Rampal, Raajit K.

6501 Background: Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic hepcidin elevation limits iron availability for red blood cell (RBC) production and contributes to anemia onset and severity. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin, a co-receptor in the bone morphogenetic protein-signaling pathway driving hepcidin expression. Methods: RALLY-MF (NCT05320198) is an ongoing Phase 2, open-label study conducted in the US. The primary aim is to evaluate DISC-0974 efficacy in participants with MF and anemia. Secondary aims include evaluating safety, pharmacokinetics (PK), and pharmacodynamics (PD). Eligible participants are ≥18 years of age with primary or secondary MF and hemoglobin (Hgb) <10 g/dL or RBC transfusion requirement. Participants enroll into 3 cohorts based on RBC units transfused in the 84 days prior to screening: non-transfusion dependent (nTD, 0 units and Hgb <10 g/dL), low transfusion burden (TD low, 1-2 units), high transfusion burden (TD high, 3-12 units). Stable dose of concomitant Janus kinase inhibitor (JAKi) is allowed. DISC-0974 is administered subcutaneously at 50 mg monthly for up to 6 doses, with escalation to 75 mg for inadequate or lost response. Primary endpoints include major hematologic response defined as transfusion independence (TI) during any consecutive 16 weeks (TD low) or 12 weeks (TD high), or a mean Hgb increase of ≥1.5 g/dL from baseline for ≥12 weeks (nTD). Secondary endpoints include PK/PD markers of iron regulation and safety assessments. Data were summarized using descriptive statistics. Results: At data cut (16 Oct 2025), 47 participants enrolled in the nTD (n=30), TD low (n=10), and TD high (n=7) cohorts, with 53% on concomitant JAKi therapy. DISC-0974 led to sustained hepcidin reduction and iron mobilization across cohorts. DISC-0974 resulted in meaningful hematologic responses among evaluable participants: 50% of nTD participants achieved a mean Hgb increase of ≥1.5 g/dL for ≥12 weeks, 71% of TD low participants achieved TI for ≥16 weeks, and 67% of TD high participants experienced a ≥50% reduction in transfusion burden, with follow-up ongoing. Major hematologic response rates were 50% for participants on and off concomitant JAKi therapy (n=18 and n=16, respectively). DISC-0974 was associated with meaningful improvement in FACIT-Fatigue scores for nTD and TD low participants. Serious adverse events (AEs, n=9) and ≥Grade 3 AEs (n=16) were considered unrelated to DISC-0974. There were no early withdrawals due to AEs. Conclusions: DISC-0974 was well tolerated and shows a favorable safety profile. Anemia response and fatigue scores improved across patients with MF and anemia, including those receiving JAKi therapy. These data validate hepcidin reduction as a promising approach to treating anemia in MF. Clinical trial information: NCT05320198 .

Abstract Background Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic hepcidin elevation limits iron availability for red blood cell production and contributes to the onset and severity of anemia, for which there is a large unmet need for safe and effective treatments. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin, a co-receptor in the bone morphogenetic protein-signaling pathway driving hepcidin expression. In studies involving healthy volunteers (Novikov, et al, J Clin Pharmacol 2024:64(8):953-962) and participants with MF (Gangat et al, Blood 2024;144(Suppl1):657), DISC-0974 dosing resulted in reduced serum hepcidin levels and increased serum iron, with a favorable safety profile. Clinically meaningful improvements in anemia were also observed: 50% of non–transfusion-dependent (nTD) participants achieved a mean hemoglobin increase of ≥1.5 g/dL for at least 12 weeks, while 80% of participants with low transfusion burden (TD low) and 40% of participants with high transfusion burden (TD high) achieved transfusion independence (TI) for ≥16 and ≥12 consecutive weeks, respectively. Aims This Phase 2, open-label, multiple-ascending dose study (NCT05320198) assesses efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) in participants with MF. Methods Participants were enrolled into 3 primary cohorts (n=30 per cohort), categorized by the units of red blood cells transfused