,140, transfusions for €10,440 ± 33,264, MF-related surgery €6,300 ± 32,724, JAKi acquisition for €32,016 ± 17,532 and anaemia treatments for €5,460 ± 7,752. Blood transfusions and anaemia treatments account for 12.5% of total direct medical costs.

Summary/Conclusion:
The direct medical costs to the national health service of MF are high. On a per capita basis, direct medical expenditure for MF is three times higher than that for chronic renal insufficiency, according to social security statistics the most expensive common pathology to treat in France in 2021 (€43,000). Ruxolitinib acquisition costs account for around one quarter of all costs, while the costs of blood transfusions and drugs to treat anaemia are also substantial.

Keyword(s): Myelofibrosis

Link to Abstract PS1844

Abstract Number: PS1845

Presentation Title: DISC-0974 (AN ANTI-HEMOJUVELIN ANTIBODY) IN NON-TRANSFUSION-DEPENDENT PATIENTS WITH MYELOFIBROSIS: LABORATORY CORRELATES OF MAJOR ANEMIA RESPONSE

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=21
DISC-0974 treatment in non-transfusion-dependent myelofibrosis patients resulted in a major anemia response rate of 52.4% and a minor response rate of 19%, with an overall response rate of 71.4%.
Major response (MR) was associated with elevated sIL-2Rα (86% vs. 36%; p=0.02) and serum erythropoietin (sEpo) >50 mU/mL (73% vs. 22%; p=0.02).
Multivariable analysis indicated independent positive associations of MR with increased sIL-2Rα (p<0.01), wild-type ASXL1 (p<0.01), wild-type SF3B1 (p=0.02), and sEpo >50 mU/mL (p=0.02).
None of the patients with MR lost their response after a median treatment duration of 13 months, suggesting a durable response.
The study highlights the potential of using biomarkers such as sIL-2Rα and sEpo levels to predict major anemia response in myelofibrosis patients treated with DISC-0974.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on DISC-0974 does not directly challenge navtemadlin’s positioning but highlights a complementary approach in treating myelofibrosis, particularly focusing on anemia management. Navtemadlin’s efficacy in spleen volume and symptom score reduction remains distinct from DISC-0974’s anemia response.

Competitive Considerations:

The study introduces DISC-0974 as a potential complementary therapy rather than a direct competitor to navtemadlin, focusing on anemia rather than spleen volume or symptom reduction.
It broadens the post–JAK inhibitor MF treatment landscape by addressing anemia, a common complication in MF, which navtemadlin does not specifically target.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies with DISC-0974 to address both anemia and other MF symptoms, potentially enhancing overall treatment efficacy.
Emphasizing navtemadlin’s unique efficacy in spleen volume reduction and symptom improvement could differentiate it from therapies like DISC-0974 that target anemia.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combination therapies and the sequencing of navtemadlin with anemia-targeting agents like DISC-0974.
Evidence gaps: Real-world data on navtemadlin’s long-term efficacy and safety, particularly in combination with other agents, would be valuable.
Communication strategy: Highlight navtemadlin’s role in improving spleen volume and symptom scores, positioning it as a core therapy in MF management post-JAK inhibitor failure.

Abstract: PS1845

Title: DISC-0974 (AN ANTI-HEMOJUVELIN ANTIBODY) IN NON-TRANSFUSION-DEPENDENT PATIENTS WITH MYELOFIBROSIS: LABORATORY CORRELATES OF MAJOR ANEMIA RESPONSE

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background:
DISC-0974 is a monoclonal antibody that targets hemojuvelin, a co-receptor to BMP-SMAD signaling that stimulates hepcidin production. Serum hepcidin level is abnormally elevated in myelofibrosis (MF) and might contribute to iron-restricted erythropoiesis (AJH 2013:88:312). In an ongoing phase 1/2 study in MF (NCT05320198), DISC-0974 was well tolerated and associated with marked reduction in serum hepcidin levels and improvement in anemia (Gangat et al. Blood, 2024;144: 657).

Aims:
The current investigator-initiated laboratory correlative study examined the impact of mutations, cytokine levels, and baseline serum erythropoietin (sEpo) level on anemia response to DISC-0974, in non-transfusion-dependent (nTD) patients with MF

Methods:
Study patients were selected from the aforementioned ongoing phase 1/2 study, based on availability of information on mutations and baseline cytokine levels. Definitions of nTD and anemia response criteria were according to the revised international working group (IWG) criteria (Blood 2024;144:1813): i) nTD was defined as the presence of ≤2 units transfused in the 12 weeks prior to enrollment; ii) a 12-week rolling average increase of hemoglobin by ≥1.5 or 1-1.4 g/dL is required for major and minor responses, respectively. Mutation and cytokine analyses were performed according to institutional protocols; next-generation sequencing panel included 48 genes and cytokine panel 12 inflammatory cytokines.

Results:
A total of 21 nTD patients with MF were included: 15 primary and 6 secondary. Driver mutation distribution was JAK2 52%, MPL 14%, and CALR-1 33%. Other mutations, included ASXL1 (N=5), SF3B1 (N=4), SRSF2 (N=1), U2AF1 (N=1), and “none of the above” (N=5). DIPSS risk distribution was high (10%) and intermediate-2 (90%). Baseline median (range) values were 8.0 g/dL (range 7.1-9.5) for hemoglobin, and 59 mU/mL (10-913) for sEpo; the latter was >50 mU/mL in 11 (55%) patients. Elevated cytokines at baseline included TNF (90%), IL-18 (43%), sIL-2Rα (34%), IL-6 (24%), and MCP-1 (14%).

DISC-0974 dose levels were 28 mg (N=2), 50 mg (N=7), 75 mg (N=7), and 100 mg (N=5). Twelve (60%) patients were on DISC-0974 monotherapy while 9 (40%) received concomitant ruxolitinib (N=5), pacritinib (N=1), or hydroxyurea (N=3). At median follow-up of 13 months (range 9-21), 4 (19%) patients have discontinued DISC-0974 (2 early discontinuations during the treatment period), all for lack of response. Details on drug safety and toxicity were summarized in a previous abstract (Gangat et al. Blood, 2024;144: 657).

Eleven (52.4%) patients achieved major (MR) and 4 (19%) minor responses, resulting in an overall response rate of 71.4%. To date, none of the patients with MR lost their response, after a median treatment duration of 13 months (range 9-21). MR correlated with elevated sIL-2Rα (86% vs. 36%; p=0.02) and sEpo >50 mU/mL (73% vs. 22%; p=0.02) and, non-significantly, monotherapy (67%) vs. combined with other drugs (33%; p=0.3), wild-type ASXL1 (60% vs. 33%; p=0.27) or SF3B1 (59% vs. 25%; p=0.21), and elevated IL-6 (80% vs. 44%; p=0.14). Multivariable analysis suggested independent postive association with increased sIL-2Rα level (p<0.01), ASXL1^WT (p<0.01), SF3B1^WT(p=0.02), and sEpo >50 mU/mL (p=0.02).

Summary/Conclusion:
The current study suggests a robust (MR >50%) and durable (median 13+ months) anemia response in MF treated with DISC-0974 and the possibility of using biomarkers for predicting MR.

Keyword(s): Anemia

Link to Abstract PS1845

Abstract Number: PS1848

Presentation Title: PROGNOSTIC ASSESSMENT OF PATIENTS WITH MYELOPROLIFERATIVE NEOPLASM-ASSOCIATED MYELOFIBROSIS IN THE RUXOLITINIB TREATMENT ERA

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=153
The RR6 model classified patients into low, intermediate, and high risk with median overall survival not reached for low and intermediate, and 32 months for high risk (P=0.012).
DIPSS did not show statistical significance in survival prediction among different risk groups (P>0.05).
Integration of HMR^mt and RASp^mt mutations with RR6 improved its prognostic performance, especially in MF and PMF patients, as evidenced by higher C-index and AUCs over 1-5 years.
RR6 model, particularly when integrated with molecular data, allows for early identification of high-risk patients, facilitating timely treatment adjustments.

Summary of Study Impact on Navtemadlin (KRT-232):

The study primarily focuses on prognostic assessment in myelofibrosis patients treated with ruxolitinib, rather than introducing a new therapeutic intervention. Therefore, it does not directly challenge navtemadlin’s positioning but provides insights into patient stratification that could be relevant for optimizing treatment sequences involving navtemadlin.

Competitive Considerations:

The study does not introduce a new competing therapy but enhances understanding of patient stratification under ruxolitinib treatment, which could indirectly support navtemadlin by identifying patients who may benefit from alternative treatments post-ruxolitinib.
It reinforces the need for effective post-JAK inhibitor therapies, highlighting the potential role of navtemadlin in the treatment landscape for JAK inhibitor-refractory MF.

Clinical or Market Strategy Implications:

Kartos may consider integrating molecular profiling into their clinical trial designs to better identify patients who could benefit from navtemadlin, potentially improving trial outcomes and patient selection.
Emphasizing navtemadlin’s efficacy in JAK inhibitor-refractory settings and its potential in combination therapies could differentiate it in the market.

Medical Affairs Implications:

KOL engagement: Discussions could focus on the durability of response with navtemadlin, management of cytopenias, and its role in treatment sequencing post-ruxolitinib.
Evidence gaps: Real-world data on navtemadlin’s efficacy in molecularly stratified populations and its performance in combination with other agents like ruxolitinib would be valuable.
Communication strategy: Highlighting navtemadlin’s unique mechanism and efficacy in refractory cases could strengthen its value proposition against other investigational agents.

Abstract: PS1848

Title: PROGNOSTIC ASSESSMENT OF PATIENTS WITH MYELOPROLIFERATIVE NEOPLASM-ASSOCIATED MYELOFIBROSIS IN THE RUXOLITINIB TREATMENT ERA

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background:
Ph^- Myeloproliferative neoplasms (MPN)-associated myelofibrosis (MF) is a heterogeneous group of disorders in which patients may present with progressive splenomegaly and varying degrees of cytopenia. Ruxolitinib is able to improve splenomegaly, alleviate burdensome symptoms and improve quality of life in patients with MPN-associated MF. Newly Maffioli et al proposed a clinical prognostic model of Response to Ruxolitinib After 6 Months (RR6) for MPN-related MF patients treated with ruxolitinib, and Coltro et al found that the integration with high molecular risk mutations (HMR^mt) and RAS pathway mutations (RASp^mt) promotes the predictive power of RR6. In this study, we retrospectively analyzed 153 patients with MPN-associated MF treated with ruxolitinib, and verify whether the RR6, Dynamic International Prognostic Scoring System (DIPSS), Myelofibrosis Secondary to polycythemia vera (PV) and essential thrombocythemia (ET)-Prognostic Model (MYSEC-PM) is applicable to this group of patients, and assess the prognostic predictive ability of RR6 after integration of HMR^mt and/or RASp^mt.

Aims:
To validate the performances of the prognostic scoring systems Response to Ruxolitinib After 6 Months (RR6) model, and evaluate its prognostic value after integrating molecular biology information[high molecular risk mutations (HMR^mt) and/or RAS pathway mutations (RASp^mt)]among myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) patients treated with ruxolitinib at our institution.

Methods:
We retrospectively analyzed the clinical data and prognostic information of 153 consecutive patients diagnosed with MPN-associated MF and treated with ruxolitinib attending our hospital between May 2016 and February 2024. All patients were categorized according to RR6, dynamic International Prognostic Scoring System (DIPSS), and Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM), and compared the predictive ability of RR6 with its model after integrating with HMR^mt and/or RASp^mt.

Results:
153 patients diagnosed with primary myelofibrosis (PMF) (n=114), post-polycythemia vera (post-PV) MF (n=17), post-essential thrombocythemia (post-ET) MF (n=22) including 73 females and 80 males, with a median age of 58 (range: 28-85) years. Patients had a median follow-up time from the initiation of ruxolitinib treatment of 45(range:7-90) months, 106 (69.3%) patients survived, 47 (30.7%) patients died, and 94 (61.4%) were still receiving ruxolitinib as of the last follow-up. According to the RR6 model, 28 (18.3%), 92 (60.1%), and 33 (21.6%) of patients were classified as low, intermediate, and high risk, with an estimated median overall survival (mOS) not reached, not reached, and 32(95% CI 24.0～39.5) months, respectively (P=0.012). Using DIPSS could not have statistical significance in survival among different risk groups (P>0.05). The RR6 after integrating HMR^mt and/or RASp^mt had a higher value for performance than the original model both in terms of C-index and 1, 2, 3, 4, and 5-year AUCs, confirming its superiority versus RR6, especially RR6+HMR^mt+RASp^mt combination in both the MF and PMF patients.