in the 84 days prior to screening: nTD (hemoglobin &lt;10 g/dL with 0 units), TD low (1-2 units), and TD high (3-12 units transfused). Additionally, an exploratory cohort of participants receiving concomitant treatment with momelotinib or pacritinib (n=10) was included. Eligible participants were ≥18 years of age with hemoglobin &lt;10 g/dL or a transfusion requirement meeting World Health Organization diagnostic criteria for primary or secondary MF. A stable dose of concomitant hydroxyurea and/or Janus kinase (JAK) inhibitor (ruxolitinib and fedratinib for primary cohorts; momelotinib and pacritinib for exploratory cohort) was allowed. Major exclusion criteria included liver iron concentration ≥7 mg/g dry weight (TD high only) and nutritional, genetic, infectious, or autoimmune anemia. DISC-0974 was administered subcutaneously at a dose of 50 mg once monthly for a total of 6 doses. Dose escalation to 75 mg was required for inadequate or loss of response. Primary endpoints included evaluating hematologic response defined for TD low and TD high as TI during any 16- and 12-week consecutive period, respectively, and for nTD as a mean hemoglobin increase of ≥1.5 g/dL from baseline for at least 12 weeks. Secondary endpoints included PK/PD markers of iron regulation and safety assessments. Data were summarized using descriptive statistics. Results As of 01 July 2025, enrollment of the exploratory cohort of momelotinib was complete (n=10). Baseline hepcidin values in the exploratory cohort were similar (mean (SD) of 83.6 (62.8) ng/mL) to baseline hepcidin values from the DISC-0974 Phase 1b study (mean (SD) of 85.8 (71.0) ng/mL, n=35), and sustained hepcidin reduction was observed after DISC-0974 dosing. Early hematologic responses observed after 1 to 3 doses in the exploratory cohort were comparable to those reported in the Phase 1b study (Gangat et al, Blood 2024;144(Suppl1):657). Based on these initial data, the protocol was amended to allow concomitant momelotinib or pacritinib in all cohorts. Preliminary results, including baseline characteristics, PD, and hematologic responses across all cohorts, will be presented.

Abstract Background Myeloproliferative neoplasms (MPNs) can progress from chronic phase to accelerated or blast phase (MPN-AP/BP), a transition with poor prognosis and limited treatment options. While some abnormalities have been described, the genomic and clonal drivers of transformation remain poorly defined. We characterized mutational and structural alterations in MPN-AP/BP, leveraging paired samples to trace clonal evolution. Methods We profiled 186 samples from 160 individuals, including 159 MPN-AP/BP and 27 chronic-phase MPN samples (26 MF, 1 PV), using targeted sequencing of a 588 gene panel (mean depth: 709x). Paired pre- and post-transformation samples were available for 26 patients (n= 52). A consensus pipeline was used to detect somatic mutations, copy number variations (CNVs), and copy-neutral loss of heterozygosity (cnLOH). Clinical cytogenetic data were integrated when available. Single-cell validation is ongoing. Results Genomic complexity was widespread: 99% of patients harbored ≥1 oncogenic mutation (median 4; range 1–10). In total, 859 mutations were identified, most commonly in JAK2 (68%), ASXL1 (28%), TET2 (26%), SRSF2 (24%), TP53 (22%), and RUNX1 (22%). 684 structural alterations were identified in 86% of patients (median 3; range 1-20), including arm-level (22.5%), segmental (&gt;5 Mb; 60%), and focal (&lt;2 Mb; 9%) alterations. Recurrent events included 9p cnLOH (16%), del(5q) (13%), del(17p) (10%), and focal deletion of 21q22.12 involving RUNX1 (10%). Complex karyotypes (≥3 abnormalities) were observed in 55% of patients. Biallelic mutations accounted for 21% (183/859) of mutations, affecting 58% of patients across 21 genes, most frequently JAK2 V617F (28%), TP53 (17%) and TET2 (14%). Patients with biallelic mutations in these genes had significantly higher blast percentages compared to those with monoallelic mutations (p&lt;0.05), highlighting an association with aggressive disease. In 26 patients with longitudinal samples (chronic phase MPN and MPN-AP/BP), 87% (125/144) of mutations were already detectable during the chronic phase, on average more than 7 years prior to transformation. Only 11% (16/144) of mutations were newly acquired, including additional RUNX1 and TP53 hits, or structural changes that converted pre-existing JAK2 V617F and TP53 R248Q mutations from monoallelic to biallelic via 9p cnLOH or 17p loss, respectively. These findings suggest transformation is often driven by outgrowth of pre-existing high-risk clones, indicating that these clones likely have a competitive advantage and that the mutations within these clones have a cooperative biological interaction which underlies this competitive advantage. To investigate this hypothesis, we examined whether patterns of recurrent co-mutations were identifiable in this cohort. We identified recurrent co-occurring mutations in SRSF2-IDH2, ASXL1-SRSF2, and ASXL1-EZH2, which were enriched at transformation (p &lt; 0.05; Fisher exact test). Importantly, presence of these co-mutations was consistently associated with a higher transformation risk in two independent cohorts of MF patients from Mayo Clinic (n= 405) and University of Florence (n= 518). Clonal architecture analysis revealed that these co-mutations frequently arose within the same malignant clone: 100% for SRSF2-IDH2, 80% for ASXL1-SRSF2, and 85% for ASXL1-EZH2, and are often within the dominant clone. Prior studies have demonstrated mechanistic interplay between SRSF2 and IDH2 (Yoshimi et al.), as well as ASXL1 and SRSF2 (Sui et al.) mutations in myeloid malignancies. We assessed functional synergy of ASXL1-EZH2 using a murine model and identified that dual deletion caused a rapidly fatal myeloid neoplasm with shorter survival than single-gene loss. These results reinforce that functional synergy emerges within a shared cellular context, supporting clonal co-dependence as a driver of progression. Single-cell RNA sequencing of ASXL1-EZH2 mutant cases is ongoing and will be presented. Conclusions Transformation to MPN-AP/BP is driven by gradual clonal remodeling and expansion of pre-existing high-risk abnormalities. Biallelic and multi-hit alterations in TP53, JAK2, TET2, and RUNX1 promote clonal dominance and blast progression. Recurrent co-mutations such as IDH2-SRSF2 and ASXL1-EZH2 arise within the same clone, exhibit functional synergy, and are linked to poor outcomes. These findings support the clinical utility of early clonal and co-mutational profiling to guide risk-adapted intervention.

Abstract Background Blast transformation (BT) occurs in approximately 15-30% of patients with chronic myelomonocytic leukemia (CMML) and remains a leading cause of death. Allogeneic stem cell transplantation (ASCT) is currently the only treatment modality with the potential to cure the disease or prolong survival. Optimal timing of ASCT is critical for maximizing benefit while minimizing risks. To that end, contemporary risk models have focused on the prognostic relevance of individual, as opposed to concurrent mutations. In the current study, we looked into the possibility of prognostic prominence from concurrent mutations in predicting BT in CMML. Methods CMML diagnostic criteria were according to the International Consensus Classification (Arber et al. Blood 2022; 140:1200). A machine-learning hierarchical clustering algorithm was developed and tailored for patient stratification using survival outcomes and co-expression of genomic alterations. To reduce complexity and improve interpretability, we generalized each cluster using existing rule induction algorithms, including the in Trees framework and JRip. The final output was a set of mutation-based cluster definitions, each representing a distinct patient subgroup with similar survival trajectories. Competing risk analysis and cumulative incidence functions were used in downstream evaluation to validate the clinical distinctiveness of the clusters. For all survival analysis, patients were censored at the time of ASCT. Time-to-BT was calculated from the date of diagnosis to the date of BT or ASCT or last contact. BT-free-survival was calculated from the date of diagnosis to the date of BT, ASCT, death, or last contact. Results The core study cohort included 605 patients from the Mayo Clinic, USA, and the external validation cohort 501 patients from Humanitas Cancer Center, Milan, Italy. Using the patient