Summary/Conclusion:
Compared to the DIPSS, the RR6 model could be applied for early identification of high risk MPN-associated MF and PMF patients treated with ruxolitinib, providing an opportunity to switch treatment regimens for such patients. The integration with HMR^mt and RASp^mt promotes the predictive power of RR6.

Keyword(s): Molecular cytogenetics | Prognostic groups | Ruxolitinib | Myelofibrosis

Link to Abstract PS1848

Abstract Number: PS1849

Presentation Title: THE APPLICABILITY OF CLINICAL, CYTOGENETIC, AND MOLECULAR PREDICTORS OF OUTCOME IN PATIENTS WITH MYELOFIBROSIS IN THE ERA OF JAK INHIBITORS

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

JAK2, CALR, and MPL mutations were present in 61%, 32%, and 5% of patients, respectively. Unfavorable karyotype was found in 23 out of 91 patients.
After a median follow-up of 62 months, the 5-year overall survival (OS) was 89%, with a progression rate to accelerated/blast phases (AP/BP) of 1.9 per 100 patient years, and an estimated median progression-free survival (PFS) of 22 years.
Unfavorable karyotype was linked to increased AP/BP progression and inferior OS (p<0.001), while CALR mutation was associated with AP/BP (p=0.02).
Transfusion dependency at any time point was strongly associated with adverse OS (p<0.001), whereas anemia alone was not. Peripheral blasts >3% were strongly associated with progression to AP/BP and inferior OS (p<0.001).
Outcome of myelofibrosis with JAK inhibitors has improved, with a shift in the relevance of DIPSS and MYSEC variables. Transfusion dependency and peripheral blasts >3% are key predictors of outcome, suggesting the need to adjust prognostic scores to optimize treatment strategies and timing for hematopoietic stem cell transplantation (HSCT).

Summary of Study Impact on Navtemadlin (KRT-232):

The study primarily focuses on prognostic factors in myelofibrosis (MF) patients treated with JAK inhibitors, rather than directly addressing navtemadlin (KRT-232). However, it highlights the evolving treatment landscape in MF, which indirectly supports the need for alternative therapies like navtemadlin, especially in JAK inhibitor-refractory cases.

Competitive Considerations:

The study does not introduce a new competing therapy but underscores the limitations of current JAK inhibitor treatments, reinforcing the potential role of navtemadlin in the treatment landscape.
It highlights the need for therapies that can address prognostic factors not improved by JAK inhibitors, potentially validating navtemadlin's role in post-JAK inhibitor MF treatment.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin's efficacy in JAK inhibitor-refractory MF and its potential to improve outcomes where JAK inhibitors fall short.
Focus on differentiation through efficacy in spleen volume reduction and symptom score improvement, as well as potential combination strategies with existing therapies like ruxolitinib.

Medical Affairs Implications:

KOL engagement: Discuss the durability of response and management of cytopenias, and explore sequencing strategies with JAK inhibitors.
Evidence gaps: Real-world data on navtemadlin's impact on prognostic factors like transfusion dependency and peripheral blasts could be valuable.
Communication strategy: Emphasize navtemadlin's unique mechanism and efficacy in refractory cases, positioning it as a critical option in the evolving MF treatment paradigm.

Link to Abstract PS1849

Abstract Number: PF843

Presentation Title: PROGNOSTIC IMPLICATIONS OF RED BLOOD CELL DISTRIBUTION WIDTH-TO-ALBUMIN RATIO IN PATIENTS WITH MYELOFIBROSIS: INSIGHTS FROM A 10-YEAR RETROSPECTIVE AND MULTICENTER COHORT

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=504
Higher red cell distribution width-to-albumin ratio (RAR) levels were significantly associated with leukemic transformation and death in myelofibrosis patients, indicating its potential as a prognostic marker.
RAR was an independent predictor of poor survival, with an adjusted hazard ratio of 1.58, even after adjusting for DIPSS-plus.
Integrating RAR into the DIPSS-plus score significantly improved prognostic accuracy, increasing the C-index from 0.709 to 0.762 and demonstrating significant net reclassification and integrated discrimination improvements.
The enhanced nomogram combining RAR and DIPSS-plus effectively stratified patients into high-risk and low-risk categories, with significant differences in 10-year survival predictions, offering a cost-effective tool for risk stratification in resource-limited settings.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on the red blood cell distribution width-to-albumin ratio (RAR) as a prognostic tool in myelofibrosis (MF) does not directly impact navtemadlin’s positioning. It focuses on prognostic stratification rather than therapeutic intervention, thus not challenging or supporting navtemadlin’s efficacy or safety profile.

Competitive Considerations:

The study does not introduce a competing therapy but rather a prognostic tool, which could complement therapeutic strategies like navtemadlin by identifying high-risk patients who might benefit from aggressive treatment.
It enhances the broader post–JAK inhibitor MF treatment landscape by potentially improving patient stratification, which could indirectly support the use of navtemadlin in well-defined patient subgroups.

Clinical or Market Strategy Implications:

Kartos may consider integrating RAR into clinical trial designs to better stratify patients and demonstrate navtemadlin’s efficacy in high-risk groups.
Emphasizing navtemadlin’s efficacy in JAK inhibitor-refractory MF, alongside the use of RAR for patient selection, could strengthen its market positioning.

Medical Affairs Implications:

KOL engagement: Discuss the potential of RAR in identifying patients who might benefit most from navtemadlin, focusing on durability of response and sequencing with JAK inhibitors.
Evidence gaps: Real-world data on navtemadlin’s performance in high RAR patients could be valuable, as well as subgroup analyses correlating RAR with treatment outcomes.
Communication strategy: Highlight navtemadlin’s role in treating JAK inhibitor-refractory MF, potentially in combination with RAR-based stratification to optimize patient outcomes.

Link to Abstract PF843

Abstract Number: PF828

Presentation Title: SURVIVAL IMPACT AND KINETICS OF HEMOGLOBIN IMPROVEMENT WITH MOMELOTINIB IN PATIENTS WITH MYELOFIBROSIS AND MODERATE TO SEVERE ANEMIA: POST HOC ANALYSES OF SIMPLIFY-1 AND MOMENTUM

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

In SIMPLIFY-1, 69% of patients with baseline (BL) moderate anemia and 50% with BL severe anemia achieved hemoglobin (Hb) >10 g/dL by week 24; mean times to first occurrence were 1.2 and 2.1 months, respectively.
In MOMENTUM, 47% with BL moderate anemia and 24% with BL severe anemia achieved Hb >10 g/dL by week 24; mean times to first occurrence were 1.0 and 1.7 months, respectively.
Achieving Hb >10 g/dL was associated with prolonged overall survival (OS) in both trials, regardless of BL anemia severity or JAK inhibitor experience.
In SIMPLIFY-1, median OS was not reached for responders with BL severe anemia compared to 44.1 months for nonresponders; in MOMENTUM, median OS was not reached for responders compared to 12.5 months for nonresponders.
Earlier intervention with momelotinib in patients with moderate anemia leads to faster and more frequent achievement of Hb >10 g/dL, suggesting improved clinical outcomes and validating Hb >10 g/dL as a positive prognostic factor.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on momelotinib does not directly challenge navtemadlin’s positioning but highlights the importance of addressing anemia in myelofibrosis, which could complement navtemadlin’s efficacy in spleen volume and symptom score reduction.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin but emphasizes anemia management, which is not a primary focus of navtemadlin.
It reinforces the need for comprehensive treatment strategies in post–JAK inhibitor MF, potentially positioning navtemadlin as part of a combination approach.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies with anemia-targeting agents like momelotinib to enhance overall treatment efficacy.
Emphasizing navtemadlin’s unique efficacy in spleen volume and symptom reduction could differentiate it from anemia-focused therapies.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combination therapies and the role of navtemadlin in improving quality of life through symptom and spleen volume reduction.
Evidence gaps: Real-world data on navtemadlin’s impact on anemia and its integration with anemia-targeting therapies could be valuable.
Communication strategy: Highlight navtemadlin’s efficacy in JAK inhibitor-refractory settings and its potential role in combination regimens.

Link to Abstract PF828

Abstract Number: PF827

Presentation Title: NEW CRITERIA FOR EVALUATING OUTCOMES OF MYELOFIBROSIS THERAPY: THE EUROPEAN LEUKEMIANET DEMYOS (DESIRABILITY OF MYELOFIBROSIS OUTCOMES)

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Three composite outcomes, DEMYO-1, DEMYO-2, and DEMYO-3, were developed using the Desirability-Of-Outcome-Ranking (DOOR) method, each representing different quartiles of weighted scores based on clinical relevance.
DEMYO-1 includes outcomes for patients alive and free of blast transformation, severe anemia, thrombocytopenia, severe symptom burden, and severe vascular or bleeding events, intended for trials with patients refractory to JAK inhibitors.
DEMYO-2 encompasses outcomes for patients alive and free of disease transformation, severe cytopenias, worsening anemia, major vascular events, and emergent adverse genetic abnormalities, targeting suboptimal responders to JAK inhibitors.
DEMYO-3 covers outcomes for patients alive and free of major events and severe clinical features, including incipient disease transformation markers, proposed for trials with JAK-inhibitor-naive patients.
DEMYO composite endpoints are designed to capture clinically relevant features of myelofibrosis, facilitating validation and providing insights into treatment outcomes.

Summary of Study Impact on Navtemadlin (KRT-232):

The study introduces new composite endpoints for evaluating myelofibrosis therapies, which could support navtemadlin’s positioning by providing a more comprehensive assessment of its benefits beyond traditional measures like spleen volume reduction and symptom score improvement.

Competitive Considerations:

The study does not introduce a competing therapy but rather a new framework for evaluating existing and future therapies, potentially validating navtemadlin’s role if it performs well against these composite endpoints.
This could shift the post–JAK inhibitor MF treatment landscape by emphasizing broader clinical outcomes, potentially benefiting therapies like navtemadlin that show multifaceted efficacy.

Clinical or Market Strategy Implications:

Kartos may consider incorporating these composite endpoints in ongoing and future trials to align with emerging evaluation standards and enhance regulatory submissions.
Emphasizing navtemadlin’s efficacy across multiple dimensions (e.g., survival, cytopenia management) could differentiate it in the market.

Medical Affairs Implications:

KOL engagement: Discuss the relevance of comprehensive endpoints like DEMYO in capturing the full therapeutic impact of navtemadlin, including durability of response and management of cytopenias.
Evidence gaps: Real-world data and subgroup analyses using DEMYO criteria could provide valuable insights into navtemadlin’s performance across diverse patient populations.
Communication strategy: Highlight navtemadlin’s potential to meet or exceed these new composite endpoints, reinforcing its value proposition compared to other investigational agents.

Link to Abstract PF827

Abstract Number: PF829

Presentation Title: SAFETY PROFILE OF LONG-TERM EXPOSURE TO RUXOLITINIB IN PATIENTS WITH MYELOFIBROSIS, ANALYSIS FROM A REAL-WORLD DATA NETWORK

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=16,745
Long-term ruxolitinib exposure (≥3 years) is associated with a higher incidence of non-melanoma skin cancer (NMSC) compared to ruxolitinib-naïve patients, with a trend toward increased risk in the long-term cohort.
Higher incidence of herpes zoster (HZ) infections was observed in ruxolitinib-treated cohorts, with a significant increase in the long-term exposure group.
Short-term ruxolitinib exposure is linked to a significantly higher rate of urinary tract infections, pneumonia, and sepsis, potentially due to these being discontinuation-leading events.
The incidence of infections and NMSC in the long-term exposure group persisted throughout follow-up without reaching a plateau, suggesting ongoing immunosuppression.

Summary of Study Impact on Navtemadlin (KRT-232):

The study primarily focuses on the long-term safety profile of ruxolitinib, highlighting increased risks of non-melanoma skin cancer (NMSC) and infections. It does not directly challenge navtemadlin’s positioning but underscores the need for alternative therapies post-JAK inhibitor failure, potentially reinforcing navtemadlin’s value proposition in this setting.

Competitive Considerations:

The study does not introduce a new competing therapy but highlights the limitations of ruxolitinib, validating the need for effective alternatives like navtemadlin.
It emphasizes the safety concerns associated with long-term JAK inhibitor use, potentially increasing interest in non-JAK inhibitor therapies for post-JAK inhibitor MF treatment.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin’s efficacy and safety profile in its clinical trial strategy and regulatory submissions, particularly in patients who have failed JAK inhibitors.
Highlighting navtemadlin’s differentiation in terms of efficacy and safety, especially in reducing spleen volume and symptom scores, could be beneficial.

Medical Affairs Implications:

KOL engagement: Discuss the durability of navtemadlin’s response and its potential role in managing cytopenias and sequencing with JAK inhibitors.
Evidence gaps: Real-world data on navtemadlin’s long-term safety and efficacy, as well as subgroup analyses, could be valuable.
Communication strategy: Emphasize navtemadlin’s efficacy in JAK inhibitor-refractory MF and its potential to address safety concerns associated with long-term JAK inhibitor use.

Link to Abstract PF829

Abstract Number: PF830

Presentation Title: IMPROVEMF UPDATE: PHASE 1/1B TRIAL OF IMETELSTAT (IME)+RUXOLITINIB (RUX) IN PATIENTS WITH INTERMEDIATE (INT)-1, INT-2, OR HIGH-RISK (HR) MYELOFIBROSIS (MF)

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=17
No dose-limiting toxicities (DLTs) were observed for imetelstat (IME) in part 1, and the recommended part 2 dose (RP2D) was determined to be 9.4 mg/kg.
Adverse events (AEs) were consistent with previous IME trials, with 15 patients experiencing AEs, including grade 3 events such as anemia, neutropenia, and leukopenia; no grade 4/5 AEs were reported.
Preliminary efficacy showed a median reduction in total symptom score (TSS) of −5 points up to week 24, with a trend of dose-dependent spleen volume decrease and reduction in variant allele frequency of several driver mutations.
Part 2 of the trial is ongoing, focusing on patients who are ruxolitinib (RUX) naive, indicating the potential of IME+RUX in patients with high unmet needs in myelofibrosis.

Summary of Study Impact on Navtemadlin (KRT-232):

The study of imetelstat (IME) in combination with ruxolitinib (RUX) does not directly challenge navtemadlin’s positioning but highlights a potential complementary approach in treating myelofibrosis (MF). The focus on combination therapy with RUX may suggest a strategic opportunity for navtemadlin to explore similar or alternative combinations.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin as it focuses on combination therapy rather than a single-agent approach. However, it validates the importance of exploring combination therapies in MF treatment.
It emphasizes the need for effective post-JAK inhibitor strategies, reinforcing navtemadlin’s role as a single-agent option in JAK inhibitor-refractory MF.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination trials with RUX or other agents to enhance navtemadlin’s efficacy and broaden its applicability.
Emphasizing navtemadlin’s efficacy as a single agent in JAK inhibitor-refractory settings could differentiate it from combination therapies like IME+RUX.

Medical Affairs Implications:

KOL engagement: Discuss the durability of response and potential sequencing with JAK inhibitors, highlighting navtemadlin’s role in refractory cases.
Evidence gaps: Real-world data on navtemadlin’s long-term efficacy and safety, as well as biomarker-driven patient selection, could be valuable.
Communication strategy: Position navtemadlin as a viable single-agent therapy in the post-JAK inhibitor landscape, contrasting with combination approaches.

Link to Abstract PF830

Abstract Number: PF831

Presentation Title: FIBROSIS GRADE BEFORE AND ITS RESOLUTION AFTER TRANSPLANTATION HAS NO PREDICTIVE VALUE IN MYELOFIBROSIS

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=208
Fibrosis grade before HCT was not associated with mutation clearance, donor chimerism, or clinical outcomes, with hazard ratios for relapse of 0.83 for grade 2 and 0.87 for grade 3, indicating no predictive value.
At day 100 post-HCT, 57% of patients showed improvement in fibrosis grade, but this was not linked to mutation clearance, donor chimerism, or clinical outcomes, with hazard ratios for relapse of 1.88 for grade 2 and 1.00 for grade 3.
Reduction in fibrosis grade post-HCT did not correlate with improved clinical outcomes, challenging the utility of fibrosis grade and its regression as predictive parameters for treatment response.
The study questions the inclusion of fibrosis grade and its resolution in response classifications for myelofibrosis undergoing transplantation.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on fibrosis grade in myelofibrosis undergoing transplantation does not directly impact navtemadlin’s positioning. It focuses on the predictive value of fibrosis grade in transplantation outcomes, which is not directly related to navtemadlin’s mechanism or target population.

Competitive Considerations:

The study does not introduce a competing therapy to navtemadlin. It does not validate or challenge navtemadlin’s role in the post–JAK inhibitor MF treatment landscape.
It highlights the complexity of myelofibrosis treatment but does not affect the broader post–JAK inhibitor MF treatment landscape where navtemadlin is positioned.

Clinical or Market Strategy Implications:

Kartos does not need to adjust its clinical trial strategy or market positioning based on this study. The focus remains on navtemadlin’s efficacy in JAK inhibitor-refractory MF.
Differentiation levers for navtemadlin should continue to emphasize its efficacy in spleen volume reduction and symptom score improvement.

Medical Affairs Implications:

KOL engagement: Discussions should focus on navtemadlin’s efficacy and safety profile, particularly in JAK inhibitor-refractory settings, rather than fibrosis grade implications.
Evidence gaps: Real-world data on navtemadlin’s long-term outcomes and biomarker correlations would be valuable, but fibrosis grade is not a priority.
Communication strategy: Emphasize navtemadlin’s unique position as a single agent with significant efficacy in JAK inhibitor-refractory MF, distinct from transplantation-related studies.

Abstract: PF831

Title: FIBROSIS GRADE BEFORE AND ITS RESOLUTION AFTER TRANSPLANTATION HAS NO PREDICTIVE VALUE IN MYELOFIBROSIS

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background:
Fibrosis grade in myelofibrosis impacts hematopoiesis by replacing healthy marrow with fibrotic tissue, contributing to cytopenias and extramedullary hematopoiesis. While allogeneic HCT is the only curative treatment and may reverse fibrosis, its role as a pre-transplant risk factor and its resolution post-HCT remain unclear, despite being included in response classifications.

Aims:
This is the first study to systematically impact the role of fibrosis and its resolution in myelofibrosis undergoing transplantation.

Methods:
We collected data of patients with primary or secondary myelofibrosis undergoing first HCT who received paired marrow biopsies before start of conditioning and at day 100 after HCT. Marrow fibrosis grade was classified in accordance with current standards as grade 0, 1, 2, and 3. For analysis, patients with grade 0 and 1 were combined. We analyzed the impact of fibrosis grade before and after transplantation as well as fibrosis grade reduction on clinical outcomes. For analysis of fibrosis grade after transplantation, landmark analysis from day 100 were performed. We assessed associations with donor chimerism, mutation clearance, relapse incidence, and survival outcomes.

Results:
We included 208 patients with paired marrow samples before start of conditioning and at day 100 after HCT, of whom 63% had primary myelofibrosis, 20% had post essential thrombocythemia and 17% had post polycythemia vera myelofibrosis. Frequencies of driver mutations were 77% for JAK2, 20% for CALR, and 3% for MPL. Risk according to DIPSS was low risk (2%), intermediate-1 (16%), intermediate-2 (60%), and high risk (20%). All patient received busulfan based reduced intensity conditioning

Fibrosis grade before HCT was grade 0 in 1%, grade 1 in 7%, grade 2 in 20%, and grade 3 72% of patients. No association with other clinical and molecular pre-HCT parameters were identified, except for high molecular risk mutations that appeared to be associated with higher grade of fibrosis (P=0.05). Fibrosis grade before HCT was not associated with mutation clearance, donor chimerism, or clinical outcomes, with a hazard ratio for relapse (with grade 0-1 as reference) of 0.83 for grade 2 (P=0.80), and 0.87 for grade 3 (P=0.85).

At day 100 after HCT, 57% of patients showed improvement in fibrosis grade. Only 3 out of 208 patients showed increased in fibrosis grade from grade 2 to grade 3. Fibrosis grade at day 100 after HCT was grade 0 in 19%, grade 1 in 31%, grade 2 in 17%, and grade 3 in 33% of patients. Fibrosis grade at day 100 was not associated with mutation clearance, donor chimerism or clinical outcomes, with a hazard ratio for relapse (with grade 0-1 as reference) of 1.88 for grade 2 (P=0.10), and 1.00 for grade 3 (P=0.99). Last, reduction in fibrosis was not associated with clinical outcomes.

Summary/Conclusion:
Neither fibrosis grade before nor at day 100 after HCT were associated with molecular response, donor chimerism, or clinical outcomes, questioning the value of fibrosis grade and fibrosis regression for response assessment as predictive parameter for outcome.

Keyword(s): Myelofibrosis

Link to Abstract PF831

Abstract Number: PF833

Presentation Title: FINAL RESULTS OF A PILOT STUDY OF ELOTUZUMAB IN PATIENTS WITH MYELOFIBROSIS

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=15
Elotuzumab (Elo) demonstrated activity in myelofibrosis (MF) with six objective responses observed in five patients, including symptom improvement, platelet response, and anemia response.
Median follow-up for living patients was 18.1 months, with median survival not reached, indicating potential for prolonged disease stabilization.
Adverse events were generally mild, with grade 3 diarrhea in one patient and grade 2 infusion-related reactions in three patients, suggesting Elo is well-tolerated.
Combination studies with JAK inhibitors in early MF are recommended based on the observed efficacy and safety profile of Elo.

Summary of Study Impact on Navtemadlin (KRT-232):

The study of elotuzumab (Elo) in myelofibrosis (MF) patients does not directly challenge navtemadlin’s positioning but suggests potential complementary strategies, particularly in combination therapies.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin, as Elo targets a different mechanism (SLAMF7) and patient population (non-JAK inhibitor candidates).
It highlights the potential for combination therapies in MF, which could influence the broader post-JAK inhibitor treatment landscape.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination trials with Elo or similar agents to enhance efficacy in MF treatment.
Emphasizing navtemadlin’s efficacy in JAK inhibitor-refractory MF and its unique mechanism of restoring p53 function could differentiate it from other therapies.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combination therapies and the role of navtemadlin in JAK inhibitor-refractory settings.
Evidence gaps: Real-world data on navtemadlin’s long-term efficacy and safety, as well as biomarker-driven patient selection, would be valuable.
Communication strategy: Highlight navtemadlin’s unique mechanism and its efficacy in improving spleen volume and symptom scores in refractory MF.

Link to Abstract PF833

Abstract Number: PF837

Presentation Title: GECACITINIB IN JAKI-NAÏVE AND JAKI-EXPOSED MYELOFIBROSIS PATIENTS: IMPROVED TRANSFUSION INDEPENDENCE

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects: 216 (137 JAKi-naïve, 79 JAKi-exposed)
Gecacitinib achieved transfusion independence (TI) conversion rates of 51.6% in JAKi-naïve patients and 28.6% in ruxolitinib-intolerant patients using an HGB threshold of 80 g/L.
For an HGB threshold of 85 g/L, TI conversion rates were 48.8% for JAKi-naïve patients and 26.5% for ruxolitinib-intolerant patients.
Median TI duration was 13.4 months for JAKi-naïve patients and not reached for JAKi-exposed patients, with a 12-month TI maintenance rate of 68.6% in ruxolitinib-intolerant patients at 80 g/L and 88.9% at 85 g/L.
Gecacitinib shows promise as a therapy for anemia management in MF, with higher efficacy in JAKi-naïve patients, supporting its use for early intervention.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on gecacitinib does not directly challenge navtemadlin’s positioning but highlights a complementary approach in managing myelofibrosis, particularly focusing on anemia and transfusion independence. Navtemadlin’s efficacy in spleen volume and symptom score reduction remains distinct.