cohort from the Mayo Clinic, machine-learning algorithms identified five molecular clusters with 3-year blast transformation (BT) rates ranging from 0% to 100% (AUC at 3 years 0.78): the order of molecular signature assignment (probability of BT/death from another cause) was i) PHF6MUT/ASXL1WT (0%/17% at 3 years; N=32), ii) NPM1MUT OR BCORMUT/ASXL1MUT OR SETBP1MUT/NRASMUT (48%/30% at 1 year; N=24), iii) RUNX1MUT/ASXL1MUT OR SRSF2MUT/NRASMUT OR EZH2MUT/ASXL1MUT OR SETBP1MUT OR BCORMUT (31%/55% at 3 years; N=132), iv) ASXL1MUT/TET2MUT OR DNMT3AMUT OR JAK2MUT (24%/28% at 3 years; N=123), and v) all other permutations (10%/40% at 3 years; N=294) [Figure 1]. Additional analysis confirmed significant differences in survival between RUNX1MUT/ASXL1MUT vs. RUNX1MUT/ASXL1WT (p&lt;0.01) OR RUNX1WT/ASXL1WT (p&lt;0.01) OR RUNX1WT/ASXL1MUT (p=0.038) [Figure 2]. Similar patterns of differences in survival were also documented for NRAS/SETBP1, ASXL1/EZH2, and NRAS/SRSF2 mutation combinations (Figure 2). A subsequent Cox regression analysis confirmed independent prognostic contributions from “PHF6MUT/ASXL1WT” (HR 5.43e-10; p&lt;0.01), NPM1MUT (HR 26.7; p&lt;0.01), “SETBP1MUT/NRASMUT” (HR 12.7; p&lt;0.01), BCORMUT(HR 5.8; p&lt;0.01), “RUNX1MUT/ASXL1MUT” (HR 2.3, p&lt;0.01), JAK2MUT (HR 2.1; p&lt;0.01), and “ASXL1MUT/TET2MUT” (HR 1.7; p=0.02). The prognostic relevance of “SETBP1MUT/NRASMUT”, “RUNX1MUT/ASXL1MUT”, NPM1MUT, and BCORMUT was validated in the external cohort from Italy (N=501). In the Mayo Clinic cohort, presence of any of the latter mutations was associated with 1-, 3-, and 5-year BT (death from other cause) rates of 27% (21%), 44% (49%), and 44% (51%), respectively (Figure 3). The corresponding values in the absence of high risk mutations were 7% (15%), 15% (37%), and 18% (52%) [Gray's p value &lt;0.01 for both BT and death from another cause; Figure 3]. Similarly, the 1-, 3-, and 5-year BT (death from another cause) rates in the Italian cohort were 21% (19%), 37% (47%), and 42% (54%) in the presence and 8% (14%), 20% (35%), and 24% (45%) in the absence of high-risk mutations (Gray's p value &lt;0.01 for BT and 0.18 for death from another cause; Figure 4). Conclusions In the current study, machine-learning algorithms enabled the discovery of concurrent mutations in CMML that were shown to be prognostically more significant than their individual constituents. Such prognostic interaction might have contributed to some of the discrepancies noted in current literature regarding the prognostic relevance of certain mutations in CMML and should be accounted for in the development of future risk models.

Abstract Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) have a propensity to transform to an accelerated or blast phase (MPN-AP/BP). The resulting disease has clinically similar manifestations to Acute Myeloid Leukemia (AML) but worse clinical outcomes. Here we present the first comprehensive description of the transcriptomic characteristics of MPN-AP/BP. Our analysis incorporates data from 261 patients of the BeatAML cohort and 56 MPN-AP/BP patients, 11 of whom had paired samples from before and after transformation. We establish that transformed MPN is a transcriptionally distinct entity from de novo AML and chronic phase MPNs. Genomic pathways traditionally associated with MPN pathogenesis, such as IL2/STAT5 signaling and IL6/JAK/STAT3 signaling were enriched in chronic-phase MPNs but are absent in transformed disease, suggesting JAK2 directed therapy may be less effective in this disease phase. We also discovered that gene expression signatures associated with doxorubicin resistance are highly enriched in transformed MPNs, which may explain the lack of efficacy of standard AML therapies. In addition, we identify that lineage composition at the time of transformation may define distinct subsets of MPN-AP/BP patients, which may assist in the future development of novel treatment strategies.

Abstract Among 64 patients with Erdheim-Chester disease treated with a BRAF inhibitor (median follow-up 4 years), we found high response rates (85%) but frequent discontinuations (61%), primarily because of adverse events. Additionally, patients experienced poor health-related quality of life and high symptom burden.