Competitive Considerations:

The study introduces gecacitinib as a potential competitor in the MF treatment landscape, particularly for anemia management, but does not directly compete with navtemadlin’s mechanism of action or primary endpoints.
Gecacitinib’s focus on transfusion independence may complement navtemadlin’s role in post-JAK inhibitor MF treatment, potentially leading to combination strategies.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination trials with gecacitinib to address both spleen volume reduction and anemia management in MF patients.
Emphasizing navtemadlin’s unique efficacy in spleen volume and symptom score reduction could differentiate it from therapies like gecacitinib.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combination therapies and the sequencing of navtemadlin with other agents like gecacitinib.
Evidence gaps: Real-world data on navtemadlin’s long-term efficacy and safety, particularly in combination with other agents, would be valuable.
Communication strategy: Highlight navtemadlin’s role in addressing spleen volume and symptom burden, positioning it as a complementary therapy to anemia-focused treatments.

Abstract: PF837

Title: GECACITINIB IN JAKI-NAÏVE AND JAKI-EXPOSED MYELOFIBROSIS PATIENTS: IMPROVED TRANSFUSION INDEPENDENCE

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background:
Gecacitinib (also known as jaktinib) is a novel dual inhibitor targeting JAK (JAK1, JAK2, JAK3, TYK2) and ACVR1. By blocking the JAK-STAT pathway, it reduces inflammation and splenomegaly. Additionally, through inhibition of ACVR1, it downregulates hepcidin, improves iron metabolism, and increases hemoglobin levels, thereby significantly reducing anemia and transfusion dependency in myelofibrosis (MF) patients. To date, the efficacy and safety of gecacitinib have been evaluated in three Phase 2 trials (ZGJAK002, ZGJAK006, ZGJAK017) and one Phase 3 trial (ZGJAK016). However, in MF, there is no consensus on using anemia-related responses as efficacy endpoints, with hemoglobin (HGB) thresholds such as 8.0 or 8.5 g/dL typically employed.

Aims:
We aimed to validate the clinical benefits of gecacitinib in achieving transfusion independence among both JAKi-naïve and JAKi-exposed patients with MF. Here, we present two thresholds for analysis as a reference.

Methods:
This analysis included MF pts who received gecacitinib 100 mg bid in 3 phase 2 trails (ZGJAK002, ZGJAK006, ZGJAK017) and one Phase 3 trial (ZGJAK016). The study evaluated two primary endpoints in non-transfusion-independent patients at baseline: Transfusion independence (TI) conversion rate, defined as the proportion achieving ≥ 12 consecutive weeks without RBC transfusions (excluding overt bleeding) and hemoglobin (HGB) levels ≥ 80 g/L or ≥ 85 g/L (dual-threshold analysis); TI duration, measured from the start of the 12-week TI period to the first transfusion requirement (non-bleeding) or HGB decline below the corresponding threshold (80 g/L or 85 g/L).

Results:
The main results are presented in Table 1. A total of 137 JAKi-naïve patients and 79 JAKi-exposed patients (45 ruxolitinib-intolerant and 34 ruxolitinib-relapsed/refractory) were included in the study. Using the hemoglobin (HGB) threshold of 80 g/L, 31 JAKi-naïve, 28 ruxolitinib-intolerant, and 8 ruxolitinib-relapsed/refractory patients were non-TI at baseline. Among these patients, the corresponding TI conversion rates were 51.6% (16/31) for JAKi-naïve patients, 28.6% (8/28) for ruxolitinib-intolerant patients, and 25.0% (2/8) for ruxolitinib-relapsed/refractory patients. The median TI duration was 13.4 months in JAKi-naïve patients, and it was not reached in JAKi-exposed patients. The 12-month TI maintenance rate was 68.6% in ruxolitinib-intolerant patients.

For the HGB threshold of 85 g/L, 43 JAKi-naïve, 34 ruxolitinib-intolerant, and 11 ruxolitinib-relapsed/refractory patients were non-TI at baseline. The corresponding TI conversion rates were 48.8% (21/43) for JAKi-naïve patients, 26.5% (9/34) for ruxolitinib-intolerant patients, and 18.2% (2/11) for ruxolitinib-relapsed/refractory patients. The median TI duration was 15.7 months in JAKi-naïve patients, while it was not reached in JAKi-exposed patients. The 12-month TI maintenance rate was 88.9% in ruxolitinib-intolerant patients.

Summary/Conclusion:
Gecacitinib demonstrated clinically meaningful TI conversion rates and prolonged transfusion-free intervals in both JAKi-naïve and JAKi-exposed patients with MF, with higher efficacy observed in JAKi-naïve patients. These outcomes were consistent regardless of the hemoglobin threshold used. This study supports gecacitinib as a promising therapy for anemia management in MF, highlighting the importance of early intervention.

Keyword(s): Janus Kinase inhibitor | Anemia | Myelofibrosis | Blood transfusion

Link to Abstract PF837

Abstract Number: PF841

Presentation Title: IMPACTMF, RANDOMIZED, OPEN-LABEL, PHASE 3 TRIAL OF IMETELSTAT VERSUS BEST AVAILABLE THERAPY IN PATIENTS WITH INTERMEDIATE-2 OR HIGH-RISK MYELOFIBROSIS RELAPSED OR REFRACTORY TO JANUS KINASE INHIBITORS

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Imetelstat (IME) demonstrated a median overall survival (OS) of 29.9 months in a phase 2 trial for myelofibrosis (MF) patients, with 32% achieving a ≥50% reduction in total symptom score and 10% achieving a ≥35% reduction in spleen volume.
IME treatment improved bone marrow fibrosis and reduced MF driver mutation variant allele frequency, correlating with improved OS.
The most common grade ≥3 adverse events were thrombocytopenia, anemia, and neutropenia, which were generally manageable and resolved to grade ≤2 in less than 4 weeks.
The phase 3 IMpactMF trial is evaluating IME versus best available therapy (BAT) in approximately 320 adults with intermediate-2 or high-risk MF relapsed or refractory to Janus kinase inhibitors, with OS as the primary endpoint.
As of December 2024, approximately 75% of patients have been enrolled across 172 sites globally, with interim analysis expected in early 2026 and final analysis in early 2027.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on imetelstat (IME) presents a potential competitive challenge to navtemadlin (KRT-232) by introducing a novel mechanism of action in the post-JAK inhibitor myelofibrosis (MF) treatment landscape. However, navtemadlin's demonstrated efficacy in spleen volume and symptom score reduction in the BOREAS trial reinforces its value proposition.

Competitive Considerations:

The IMpactMF trial introduces imetelstat as a potential competitor with a different mechanism (telomerase inhibition) and a focus on overall survival (OS) as a primary endpoint, which could appeal to clinicians seeking long-term outcomes.
Navtemadlin's efficacy in JAK inhibitor-refractory MF is validated, but the introduction of imetelstat may shift focus towards combination therapies or alternative mechanisms.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin's efficacy in symptom and spleen volume reduction, potentially exploring combination strategies with other agents like ruxolitinib to enhance outcomes.
Highlighting navtemadlin's safety profile and its role in improving quality of life could differentiate it from imetelstat, which has notable cytopenia-related adverse events.

Medical Affairs Implications:

KOL engagement: Discussions could focus on the durability of response and management of cytopenias, positioning navtemadlin as a viable option in sequencing with JAK inhibitors.
Evidence gaps: Real-world data on long-term outcomes and subgroup analyses could strengthen navtemadlin's positioning, especially in patients with specific biomarker profiles.
Communication strategy: Emphasizing navtemadlin's unique benefits in symptom management and spleen volume reduction could reinforce its value against other investigational agents like imetelstat.

Link to Abstract PF841

Abstract Number: PF842

Presentation Title: LYMPHOCYTE TO MONOCYTE RATIO MAY PREDICT TRANSFORMATION TO MYELOFIBROSIS FOR POLYCYTHEMIA VERA PATIENTS TREATED WITH RUXOLITINIB: EXPERIENCE FROM MAJIC-PV TRIAL

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=180
LMR at baseline and six months in ruxolitinib-treated PV patients predicted transformation to myelofibrosis (PPV-MF) with high specificity and sensitivity, achieving a specificity of 0.805 and sensitivity of 0.8 at baseline, and specificity of 0.831 and sensitivity of 1 at six months.
LMR did not meet the ideal threshold for predicting other transformations or achieving a partial molecular response, although the six-month NLR approached the threshold for patients treated with BAT.
Ruxolitinib treatment resulted in fewer transformations to myelofibrosis compared to BAT, with 5 cases in the ruxolitinib arm versus 10 in the BAT arm.
This analysis suggests LMR could be a potential predictive marker for transformation to PPV-MF in ruxolitinib-treated PV patients, warranting further studies to confirm its clinical utility.

Summary of Study Impact on Navtemadlin (KRT-232):

The study does not directly impact navtemadlin’s positioning as it focuses on predictive markers for transformation in polycythemia vera (PV) patients treated with ruxolitinib, rather than on treatment efficacy in myelofibrosis (MF) post-JAK inhibitor failure. However, it highlights the importance of understanding disease progression, which could indirectly support navtemadlin’s role in managing MF.

Competitive Considerations:

The study does not introduce a competing therapy to navtemadlin but emphasizes the need for effective treatments post-JAK inhibitor failure, reinforcing navtemadlin’s potential role in this space.
It underscores the complexity of MF progression, suggesting that navtemadlin’s efficacy in JAK inhibitor-refractory MF could be a significant advantage in the treatment landscape.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin’s efficacy in JAK inhibitor-refractory MF and exploring combination strategies, such as with ruxolitinib, to enhance treatment outcomes.
Highlighting navtemadlin’s efficacy and safety profile, particularly in terms of spleen volume reduction and symptom score improvement, could differentiate it in the market.

Medical Affairs Implications:

KOL engagement: Discuss the durability of navtemadlin’s response and its potential role in sequencing with JAK inhibitors.
Evidence gaps: Real-world data on navtemadlin’s long-term efficacy and safety, as well as biomarker correlations, would be valuable to clinicians.
Communication strategy: Emphasize navtemadlin’s unique position as a single agent showing significant efficacy in JAK inhibitor-refractory MF, compared to other investigational agents.

Link to Abstract PF842

Abstract Number: PF845

Presentation Title: ALPHABETA T-CELL / CD19 GRAFT DEPLETED ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN COMBINATION WITH POST-TRANSPLANT RUXOLITINIB FOR MYELOFIBROSIS

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=28
No graft failure occurred, with a cumulative incidence of grade 2-4 and 3-4 acute GVHD at day 100 being 29% and 7%, respectively, and only 1 case of moderate-severe chronic GVHD.
The 2-year non-relapse mortality (NRM) was 16%, with hematological and molecular relapse rates at 15% and 25%, respectively.
Overall survival at 2 years was 84% (95% CI 70-99), event-free survival was 69% (95% CI 52-92), and GVHD-free, relapse-free survival (GRFS) was 62% (95% CI 45-86).
Combining myeloablative conditioning with ex vivo αβTCR/CD19 depletion and post-transplant ruxolitinib supports engraftment and reduces severe GVHD, with MRD-guided DLI further improving outcomes.

Summary of Study Impact on Navtemadlin (KRT-232):

The study does not directly challenge navtemadlin’s positioning as it focuses on a different therapeutic approach (allo-SCT with ruxolitinib) for myelofibrosis. However, it highlights the potential of combining existing therapies to improve outcomes, which could indirectly support navtemadlin’s use in combination strategies.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin but validates the role of ruxolitinib in combination therapies, which could complement navtemadlin’s development in combination with ruxolitinib.
It emphasizes the need for effective post–JAK inhibitor treatments, reinforcing the importance of navtemadlin’s role in the MF treatment landscape.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing combination strategies in their clinical trials, particularly with ruxolitinib, to enhance navtemadlin’s efficacy and market positioning.
Focus on differentiation through efficacy in JAK inhibitor–refractory patients and potential biomarkers for patient selection.

Medical Affairs Implications:

KOL engagement: Discuss the durability of response and potential sequencing with JAK inhibitors, highlighting navtemadlin’s role in refractory cases.
Evidence gaps: Real-world data on navtemadlin’s efficacy in combination with ruxolitinib and subgroup analyses could be valuable.
Communication strategy: Emphasize navtemadlin’s unique mechanism and efficacy in refractory MF, positioning it as a key player in combination therapies.

Abstract: PF845

Title: ALPHABETA T-CELL / CD19 GRAFT DEPLETED ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN COMBINATION WITH POST-TRANSPLANT RUXOLITINIB FOR MYELOFIBROSIS

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background:
Myelofibrosis (MF) remains curable only through allogeneic stem cell transplantation (allo-SCT), however, the widespread use of allo-SCT is restricted by factors such as advanced patient age and increased risks of graft failure and Graft-versus-Host Disease (GVHD).

Aims:
We aimed to develop an allo-SCT platform utilizing myeloablative conditioning with ex vivo αβTCR/CD19 depletion, further tailored for MF patients by incorporating post-transplant ruxolitinib (RUX) and MRD-guided donor lymphocyte infusions (DLI), to improve GVHD-free, relapse-free survival (GRFS) in MF.

Methods:
This retrospective study analyzed 28 primary or secondary MF patients who underwent allo-SCT at UMCU (June 2017-January 2024, data cutoff: October 1, 2024). Written consent followed JACIE guidelines. Peripheral blood-derived allografts from 10/10 or 9/10 matched donors were used. Myeloablative conditioning included ATG (Thymoglobulin®), fludarabine, and busulfan. αβTCR/CD19 graft engineering was done using established protocols (Stuut et al., BMT, in press). GVHD prophylaxis involved MMF (28 days) and ruxolitinib (5 mg BID, 14 days). From 2021 onwards, minimal residual disease (MRD) was monitored by droplet digital PCR (ddPCR), with preemptive DLIs administered for MRD exceeding 0.1% at two consecutive timepoints. Immune reconstitution was assessed using flow cytometry per standard care, and proteomic analysis was performed using the Olink® platform at weeks 1, 2, 3 and 4 post allo-SCT.

Results:
The median patient age was 65 years (range 43-72). No graft failure occurred. The cumulative incidence (CI) of grade 2-4 and 3-4 acute GVHD at day 100 was 29% and 7%, respectively, with only 1 case of moderate-severe chronic GVHD. The 2-year non-relapse mortality (NRM) was 16%. The 2-year hematological and molecular relapse rates were 15% and 25%, respectively. Four of five patients with hematological relapse achieved complete remission (CR) following therapeutic DLI (n=3) or second allo-SCT (n=1) (Figure 1). Patients with molecular relapse received a median of two pre-emptive DLIs (1×10⁶ and 5×10⁶ CD3 cells/kg), which was successful in all but one patient who died from a cardiac event. At 2 years, the overall survival was 84% (95% CI 70-99), event-free survival was 69% (95% CI 52-92), and GRFS was 62% (95% CI 45-86).

Flow cytometry revealed that early immune reconstitution (<100 days) was primarily driven by NK and γδT cells, with αβT and B cells recovering gradually over time. By one year post allo-SCT, median cell counts reached 193 cells/uL for B cells, 204 cells/uL for CD8⁺ T cells⁺, and 155 cells/uL for CD4⁺ T cells. Proteomic analyses at weeks 2 and 4 post allo-SCT showed a relative decrease of proteins linked to Th1 responses and antigen presentation compared to healthy donors.

Summary/Conclusion:
Combining myeloablative conditioning with ex vivo αβTCR/CD19 depletion and a short course of RUX post-allo-SCT supports engraftment while reducing severe GVHD. This approach likely mitigates GVHD by delaying αβT and B cell reconstitution and suppressing pro-inflammatory pathways. MRD-guided DLI further improves outcomes, yielding a promising 2-year GRFS in MF patients with a very low incidence of moderate-severe cGVHD.

Keyword(s): Myelofibrosis | Allogeneic hematopoietic stem cell transplant | Ruxolitinib

Link to Abstract PF845

Abstract Number: PF849

Presentation Title: HEMATOLOGIC IMPROVEMENT EXPERIENCED BY PACRITINIB-TREATED PATIENTS WITH MYELOFIBROSIS IN REAL-WORLD CLINICAL SETTINGS

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=90
52.2% of patients treated with pacritinib achieved a platelet (PLT) response within 90 days, with a median time to response of 51 days.
Patients with a PLT response showed significant increases in median PLT counts from 64 x10⁹/L at index to 97.5 x10⁹/L at day 90, remaining stable through day 180.
Hemoglobin levels also improved in patients with a PLT response, increasing from a median of 8.8 g/dL at index to 9.4 g/dL at day 90.
Overall survival (OS) was similar between patients achieving a PLT response and those who did not, indicating the need for longer follow-up to assess survival benefits.
OS in patients with thrombocytopenia treated with pacritinib compares favorably to historical controls.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on pacritinib does not directly challenge navtemadlin’s positioning but highlights an alternative treatment option for myelofibrosis patients with thrombocytopenia. Navtemadlin’s efficacy in JAK inhibitor-refractory MF remains distinct, particularly in spleen volume and symptom score reduction.

Competitive Considerations:

The study introduces pacritinib as a potential competitor in the MF treatment landscape, particularly for patients with thrombocytopenia, but does not directly compete with navtemadlin’s mechanism or target population.
Pacritinib’s focus on hematologic improvement complements the broader MF treatment landscape, potentially positioning it as a supportive therapy rather than a direct competitor to navtemadlin.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin’s unique efficacy in spleen volume and symptom score reduction, particularly in JAK inhibitor-refractory settings, to differentiate from pacritinib.
Highlighting navtemadlin’s role in combination therapies, such as with ruxolitinib, could further strengthen its market position.

Medical Affairs Implications:

KOL engagement: Focus on discussing navtemadlin’s efficacy in spleen volume reduction and symptom improvement, and its potential in combination therapies.
Evidence gaps: Real-world data on navtemadlin’s long-term outcomes and biomarker correlations could enhance its clinical appeal.
Communication strategy: Emphasize navtemadlin’s efficacy in JAK inhibitor-refractory MF and its potential in combination regimens to differentiate from other treatments like pacritinib.

Abstract: PF849

Title: HEMATOLOGIC IMPROVEMENT EXPERIENCED BY PACRITINIB-TREATED PATIENTS WITH MYELOFIBROSIS IN REAL-WORLD CLINICAL SETTINGS

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background:
Patients (pts) with myelofibrosis (MF) and thrombocytopenia have poor prognosis, worse overall survival (OS) and greater treatment burden. Pacritinib (PAC) is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 associated with hematological stability or improvement with full-dose but real-world data on the hematological response is limited.

Aims:
To evaluate treatment outcomes for pts with MF and thrombocytopenia who achieved a platelet (PLT) response within 90 days of PAC initiation in real-world clinical practice.

Methods:
Integra-PrecisionQ database, de-identified electronic health data and practice management data (roughly 80% community oncology practices) was used for this retrospective observational study. Pts with MF treated with PAC between 6/01/2022 and 6/30/2024 with PLT <100 x10⁹/L at the time of PAC initiation (index) were included. PLT response was defined per International Working Group (IWG) criteria: baseline PLT <20 x10⁹/L increasing to >20 x10⁹/L and by at least 100%, or baseline PLT 20-100 x10⁹/L with an absolute increase of ≥30 x10⁹/L. Treatment-related outcomes including PLT and hemoglobin levels (Hb) from post-index day 90 through the end of the study period, and OS probabilities from post-index day 90 were estimated for pts achieving a PLT response within 90 days of index. Continuous variables were summarized using medians, and interquartile range (IQR), and categorical variables were described using counts and percentages.

Results:
Among the 90 pts treated with PAC with PLT <100 x10⁹/L at index and ≥90 days of follow-up, 52.2% (47/90) met the criteria for PLT response with median time to response of 51 days (IQR: 21, 103) from index. 70.2% (33/47) of pts with a PLT response achieved PLT response within 90-days following PAC initiation with a median time to response of 26 days (16, 57). Among those with a PLT response by day 90 (n=33), the median age was 76 years (IQR: 70, 80) at index, 66.7% were males, and 64% were White. An equal number of pts received PAC in the first- and second-line (n=14 each). For those with a PLT response by day 90 (n=33), the median (IQR) PLT count was 64 x10⁹/L (45, 81) at index, 97.5 x10⁹/L (67, 128) at post-index day 90, and remained stable through day 180 (94 x10⁹/L; IQR: 63, 116). Among pts who did not meet the PLT response criteria by day 90 (n=57), median PLT count was 41 x10⁹/L (23, 57) at index, 33 x10⁹/L (19, 55) at day 90, and remained stable through day 180 (35.5 x10⁹/L; IQR: 21, 53). Increases in median (IQR) Hb were observed among pts with a PLT response by day 90 from index (8.8 g/dL; 7.9, 10.1) to day 90 (9.4 g/dL; 7.9, 10.6), and through day 180 (9.2 g/dL; 7.9, 10.6). Among those not achieving a PLT response by day 90, median (IQR) Hb remained stable from index (8.8 g/dL; 7.5, 10.6) through day 90 (8.5 g/dL; 7.7, 9.8) and day 180 (8.5 g/dL; 7.7, 10.1). From post-index day 90, 6-month survival probability was

Summary/Conclusion:
Almost half of PAC-treated pts with thrombocytopenia experienced a PLT response in this real-world analysis. Meaningful increases in PLT and Hb were observed in pts with a PLT response within 90 day of PAC initiation. OS was consistent among pts meeting the criteria for PLT response by day 90 and those who did not suggesting that longer follow-up may be required to delineate survival benefits from in those with a PLT response. However, OS in patients with thrombocytopenia compares favorably to published historic controls.

Keyword(s): Platelet | Real world data | Thrombocytopenia | Janus Kinase inhibitor

Link to Abstract PF849

Abstract Number: PF850

Presentation Title: GECACITINIB-INDUCED SPLEEN VOLUME REDUCTION (SVR) AND ITS PROGNOSTIC VALUE FOR OVERALL SURVIVAL (OS) IN MYELOFIBROSIS

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=118
Spleen volume reduction (SVR) ≥35% at week 24 was significantly associated with improved overall survival (OS) in patients treated with gecacitinib, with a hazard ratio (HR) of 0.13 (95% CI: 0.04, 0.45; P =0.0013).
Trends toward improved OS were observed in the ≥20% to <35% SVR group (HR =0.45, P =0.14) and the ≥10% to <20% SVR group (HR =0.75, P =0.60), though these did not reach statistical significance.
The DIPSS Intermediate-1 group showed a significant survival advantage over the Intermediate-2/High group (HR = 0.33, 95% CI: 0.11, 0.97).
Higher baseline hemoglobin levels (≥100g/L) showed a potential protective trend for survival (HR =0.47, 95% CI: 0.20, 1.10), though not statistically significant.
Other factors such as dose group, bone marrow fibrosis grade, JAK2 mutation status, myelofibrosis type, and disease duration did not significantly affect survival risk.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on gecacitinib does not directly challenge navtemadlin’s positioning but highlights the competitive landscape in myelofibrosis treatment, particularly in the context of JAK inhibitor-naïve patients. Navtemadlin’s efficacy in JAK inhibitor-refractory MF remains distinct.

Competitive Considerations:

The study introduces gecacitinib as a potential competitor in the MF space, particularly for JAK inhibitor-naïve patients, but does not directly compete with navtemadlin, which targets JAK inhibitor-refractory cases.
Gecacitinib’s dual inhibition mechanism may influence the broader MF treatment landscape by offering an alternative for patients who have not yet received JAK inhibitors.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin’s unique positioning in JAK inhibitor-refractory MF and explore combination strategies with JAK inhibitors for broader applicability.
Highlighting navtemadlin’s efficacy in spleen volume reduction and symptom score improvement could differentiate it from other therapies.

Medical Affairs Implications:

KOL engagement: Focus on discussing navtemadlin’s role in refractory settings, its efficacy in symptom management, and potential sequencing with JAK inhibitors.
Evidence gaps: Real-world data on long-term outcomes and biomarker-driven patient selection could enhance navtemadlin’s clinical narrative.
Communication strategy: Emphasize navtemadlin’s efficacy in refractory MF and its potential in combination therapies to strengthen its value proposition.

Link to Abstract PF850

Abstract Number: PF851

Presentation Title: OPHTHALMOLOGICAL MANIFESTATIONS OF MYELOFIBROSIS AT THE ONSET AND DURING THERAPY

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Ophthalmologic manifestations in primary MF include higher frequency of retinal angiopathy, angioretinopathy, decreased retinal sensitivity, FAZ remodeling, and low vascular and perfusion density of the retina, choroid, and optic disc.
Ruxolitinib therapy for MF showed a positive therapeutic effect on ophthalmologic parameters, improving FAZ perimeter, and increasing vascular and perfusion density compared to the onset of MF and hydroxycarbamide therapy.
Retinal angiopathy and angioretinopathy were associated with low platelet count, low erythrocyte count, low hemoglobin level, high fibrosis degree, and presence of the JAK2V617F mutation.
Increased frequency of angiopathy correlated with leukocyte counts outside the normal range, high erythrocyte count, and high risk according to DIPSS.
The study highlights the importance of including ophthalmological consultation in the examination algorithm for MF patients.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on ophthalmological manifestations in myelofibrosis (MF) does not directly impact navtemadlin’s positioning. It focuses on the ocular effects of MF and treatments like ruxolitinib, without addressing MDM2 inhibitors or navtemadlin specifically.