Introduction TP53 alterations (TP53+) are seen in &lt;5% of patients (pts) with chronic myeloproliferative neoplasms (MPNs) but are more common in accelerated/blast phase (MPN-AP/BP) [Luque Paz D, et al 2020]. While pts with low-burden TP53+ (Variant allele frequency (VAF) &lt;5%) may remain stable for years [Kubesova et al, 2018]; biallelic loss of TP53 is thought to confer higher risk for progression [Li et al, 2022] and worse overall survival (OS) than non-TP53+ pts [Rolles et al, 2023]. However, TP53 abnormalities have not been incorporated into currently utilized molecular based prediction models (MIPSS or MIPSS70) or compared with currently validated high molecular-risk (HMR) mutations (mut). We report the outcomes of the largest cohort of TP53+ MPN pts to date in comparison with HMR mut, and identify a VAF cut-off associated with highest risk of progression to MPN-AP/BP. Methods We retrospectively reviewed 2583 MPN pts from Mount Sinai Hospital (MSH) and Memorial Sloan Kettering Cancer Center (MSK) with at least one next generation sequencing (NGS) performed. Deidentified data from an additional cohort of 8 TP53+ MPN pts was received from University of Miami Sylvester Cancer Center (UMiami). Patient characteristics such as MPN subtype, gender, age at MPN diagnosis, driver mutation, thrombosis history were recorded. We also recorded date of transformation to MPN-AP/BP, dates of NGS testing, mutational and cytogenetic data, and survival status. We defined multi-hit TP53 as presence of =/&gt;2 TP53mut, VAF &gt; 50% or TP53 mutation + 17p deletion. Additional cohorts of pts with HMR mut (ASXL1, EZH2, IDH1/2, U2AF1, SRSF2 as per MIPSS70v.2) from MSH and non-TP53+ pts from the MPN-Research Consortium Tissue Bank were used as comparator arms. Patient characteristics were compared between TP53 single-hit and multi-hit using Chi-Sq test for categorical variables and Kruskal-Wallis test for continuous variables. Cumulative incidence function and Kaplan-Meier method were used to compare leukemic transformation and OS, respectively, between groups. Successive VAF levels with minimum groups of 25% of the total cohort were used to identify an optimal VAF cut-off. Results Of the 2583 MPN pts from MSH and MSK, 66 pts (2.6%) were found to have a TP53 mutation. Including 8 additional pts from UMiami, we analyzed a total of 74 TP53+ MPN pts; 40 single-hit and 34 multi-hit. Median age at MPN diagnosis was 61 years with a male predominance (60%). Distribution of driver mut was similar in single-hit vs multi-hit cohort with JAK2V617F being the most common (58%), whereas 11% of pts had triple negative disease . Thrombotic history was available for 45 TP53+ pts, with a high frequency of venous/arterial thrombosis (21/45 or 46.7%) in the TP53+ group as compared to 18.5% in the non-TP53+ MPN cohort (p= 0.0001). A significantly higher number of multi-hit TP53+ pts had a concurrent complex karyotype (79% vs 24% in single-hit; p&lt;.001). MPN diagnosis at the time of detection of TP53+ was ET/PV (25.7%), MF (44.6%), MDS/MPN overlap syndrome (6.8%), MPN-U (2.7%) and MPN-AP/BP (20.3%), respectively. One or more genetic samples with TP53+ was available prior to transformation to MPN-AP/BP in 77% of pts (21/34 multi-hit; 36/40 single-hit) while a TP53+ was detected at the time of MPN-AP/BP diagnosis in the rest. Multi-hit TP53+ was associated with a significantly higher incidence of transformation to MPN-AP/BP as compared to single-hit; [65% vs 17.5%; HR=4.08 (1.71-9.71), p=0.0015]. Compared with HMR mut, multi-hit (HR=2.41; p=0.004) but not single-hit (HR=0.53; p=.277) TP53+ MPN pts were found to have a significantly increased risk of MPN-AP/BP transformation. One-year OS from the time of mutation detection was significantly inferior for both multi-hit (53.3%) and single-hit (75%) TP53+ pts as compared to HMR mut (98.8%, p=&lt;.001). Cut-point analysis identified VAF &gt;36% to be associated with the highest risk of transformation (HR=3.08) with lowest p-value (0.002). Conclusions Multi-hit TP53 alterations are associated with a significantly increased risk of leukemic evolution as compared to previously validated HMR mut, whereas both multi and single-hit TP53 mut are associated with worse OS highlighting the importance of TP53 in MPN disease progression.