Competitive Considerations:

The study does not introduce a competing therapy to navtemadlin. It highlights the safety of ruxolitinib on ocular health, which may indirectly support its use in combination with navtemadlin.
It reinforces the importance of comprehensive patient management in MF, potentially supporting navtemadlin’s role in a broader treatment strategy post-JAK inhibitor failure.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin’s efficacy in combination with ruxolitinib, as explored in the POIESIS trial, to address suboptimal responders.
Differentiation levers should focus on navtemadlin’s unique mechanism of restoring p53 function and its efficacy in JAK inhibitor-refractory MF.

Medical Affairs Implications:

KOL engagement: Discuss the potential for navtemadlin to be part of a combination therapy strategy, addressing durability of response and sequencing with JAK inhibitors.
Evidence gaps: Real-world data on navtemadlin’s long-term effects and its impact on quality of life, including ocular health, could be valuable.
Communication strategy: Emphasize navtemadlin’s efficacy in refractory settings and its potential synergy with existing therapies like ruxolitinib.

Link to Abstract PF851

Abstract Number: PF852

Presentation Title: RESULTS OF ALLOGENEIC STEM CELL TRANSPLANTATION IN ADVANCED MYELOFIBROSIS

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=420
Five-year overall survival (OS) for patients with ≥5% blasts was 46.1%, with stratified OS rates of 57.6% for advanced chronic phase (advCP), 49.4% for accelerated phase (AP), and 26.0% for blast phase (BP).
Allo-HSCT showed a five-year OS of 52.8% compared to 31.6% in non-transplanted patients, indicating a potential survival advantage, though not statistically significant (p = 0.169).
Subgroup analysis suggested younger patients (<65 years), those with hemoglobin <10 g/dL, and platelet count <100K may benefit more from allo-HSCT, particularly in advCP and AP phases.
Non-relapse mortality remains a significant challenge, highlighting the need for improved pre-transplant disease control and optimized conditioning regimens.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on allogeneic stem cell transplantation (allo-HSCT) in advanced myelofibrosis (MF) does not directly challenge navtemadlin’s positioning. Instead, it highlights the limitations of current curative approaches, reinforcing the need for effective treatments like navtemadlin in the post–JAK inhibitor setting.

Competitive Considerations:

The study does not introduce a new competing therapy but underscores the challenges of allo-HSCT, validating the need for alternative treatments like navtemadlin.
It highlights the unmet need in the post–JAK inhibitor MF treatment landscape, where navtemadlin has shown promising results.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin’s role in improving outcomes for patients who are not candidates for allo-HSCT or have failed JAK inhibitors.
Focus on differentiation through navtemadlin’s efficacy in spleen volume reduction and symptom score improvement, as well as its oral administration advantage.

Medical Affairs Implications:

KOL engagement: Discuss navtemadlin’s potential as a non-transplant option, its efficacy in JAK inhibitor–refractory MF, and its role in combination therapies.
Evidence gaps: Real-world data on navtemadlin’s long-term outcomes and its use in specific subgroups (e.g., younger patients, those with anemia) could be valuable.
Communication strategy: Highlight navtemadlin’s efficacy and safety profile compared to the high-risk nature of allo-HSCT, positioning it as a viable alternative or adjunct in MF management.

Link to Abstract PF852

Abstract Number: PF854

Presentation Title: A REAL-WORD STUDY ON THE EFFICACY AND SAFETY OF SELINEXOR PLUS RUXOLITINIB REGIMEN IN RUXOLITINIB-RESISTANT MYELOFIBROSIS

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=33
The combination of Selinexor (SEL) and Ruxolitinib (RUX) demonstrated promising efficacy in RUX-resistant myelofibrosis (MF) patients, with spleen size reduction observed in 75.8% of patients and a median response time of 2.5 months.
Peripheral monocyte decline was noted in 84.8% of patients after three weeks of treatment, and peripheral blood blasts decreased in 54.5% of patients after one month.
Four patients successfully underwent bridging to transplantation and are currently surviving with good recovery.
The most common adverse reactions included nausea, vomiting, and cytopenia, indicating a manageable safety profile for the SEL and RUX regimen.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on selinexor plus ruxolitinib supports navtemadlin’s positioning by highlighting the need for effective treatments in JAK inhibitor-resistant myelofibrosis. While it introduces a potential combination therapy, it does not directly compete with navtemadlin’s unique mechanism as a single-agent MDM2 inhibitor.

Competitive Considerations:

The study introduces a combination therapy that could be seen as a competitor, but it also validates the need for alternative treatments in the post-JAK inhibitor setting, reinforcing navtemadlin’s role.
It highlights the ongoing challenge in treating JAK inhibitor-resistant MF, suggesting a broader acceptance of novel therapies like navtemadlin.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin’s single-agent efficacy and exploring combination strategies, possibly with ruxolitinib, to enhance its market positioning.
Focus on differentiation through navtemadlin’s unique mechanism of action, efficacy in spleen volume reduction, and symptom score improvement.

Medical Affairs Implications:

KOL engagement: Discuss the durability of response and management of cytopenia, and explore sequencing strategies with JAK inhibitors.
Evidence gaps: Real-world data and subgroup analyses, particularly in high-risk patients, could strengthen navtemadlin’s clinical narrative.
Communication strategy: Emphasize navtemadlin’s efficacy as a single agent and its potential in combination therapies to differentiate from other investigational agents.

Abstract: PF854

Title: A REAL-WORD STUDY ON THE EFFICACY AND SAFETY OF SELINEXOR PLUS RUXOLITINIB REGIMEN IN RUXOLITINIB-RESISTANT MYELOFIBROSIS

Type: Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background:
Selinexor(SEL) is a selective exportin 1 (XPO1) inhibitor, which blocks XPO1-mediated nuclear cargo export. Selinexor has been linked to restoring p53 activity, and also has shown inhibitory effects on signaling pathways involving transforming growth factor β (TGF-β) and NF-κB pro-inflammatory signaling. Ruxolitinib(RUX) discontinuation rates were approximately 50% by 3 years.

Aims:
Report on the efficacy and safety of SEL combined with RUX in RUX-resistant MF patients in a retrospective study.

Methods:
This is a retrospective multicenter study aimed at evaluating the efficacy and safety of SEL combined with RUX regimen in RUX-resistant MF patients. The study included 33 MF patients with a poor response to RUX: 21 with PMF, 5 with post-PV MF, and 7 with post-ET MF. Patients received SEL at 20 mg, 40 mg, or 60 mg QW plus RUX (dosage determined by the investigator).

Results:
The median age is 53 (range,37-71) years and the median duration of previous RUX treatment is 13.4 (4.5-45) months. 15(45.45%) of patients had peripheral blood blasts of 1-9%. 24 patients (72.7%) harbored JAK2 mutation, 3 (9.1%) patients CALR mutation and 1 (3.0%) patient with MPL mutation. All patients had splenomegaly, and 12 (36.4%) were transfusion-dependent. According to the DIPSS risk score, 14 patients (52.4%) were classified as high-risk, 13 (39.4%) as intermediate-2 risk, and 6 (23.8%) as unknown risk. Spleen size reduced in 25 patients (75.8%) with a median response time of 2.5 months (1-3.5). Four patients underwent bridging to transplantation and are currently surviving with good recovery. 28(84.8%) patients with peripheral monocyte decline following three weeks of SEL and RUX therapy. Peripheral blood blasts decreased in 18 patients (54.5%) after one month of treatment. The most common adverse reactions are nausea, vomiting, and cytopenia.

Summary/Conclusion:
The combination of SEL and RUX showed promising efficacy and manageable safety profile in RUX-resistant patients with myelofibrosis.

Keyword(s): Ruxolitinib | Myelofibrosis

Link to Abstract PF854

Abstract Number: PF855

Presentation Title: THE PROGNOSTIC IMPACT OF CYTOGENETIC AND MOLECULAR TESTING IN SECONDARY MYELOFIBROSIS

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=102
Three-year overall survival (OS) was 79.9%, with 21.6% of patients deceased and 4.9% transforming to acute myeloid leukemia (AML) during a median follow-up of 3.5 years.
Unfavorable karyotype was present in 25.9% of cases, but karyotype analysis did not predict survival, potentially due to low detection rates of significant abnormalities.
Mutated high molecular risk (HMR) genes were found in 22.1% of cases, with a significant impact on survival; median survival was not reached for no HMR, 3.8 years for one HMR, and 1.7 years for two or more HMR mutations (p<0.0001).
HMR gene status had a higher prognostic accuracy (C-index 0.847) compared to the MYSEC-PM risk-group (C-index 0.658), suggesting its potential utility in improving risk stratification for secondary myelofibrosis (SMF) patients.

Summary of Study Impact on Navtemadlin (KRT-232):

The study primarily focuses on the prognostic impact of cytogenetic and molecular testing in secondary myelofibrosis (SMF), which does not directly challenge or support navtemadlin’s positioning. However, it highlights the importance of genetic profiling in myelofibrosis, which could be relevant for patient stratification in navtemadlin trials.

Competitive Considerations:

The study does not introduce a competing therapy but emphasizes the role of genetic markers in prognosis, which could complement navtemadlin’s development by identifying patients who might benefit most from treatment.
It underscores the need for personalized treatment approaches in the post–JAK inhibitor MF landscape, potentially enhancing navtemadlin’s positioning if integrated with genetic profiling.

Clinical or Market Strategy Implications:

Kartos may consider incorporating genetic profiling into clinical trial designs to better stratify patients and enhance efficacy outcomes.
Emphasizing navtemadlin’s efficacy in genetically defined subgroups could differentiate it from other treatments, leveraging biomarkers as a key differentiation lever.

Medical Affairs Implications:

KOL engagement: Discuss the potential for integrating genetic profiling with navtemadlin treatment to optimize patient outcomes and address unmet needs in MF.
Evidence gaps: Real-world data on navtemadlin’s efficacy in genetically stratified populations could be valuable, as well as further subgroup analyses.
Communication strategy: Highlight navtemadlin’s potential in personalized medicine approaches, particularly in patients with specific genetic profiles that indicate higher risk.

Link to Abstract PF855

Abstract Number: PF856

Presentation Title: A PHASE 1B/2 STUDY OF DISC-0974, AN ANTI-HEMOJUVELIN ANTIBODY, IN PATIENTS WITH MYELOFIBROSIS AND ANEMIA

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=35
DISC-0974 demonstrated meaningful and sustained hepcidin reductions across all dose levels, leading to increased iron mobilization.
Hematologic responses were observed in all evaluable participants (28-100 mg doses), with 60% of TD-high achieving minor response and 40% major response; 100% of TD-low achieved minor response and 80% major response; 68% of nTD achieved any Hgb response, and 50% achieved a major response.
Mean FACIT-Fatigue scores improved significantly by the end of the study, indicating enhanced patient quality of life.
DISC-0974 was generally well-tolerated, with one adverse event of diarrhea possibly related to the drug. Serious adverse events included arthralgia and infections, with some ≥Grade 3 adverse events reported.
Hematologic responses were achieved regardless of concomitant JAK-inhibitor therapy, suggesting DISC-0974's potential as a complementary treatment in myelofibrosis with anemia.

Summary of Study Impact on Navtemadlin (KRT-232):

The study on DISC-0974 does not directly challenge navtemadlin’s positioning but highlights a complementary approach in treating myelofibrosis, particularly addressing anemia through hepcidin reduction. This could enhance overall treatment strategies when used alongside navtemadlin.

Competitive Considerations:

The study introduces DISC-0974, which targets anemia in MF patients, potentially complementing navtemadlin rather than competing directly, as navtemadlin focuses on spleen volume and symptom score reduction.
DISC-0974 could shift the post–JAK inhibitor MF treatment landscape by addressing anemia, a common complication, thereby enhancing patient outcomes when used in combination with other therapies like navtemadlin.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination trials with DISC-0974 to address both spleen-related symptoms and anemia in MF, potentially improving overall patient outcomes.
Emphasizing navtemadlin’s efficacy in spleen volume and symptom score reduction, alongside DISC-0974’s anemia management, could provide a comprehensive treatment approach.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combination therapy with DISC-0974 to manage both spleen-related symptoms and anemia, enhancing overall treatment efficacy.
Evidence gaps: Real-world data on combination therapy outcomes, subgroup analyses on anemia management, and biomarker correlations could be valuable for clinicians.
Communication strategy: Highlight navtemadlin’s unique role in spleen volume and symptom score reduction, while positioning DISC-0974 as a complementary agent for anemia management.

Link to Abstract PF856

Abstract Number: PF859

Presentation Title: CLINICAL PATHWAYS AND PROGNOSTIC STRATEGIES IN MYELOFIBROSIS: A REAL-WORLD ANALYSIS OF GERMAN PRACTICE

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Among 350 MF patients, 291 received therapy, with 267 undergoing drug treatment and 24 non-drug therapies. Median age at diagnosis was 68, with common comorbidities including hypertension (40%) and diabetes (14%).
Cytogenetic testing was performed in 70% of patients, with JAK2 V617F mutations detected in 96% of those tested. Prognostic scoring was underutilized, with IPSS used in 22% and DIPSS in 18% of cases.
JAK inhibitors, particularly ruxolitinib, were preferred across treatment lines, used in 72% of first-line treatments. Hydroxyurea was used in 28% of first-line patients, mainly those with minimal splenomegaly.
Ruxolitinib-treated patients showed prolonged time to next treatment (TTNT) compared to non-JAKi-treated patients, with key therapeutic goals achieved including spleen size reduction (60%) and hemoglobin improvement (39%).
Real-world management highlights the need for optimized anemia management and broader adoption of molecular risk stratification. Future studies should evaluate the long-term impact of JAKi sequencing on disease progression and survival.

Summary of Study Impact on Navtemadlin (KRT-232):

The study provides real-world insights into myelofibrosis (MF) management in Germany, emphasizing the dominance of JAK inhibitors, particularly ruxolitinib, across treatment lines. While it does not directly challenge navtemadlin, it highlights the need for alternative therapies post-JAK inhibitor failure, reinforcing navtemadlin's potential role in this space.

Competitive Considerations:

The study does not introduce a new competing therapy but underscores the reliance on JAK inhibitors, validating the need for effective post-JAK inhibitor options like navtemadlin.
It highlights the current treatment landscape's limitations, suggesting a potential market for navtemadlin in JAK inhibitor-refractory MF patients.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin's efficacy in JAK inhibitor-refractory settings and explore combination strategies, such as with ruxolitinib, to enhance its market positioning.
Focus on differentiating navtemadlin through its unique mechanism of restoring p53 function and its efficacy in reducing spleen volume and symptom scores.

Medical Affairs Implications:

KOL engagement: Discuss the durability of navtemadlin's response, its role in cytopenia management, and sequencing strategies with JAK inhibitors.
Evidence gaps: Real-world data on navtemadlin's long-term outcomes, subgroup analyses, and biomarker correlations would be valuable to clinicians.
Communication strategy: Highlight navtemadlin's efficacy in JAK inhibitor-refractory MF and its potential as a single-agent therapy, differentiating it from other investigational agents.

Link to Abstract PF859

Abstract Number: PF861

Presentation Title: AN OPEN-LABEL CLINICAL TRIAL OF RVU120 AS MONOTHERAPY AND IN COMBINATION WITH RUXOLITINIB IN PATIENTS WITH INTERMEDIATE OR HIGH-RISK, PRIMARY OR SECONDARY MYELOFIBROSIS (POTAMI-61).

Session: Myeloproliferative neoplasms - Clinical

Abstract Summary:

Number of Patients/Subjects=20
RVU120, as monotherapy or combined with RUX, was tolerated in MF patients, with most adverse events being grade 1-2, including nausea (33%) and vomiting (25%).
Initial clinical activity was observed, with three patients showing early signs of improvement, including spleen size reduction and hematology improvement.
No deaths were reported, and safety profiles were comparable between monotherapy and combination therapy cohorts.
Further exploration of RVU120 in MF patients is warranted based on initial data from the POTAMI-61 trial.

Summary of Study Impact on Navtemadlin (KRT-232):

The study of RVU120, a CDK8/19 inhibitor, does not directly challenge navtemadlin’s positioning but introduces a potential complementary approach in the treatment of myelofibrosis (MF). The initial findings suggest RVU120 could be explored further, particularly in combination with JAK inhibitors like ruxolitinib, which may enhance therapeutic efficacy in MF patients.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin but suggests a novel mechanism that could be complementary. RVU120’s combination with ruxolitinib may offer an alternative for patients with suboptimal responses to JAK inhibitors.
RVU120 could potentially expand the post–JAK inhibitor MF treatment landscape by providing an additional therapeutic option, especially in combination settings.

Clinical or Market Strategy Implications:

Kartos may consider exploring combination strategies with RVU120 or similar agents to enhance navtemadlin’s efficacy, particularly in patients with suboptimal responses to JAK inhibitors.
Emphasizing navtemadlin’s efficacy in spleen volume reduction and symptom score improvement could differentiate it from emerging therapies like RVU120.

Medical Affairs Implications:

KOL engagement: Discuss the potential for combination therapies and the role of navtemadlin in sequencing with JAK inhibitors.
Evidence gaps: Real-world data on long-term outcomes and biomarker correlations for navtemadlin could strengthen its clinical positioning.
Communication strategy: Highlight navtemadlin’s unique mechanism of restoring p53 function and its proven efficacy in JAK inhibitor–refractory MF.

Link to Abstract PF861

Abstract Number: PS2075

Presentation Title: SPLENOMEGALY AND LOW CD34+ CELL DOSE ARE ASSOCIATED WITH POOR GRAFT FUNCTION FOLLOWING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR MYELOFIBROSIS

Session: Stem cell transplantation - Clinical

Abstract Summary:

Number of Patients/Subjects=183
Prevalence of poor graft function (PGF) at day 100 post-transplant was 28%, with significant delays in neutrophil and platelet engraftment in PGF patients.
Splenomegaly ≥15cm and low CD34+ cell dose (≤6.75 × 10⁶/kg) were significant independent risk factors for PGF, with odds ratios of 3.9 and 2.5, respectively.
PGF was associated with a 2.9-fold increased risk of death, with 36-month survival rates of 65.7% for PGF patients versus 85.4% for non-PGF patients.
Donor type, ABO mismatch, and other factors were not statistically significant in affecting PGF risk, highlighting the critical role of splenomegaly and CD34+ cell dose in post-HCT outcomes.

Abstract: PS2075

Title: SPLENOMEGALY AND LOW CD34+ CELL DOSE ARE ASSOCIATED WITH POOR GRAFT FUNCTION FOLLOWING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR MYELOFIBROSIS

Type: Poster Presentation

Session title: Stem cell transplantation - Clinical

Summary of Study Impact on Navtemadlin (KRT-232):

The study primarily focuses on risk factors for poor graft function (PGF) post-hematopoietic stem cell transplantation in myelofibrosis, which does not directly challenge or support navtemadlin’s positioning. However, it highlights the importance of managing splenomegaly, a condition navtemadlin addresses through spleen volume reduction.

Competitive Considerations:

The study does not introduce a competing therapy to navtemadlin but underscores the clinical challenge of splenomegaly in myelofibrosis, indirectly validating navtemadlin’s role in addressing this issue.
It highlights the need for effective treatments post-JAK inhibitor failure, reinforcing navtemadlin’s potential value in the treatment landscape.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin’s efficacy in reducing spleen volume as a key differentiator in its clinical trial strategy and market positioning.
Highlighting navtemadlin’s potential to improve outcomes in patients with significant splenomegaly could be a strategic focus.

Medical Affairs Implications:

KOL engagement: Discuss the role of navtemadlin in managing splenomegaly and its potential impact on post-transplant outcomes.
Evidence gaps: Real-world data on navtemadlin’s impact on splenomegaly and its correlation with improved transplant outcomes could be valuable.
Communication strategy: Emphasize navtemadlin’s efficacy in spleen volume reduction and symptom score improvement as key benefits over other treatments.

Abstract: PS2075

Title: SPLENOMEGALY AND LOW CD34+ CELL DOSE ARE ASSOCIATED WITH POOR GRAFT FUNCTION FOLLOWING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR MYELOFIBROSIS

Type: Poster Presentation

Session title: Stem cell transplantation - Clinical

Background:
Poor graft function (PGF) is a significant contributor to non-relapse mortality (NRM) following hematopoietic stem cell transplantation (HCT) for myelofibrosis (MF). Risk factors such as splenomegaly, low cell dose, alternative donor sources and viral reactivation have been associated with PGF, although prior studies prior studies primarily involved reduced-intensity regimens across diverse diseases rather than MF specifically.

Methods:
We retrospectively analyzed 209 consecutive patients who underwent first allogeneic-HCT for MF at our institution (January 2016-March 2024). All donor types, conditioning and GVHD prophylaxis strategies were included. Primary endpoints were PGF prevalence at day 100 (defined as new or persistent mild to moderate cytopenias at day 100 in at least two cell lines (ANC≤1.5, Platelets≤30, hemoglobin≤8.5),^1-3 and overall survival (OS). Risk factors associated with day 100 PGF were evaluated using logistic regression. Only patients alive without progression of malignancy at each timepoint were included.

Results:
A total of 183 patients with a median age of 63 years (range; 20-75 years) were evaluable at day 100. All except 4 patients (98%) received myeloablative conditioning. Donors included HLA-matched related, (n=51, 28%) unrelated (n=94, 51%), haploidentical (n=18, 10%), or mismatched unrelated (n=20, 11%). Median time to neutrophil and platelet engraftment was 17 days (range; 11-43 days) and 28 days (range; 8-764), respectively.

The prevalence of PGF at day 100 was 28% (52/183). Median follow-up in surviving patients was 37 months (range; 3-93), time to neutrophil (median 20 vs 16) and platelet engraftment (median 58 vs 24 days) was significantly increased (P<0.001) in PGF patients when compared to those who did not develop PGF.

In univariate analysis, significant risk factors for day 100 PGF included splenomegaly ≥15cm with an odds ratio (OR) of 3.4 (95%CI 1.5-7.5, p=0.003) and a low infused CD34+ cell dose below the median (≤6.75 × 10⁶/kg) (OR 2.2, 95%CI 1.1-4.2, p=0.02). These factors remained significant on multivariate analysis (splenomegaly >15 cm: OR 3.9, 95% CI: 1.7-9.1, p=0.001, CD34+

PGF prevalence varied by spleen size and CD34+ dose. Compared with those who did not develop day 100 PGF, patients with PGF were significantly (49% vs 22%, p<0.001) more likely to have splenomegaly (≥15 cm) and had received a lower CD34+ cell dose at transplant. In contrast, patients with PGF were significantly (4% vs 19%, p=0.01) less likely to have spleen <15 cm and had received a high CD34+ cell dose. In landmark analysis starting at day 100, PGF was associated with a 2.9-fold increased risk of death (HR: 2.9, 95% CI: 1.4-5.9, p=0.004), with 36-month survival rates of 65.7% vs 85.4%, in univariate analysis.

Summary/Conclusion:
PGF is a major cause of morbidity and mortality post-HCT for MF. Splenomegaly>15cm and low CD34+ doses were the only independent risk factors associated with PGF at day 100, while donor type and ABO mismatch were not significant. Patients experiencing PGF had a nearly threefold increased risk of death compared to those without PGF. Our findings underscore the impact of splenomegaly and CD34+ cell dose on post-HCT outcome, emphasizing the need for tailored transplant strategies to mitigate PGF risk.