Background Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic hepcidin elevation limits iron availability for red blood cell production and contributes to onset and severity of anemia, for which there is a large unmet need for safe and effective treatments. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin, a co-receptor in the bone morphogenetic protein-signaling pathway driving hepcidin expression. A completed healthy volunteer study demonstrated serum hepcidin reductions, serum iron increases, and increasing trends in hematologic parameters, with no safety signal identified. Aims This Phase 1b/2, open-label, multiple-ascending dose study (NCT05320198) assessed safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and initial efficacy of DISC0974 in patients with MF and anemia. Methods Eligible participants were ≥18 years of age with intermediate-2 or high-risk MF and anemia. Anemia was defined as baseline hemoglobin (Hgb) &lt;10 g/dL with or without intermittent transfusion requirement (non-transfusion dependent [nTD]) or transfusion dependent (TD), as defined by the IWG-MRT. A stable dose of concomitant hydroxyurea and/or Janus kinase (JAK) inhibitor was allowed. Major exclusion criteria included liver iron concentration ≥7 mg/g dry weight and nutritional, genetic, infectious, or autoimmune anemia. Dose escalation was based on a Bayesian optimal interval design with accelerated titration. DISC-0974 was administered subcutaneously monthly for 6 doses. Primary endpoints included evaluating DISC-0974 safety and tolerability. Secondary endpoints included PK/PD markers of iron regulation and hematologic parameters. Hematologic response was defined for TD as transfusion independence (TI) during any 12-week consecutive period and for nTD as ≥1.5 g/dL Hgb increase from baseline at any time point. Durability was evaluated as mean Hgb ≥1.5 g/dL above baseline during any 12-week period. Data were summarized using descriptive statistics. Results At the time of data cut, 34 participants were enrolled at 5 dose levels: 14 mg (n=1), 28 mg (n=7), 50 mg (n=12), 75 mg (n=8), and 100 mg (n=6). Treatment with DISC-0974 resulted in meaningful and sustained hepcidin reductions with mean change from baseline (mean 88.2 ng/mL; range [8.7, 374.7]) reaching over 80% across treated participants. This corresponded to iron mobilization at all dose levels. Efficacy Hematologic responses were evaluated in participants dosed at 28 to 100 mg. Responses were achieved independent of baseline transferrin saturation (TSAT) values. Initial hematologic responses in nTD participants were observed around the time of administration of the second dose, with a rise in absolute reticulocyte count preceding responses. Mean erythropoietin values decreased from baseline (mean 68.2 mIU/mL; range [13.2, 1815]) in participants treated at 50 to 100 mg. Hemoglobin responses were achieved in 69% (20/29) of nTD participants; 60% of nTD participants (9/15) achieved a durable response. TSAT values above normal range (50%) were observed in all participants with a durable response. One of two evaluable TD participants achieved TI at the end of study. All evaluable participants with a baseline transfusion requirement (n=8) had ≥50% reduction in transfusions over a rolling 8-week window compared to baseline. Hematologic response was observed in 6 of 10 participants with concomitant JAK inhibitor therapy. Safety One adverse event (AE), diarrhea, was at least possibly related to DISC-0974 and reported in ≥2 participants. Grade 3 AEs included headache reported in 1 participant treated at 28 mg (not related to DISC-0974) and Grade 3 anemia reported in 2 participants treated at 28 mg and 4 participants treated at 50 mg (1 at 50 mg was deemed related to DISC-0974; all others were deemed not related). One serious AE of Grade 2 arthralgia was reported and deemed not related to DISC-0974. Summary/Conclusions DISC-0974 demonstrated acceptable safety and tolerability at all evaluated dose levels. Hematologic responses were achieved in nTD and TD participants, regardless of concomitant JAK inhibitor use. Sustained hepcidin reduction with DISC-0974 led to increased serum iron that preceded hematological response. Additional Phase 1b data, including longer follow-up, will be presented.

Background and Rationale: Systemic mastocytosis (SM) is a clonal hematologic neoplasm characterized by abnormal accumulation of mast cells which can lead to symptoms related to mast cell degranulation and/or, in the case of advanced systemic mastocytosis (AdvSM), organ dysfunction due to mast cell infiltration. AdvSM is a category of SM comprised of aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and SM with an associated hematologic neoplasm (SM-AHN). Among these, SM-AHN is the most common subtype, accounting for approximately 70% of AdvSM. A KIT D816V mutation found in up to 95% of SM cases is the primary oncogenic driver, making it a key therapeutic target. Avapritinib, a highly potent and selective inhibitor of D816V mutant KIT, has demonstrated high rates of rapid, deep, and durable responses in all AdvSM subtypes, including SM-AHN (Gotlib et al. Nature Medicine, 2021; DeAngelo et al., Nature Medicine, 2021). However, despite showing prolonged OS and low risk of progression of the SM component, some patients (20%) exhibit progression of the AHN component, including transformation to AML. In some patients, combination therapy with avapritinib and AHN-directed therapy may therefore be necessary for optimal control of SM-AHN. Hypomethylating agents (HMA) form the backbone of therapy for advanced myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN); hematologic neoplasms most likely to co-occur with SM in patients (pts) with SM-AHN. To date, the combination of HMA and KIT inhibitors has not been clinically evaluated. In this study, we aim to assess the safety and tolerability of the combination of avapritinib and decitabine in patients with SM-AHN. Study design and Methods: The primary objective of the study is to establish the recommended dose (RP2D) of avapritinib in combination with decitabine based on dose-limiting toxicity, overall safety, and clinical activity data. A dose evaluation steering committee (DESC) comprised of participating investigators will review the totality of safety and efficacy data to determine RP2D. Secondary endpoints include SM overall response rate by the end of 6 cycles by the m-IWG consensus criteria and proposed ECNM-AIM criteria (Gotlib et al., J Allergy Clin Immunol Pract, 2022) and incidence/frequency of adverse events. Exploratory endpoints include patient reported outcomes, PFS, OS, and correlative biomarkers linked to mast cell disease or AHN. Pts with a diagnosis of SM-AHN by the WHO 2022 criteria will be eligible for inclusion. Pts must have any of the following myeloid AHN per WHO 2022 criteria: MDS, CMML, MDS/MPN with neutrophilia, MDS/MPN with SF3B1 mutation and thrombocytosis, or MDS/MPN-NOS. Patients with MDS must have intermediate, high- or very-high risk by IPSS-R. Patients with very-low or low-risk MDS by IPSS-R must be intolerant/refractory to ESA or have serum EPO &gt; 200 U/L. A baseline platelet count of ≥ 75 x 109/L and ≥ 25 x 109/L will be required for inclusion in the dose-finding and the dose-expansion phases, respectively. Key exclusion criteria include a diagnosis of AML, history of intracranial hemorrhage, prior treatment with avapritinib or decitabine with documented progression in SM or AHN component, respectively, or treatment with alternative KIT inhibitor or azacitidine within 4 weeks of study treatment initiation. In the dose finding part of the study, a Bayesian adaptive design will be employed to assess different doses of avapritinib (50 to 200 mg PO daily) in combination with fixed doses of decitabine (oral decitabine/cedazuridine: 35/100 mg/day or intravenous decitabine: 20 mg/m2/day on days 1-5) in a 28-day treatment cycle. Close attention will be paid to treatment-emergent thrombocytopenia with protocol-driven treatment holds and dose modification strategies employed when platelet count drops below 50 x 109/L. After RP2D is determined, an additional 10 patients will be enrolled in the dose expansion phase. Patients with platelet count ≥ 25 x 109/L and &lt; 75 x 109/L, will receive lead-in dosing with decitabine or decitabine/cedazuridine with the ability to add avapritinib if sufficient platelet thresholds are achieved. Planned correlative studies include serial single-cell multi-omics utilizing scDNA-seq and immunophenotyping to assess impact of combination treatment on a molecularly complex disease state. This study is currently open to accrual (NCT06327685).

ABSTRACTSpleen volume reduction (SVR) is a key endpoint in inhibitors of Janus kinase (JAK) inhibitor studies. Retrospective analyses have demonstrated an association between SVR and improved overall survival (OS) among patients treated with ruxolitinib with a platelet count > 100 × 109/L. Whether this association occurs in patients with thrombocytopenia is unclear. Pacritinib, a JAK2/IRAK1/ACVR1 inhibitor, demonstrated improved SVR versus best available therapy (BAT [best available therapy]; including ruxolitinib) in patients with myelofibrosis and platelet counts ≤ 100 × 109/L in the PERSIST‐2 study. Patients on study at the start of the 12‐week SVR window on pacritinib 200 mg twice daily or BAT were included. OS was evaluated among SVR responders versus non‐responders using different SVR thresholds (≥ 35%, ≥ 20%, ≥ 10%, and > 0%). Among patients on pacritinib (n = 89), SVR ≥ 10% demonstrated the greatest separation in OS curves between responders and non‐responders (HR, 0.00; 95% CI, 0.00–0.14; p < 0.01), though SVR ≥ 0% and SVR ≥ 20% were also associated with improved OS. No SVR threshold conferred OS benefit on BAT (n = 84), including ruxolitinib (n = 39). In patients with myelofibrosis and platelets ≤ 100 × 109/L, achieving SVR on pacritinib, but not BAT (including ruxolitinib), was associated with significant OS benefit, suggesting that pacritinib may offer a unique survival advantage in patients with myelofibrosis and thrombocytopenia who achieve any SVR. Trial Registration: ClinicalTrials.gov number: NCT02055781