Keyword(s): CD34 | Myelofibrosis | Splenomegaly | Allogeneic hematopoietic stem cell transplant

Link to Abstract PS2075

Abstract Number: PF1242

Presentation Title: EFFICACY OF PACRITINIB VS MOMELOTINIB IN PATIENTS WITH THROMBOCYTOPENIC MYELOFIBROSIS: A MATCHED ADJUSTED INDIRECT TREATMENT COMPARISON

Session: Platelet disorders

Abstract Summary:

Number of Patients/Subjects: Effective sample sizes for endpoints ranged from 36-47% of the full study samples.
The MAIC did not show statistically significant differences between pacritinib (PAC) and momelotinib (MMB) for the evaluated outcomes, though all endpoints favored PAC with odds ratios (ORs) for TSS-50, SVR-35, and RBC TI-R being 2.05, 1.45, and 1.32, respectively.
Overall survival (OS) favored PAC with a hazard ratio (HR) of 0.50, though not statistically significant.
The analysis revealed a consistent, nominal trend towards PAC benefit across all efficacy endpoints and OS in patients with thrombocytopenic myelofibrosis (TMF), most of whom had moderate thrombocytopenia.
This MAIC provides evidence supporting consideration of pacritinib as a therapeutic option for TMF patients with moderate thrombocytopenia, despite the limitations of not being a direct head-to-head comparison and the limited sample size.

Summary of Study Impact on Navtemadlin (KRT-232):

The study does not directly impact navtemadlin’s positioning as it focuses on a different patient subset (thrombocytopenic myelofibrosis) and compares pacritinib and momelotinib, which are JAK inhibitors. Navtemadlin targets a different mechanism (MDM2 inhibition) and is positioned for JAK inhibitor-refractory myelofibrosis.

Competitive Considerations:

The study does not introduce a direct competitor to navtemadlin, as it evaluates therapies for thrombocytopenic myelofibrosis, a different subset of MF patients.
It highlights the need for diverse treatment options in MF, reinforcing navtemadlin’s role in JAK inhibitor-refractory cases.

Clinical or Market Strategy Implications:

Kartos may not need to adjust its strategy based on this study, but should continue emphasizing navtemadlin’s unique mechanism and efficacy in JAK inhibitor-refractory MF.
Focus on differentiation through efficacy in spleen volume reduction and symptom score improvement, particularly in JAK inhibitor-refractory settings.

Medical Affairs Implications:

KOL engagement: Discuss navtemadlin’s efficacy in refractory cases and its potential role in combination therapies.
Evidence gaps: Real-world data on navtemadlin’s long-term efficacy and safety, especially in combination with other agents, would be valuable.
Communication strategy: Emphasize navtemadlin’s novel mechanism and its efficacy in a challenging patient population (post-JAK inhibitor failure).

Abstract: PF1242

Title: EFFICACY OF PACRITINIB VS MOMELOTINIB IN PATIENTS WITH THROMBOCYTOPENIC MYELOFIBROSIS: A MATCHED ADJUSTED INDIRECT TREATMENT COMPARISON

Type: Poster Presentation

Session title: Platelet disorders

Background:

Thrombocytopenia is a prognostic marker associated with reduced survival, increased symptoms, profound anaemia and lower likelihood of myelofibrosis treatment response. Pacritinib (PAC: a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1) and momelotinib (MMB: a JAK1/JAK2/ACVR1 inhibitor) studies have included patients with thrombocytopenic myelofibrosis (TMF).

Aims:
In the absence of direct head-to-head comparative evidence from randomised controlled trials (RCTs), this study conducted a matching adjusted indirect comparison (MAIC) to evaluate the effectiveness of PAC vs MMB for treatment of patients with TMF, particularly those with moderate thrombocytopenia.

Methods:
Data were from three Phase 3, 24-week RCTs in patients with TMF respectively treated with PAC 200 mg BID (individual patient data [IPD] from PERSIST-2 [NCT02055781]) and MMB 200 mg QD (published subgroup analysis of patients with platelet count [PLTc] <100×10⁹/L from MOMENTUM [NCT04173494] and SIMPLIFY-1 [NCT01969838]). To best match with the available MMB trial data, only those PAC patients from PERSIST-2 with baseline PLTc 24–99×10⁹/L were included for analysis and matched on baseline characteristics (age, sex, prior JAKi use, PLTc).

The MAIC evaluated the percentage of patients achieving the Week 24 efficacy endpoints: ≥50% total symptom score reduction (TSS-50), ≥35% spleen volume reduction (SVR-35) and red blood cell transfusion independence response (RBC TI-R). Also evaluated was overall survival (OS), with matching adjustments made for baseline prognostic factors including age, sex, prior JAKi use, PLTc and high-risk Dynamic International Prognostic Score (DIPSS). Reweighted effects were estimated using either logistic regression or Cox regression models. The comparison between the treatments was estimated using odds ratios (ORs) for efficacy outcomes and hazard ratio (HR) for OS, together with the associated 95% confidence intervals (CIs).

Results:
After matching, the proportion of patients from PERSIST-2 with moderate thrombocytopenia (50‒99×10⁹/L PLTc) was 79‒83%. The effective sample sizes for endpoints ranged from 36-47% of the full study samples, and baseline characteristics became balanced after matching. The MAIC did not indicate statistically significant differences between PAC and MMB for the outcomes evaluated, though all endpoints favoured pacritinib with ORs (95% CI): 2.05 (0.75; 5.64) for TSS-50; 1.45 (0.38, 5.59) for SVR-35; 1.32 (0.46; 3.80) for RBC TI-R and HR for OS of 0.50 (95% CI: 0.20;1.28) (Figure).

Summary/Conclusion:
This MAIC revealed a consistent, nominal trend towards PAC benefit across all efficacy endpoints and OS as evaluated in patients with TMF, most of whom had moderate thrombocytopenia. When comparing therapies across disparate trials with differences in study design, it is essential to account for differences (including those of study populations) by adjusting for effect modifiers. Importantly, this analysis accounted for key baseline patient prognostic differences to ensure balanced analytic populations between the trials. Considering the limitations of not being a direct head-to-head comparison and the limited sample size, this MAIC provides evidence supporting consideration of pacritinib as a therapeutic option for TMF patients with moderate thrombocytopenia.

Keyword(s): Janus Kinase inhibitor | Anemia | Thrombocytopenia | Myelofibrosis

Link to Abstract PF1242

Abstract Number: PS2280

Presentation Title: HEALTH-RELATED QUALITY OF LIFE AND SYMPTOM BURDEN IN PRE-FIBROTIC AND OVERT MYELOFIBROSIS COMPARED TO THE GENERAL POPULATION AND PHYSICIAN PERCEPTIONS: RESULTS FROM THE GIMEMA-PROPHECY STUDY

Session: Quality of life and palliative care

Abstract Summary:

Number of Patients/Subjects=137
Pre-PMF patients showed clinically significant HRQoL impairments compared to the general population, particularly in physical (Δ =-9.0), role (Δ =-10.3), and cognitive (Δ =-4.5) functions, as well as increased fatigue (Δ =8.7) and dyspnea (Δ =7.1).
Overt-PMF patients exhibited more pronounced HRQoL deficits, notably in role (Δ =-20.9), physical (Δ =-11.6), and social (Δ =-8.2) functions, with significant fatigue (Δ =13.4) and reduced global health status (Δ =-9.2).
Symptom burden was high in both pre-PMF and overt-PMF, with fatigue, abdominal discomfort, concentration issues, and bone pain prevalent in pre-PMF.
Physicians often underestimated symptom severity, particularly early satiety and itching, highlighting the need for improved patient-physician communication and assessment of symptom burden.

Abstract: PS2280

Title: HEALTH-RELATED QUALITY OF LIFE AND SYMPTOM BURDEN IN PRE-FIBROTIC AND OVERT MYELOFIBROSIS COMPARED TO THE GENERAL POPULATION AND PHYSICIAN PERCEPTIONS: RESULTS FROM THE GIMEMA-PROPHECY STUDY

Type: Poster Presentation

Session title: Quality of life and palliative care

Summary of Study Impact on Navtemadlin (KRT-232):

The study primarily focuses on health-related quality of life (HRQoL) and symptom burden in pre-fibrotic and overt myelofibrosis, rather than directly addressing treatment efficacy or safety. Therefore, it does not directly impact navtemadlin’s positioning but highlights the importance of symptom management in myelofibrosis, which could be relevant for navtemadlin’s clinical strategy.

Competitive Considerations:

The study does not introduce a competing therapy but emphasizes the symptom burden in myelofibrosis, which could validate the need for effective treatments like navtemadlin.
It highlights the unmet need in symptom management post-JAK inhibitor failure, reinforcing navtemadlin’s potential role in the treatment landscape.

Clinical or Market Strategy Implications:

Kartos may consider emphasizing navtemadlin’s potential impact on symptom relief in their clinical trial strategy and marketing efforts.
Highlighting navtemadlin’s efficacy in reducing symptom scores could differentiate it from other treatments.

Medical Affairs Implications:

KOL engagement: Discuss the importance of addressing symptom burden and HRQoL in myelofibrosis, and how navtemadlin could play a role.
Evidence gaps: Real-world data on navtemadlin’s impact on HRQoL and symptom management would be valuable.
Communication strategy: Emphasize navtemadlin’s potential benefits in symptom reduction and HRQoL improvement compared to other agents.

Abstract: PS2280

Type: Poster Presentation

Session title: Quality of life and palliative care

Background:
The symptom burden and deterioration of health-related quality of life (HRQoL) in overt primary myelofibrosis (overt-PMF) are well-documented. In contrast, the impact of pre-fibrotic myelofibrosis (pre-PMF) remains unclear. Preliminary data showed significant HRQoL impairment in pre-PMF patients, but comparisons with the general population warrant further investigation.

Aims:
This subgroup analysis compares HRQoL in patients with pre-PMF and overt-PMF to that of the general population. It also seeks to assess the symptom burden reported by patients and documented by physicians in both disease stages.

Methods:
Baseline data from patients with MF enrolled in the PROPHECY study of the GIMEMA Foundation were analyzed. HRQoL was assessed using the EORTC QLQ-C30 questionnaire, which includes 5 functional scales: physical (PF), role (RF), emotional (EF), cognitive (CF), and social (SF); 3 symptom scales: fatigue (FA), nausea/vomiting (NV), and pain (PA); 6 single-item scales: dyspnea (DY), sleep disturbance (SL), appetite loss (AP), constipation (CO), diarrhea (DI), and financial impact (FI); and the global health status/QoL (QL) scale. The prevalence and severity of symptoms reported by patients and perceived by clinicians were evaluated using the 10-item MPN-SAF TSS questionnaire. Significant differences in HRQoL between groups (pre-/overt-PMF and the general population) were assessed according to predefined thresholds (Cocks K. et al., J Clin Oncol 29:89-96, 2011). Analyses were adjusted for sex, age, and comorbidities.

Results:
A total of 137 PMF patients were enrolled across 21 Italian centers from June 2022 to November 2023. The median age was 68.5 years. At baseline, splenomegaly was present in 46% of patients, 38.7% had at least one comorbidity, and 17.8% had a history of prior thrombotic events. A total of 82 patients were diagnosed with overt-PMF and 55 with pre-PMF. Compared to the general population, a clinically significant difference emerged for pre-PMF patients in the following EORTC QLQ-C30 scales: PF (mean difference (Δ) =-9.0), RF (Δ =-10.3), CF (Δ =-4.5), as well as for FA (Δ =8.7), DY (Δ =7.1), and FI (Δ =-3.9). Differences were also observed in overt-PMF patients compared to the general population, particularly for RF (Δ =-20.9), PF (Δ =-11.6), SF (Δ =-8.2), CF (Δ =-7.1), QL (Δ =-9.2) and FA (Δ =13.4), and less markedly for SL (Δ =5.7) and AP (Δ =5.1). The overall symptom burden was high, as assessed by the MPN-SAF TSS. Although generally more severe in overt-PMF, symptoms were also frequent in pre-PMF. FA, abdominal discomfort, concentration problems, and bone pain were more frequent in pre-PMF. Additional analyses based on 116 patient-physician paired MPN-SAF TSS questionnaires, showed that physicians generally underestimated symptom severity, with early satiety and itching showing the most notable discrepancies (Figure 1).

Summary/Conclusion:
The extended data analysis confirms a similar symptom burden between overt-PMF and pre-PMF. Clinically significant differences were observed in both conditions compared to the general population. The observed misalignment between physician- and patient-reported symptoms underscores the need for a more nuanced approach to evaluating the overall burden of the disease and treatment experienced by these patients.

Keyword(s): Quality of life | Patient reported outcomes | Myelofibrosis | Myeloproliferative disorder

Link to Abstract PS2280