Padron, Eric

Abstract Background: Mutations in ethanolamine kinase-1 (ETNK1) have been identified in a wide range of myeloid neoplasms (MN), but their clinical significance remains poorly defined. Key gaps remain, including the true prevalence, variant- and disease-specific co-mutation patterns, cytogenetic patterns, and prognostic impact, highlighting the need for broader multi-institutional studies to refine our understanding and risk stratification. We present findings from an ongoing multi-institutional study of ETNK1-mutated (ETNK1mut) MN. Methods We analyzed 106 patients with ETNK1mut MN across the Mayo Clinic Comprehensive Cancer Center (Minnesota, Arizona, and Florida), H. Lee Moffitt Cancer Center (Tampa, FL), Massachusetts General Hospital (Boston, MA), and University of Milano-Bicocca (Monza, Italy), integrating clinical, hematologic, cytogenetic, and next-generation sequencing (NGS) data. Appropriate IRB approval was obtained. Diagnoses were assigned by the 5th edition of the World Health Organization and 2022 European LeukemiaNet criteria. A clone was considered dominant if it had the highest variant allele frequency (VAF) or VAF within 5% of the highest co-mutation. Overall survival (OS) was assessed by Kaplan-Meier. Comparison cohorts for OS included 83 ETNK1 wild-type (ETNK1wt) myelodysplastic syndrome (MDS) and 415 ETNK1wt acute myeloid leukemia (AML) patients without TP53 mutations. GraphPad Prism v10 was used for statistical analysis. Results Median age at diagnosis was 70 years (range 30.4-90), with a male predominance of 72.6% (n=77). ETNK1mut were identified in MDS (n=47, 44.3%), myelodysplastic/myeloproliferative neoplasms (MDS/MPN; n=23, 21.7%), myeloproliferative neoplasms (MPN; n=13, 12.3%), AML (n=12, 11.3%), clonal cytopenia of undetermined significance (CCUS; n=5, 4.7%), and other entities (n=6, 5.7%) including atypical chronic myeloid leukemia (n=1) and systemic mastocytosis (n=1). Over a median follow-up of 33.6 months (IQR 15-91.8), 49.1% (n=52) patients died and 19.4% (n=18 of 93 at risk) progressed to AML. Cytogenetics were available in 103 patients; 57.3% (n=59) had a normal karyotype, while 30.1% (n=31) had abnormal and 12.6% (n=13) had complex karyotypes. None harbored classical MDS-associated deletions such as del(5q), del(7q), or del(20q). The most frequent cytogenetic abnormalities included translocations (n=17), monosomy 7 (n=9), and trisomy 8 (n=8). Of 17 translocations, 8 (47%) involved chromosome 1, two of which (11.8%) involved der(1;7)(q10;p10). The most common ETNK1 mutation was N244S (n=70, 66.0%), followed by K378N (n=12, 11.3%) and G245 variants (n=9, 8.5%), including G245V and G245D. VAF data were available for 103 patients; the median ETNK1 VAF was 31.4% (range 2.0-54.8%). High VAF (≥40%) was observed in 27.2% (n=28) of patients. ETNK1 was the dominant mutation in 33% (n=34) of cases, shared equal dominance with a co-mutation in 13% (n=14), and was a subclone in 56% (n=58). Co-mutations were detected in 77% (n=82) of patients, with a median of 4 (range 0-13) co-mutated genes. A third of patients (n=37, 35%) had ≥5 co-mutations. The most frequently co-mutated genes were epigenetic regulators including ASXL1 (n=29, 27%), TET2 (n=17, 16%), EZH2 (n=12, 11%), and DNMT3A (n=12, 11%), followed by splicing factor genes including U2AF1 (n=13, 12%), SRSF2 (n=10, 9%), and ZRSR2 (n=10, 9%). Mutations in signaling genes (JAK2, NRAS, SETBP1) and transcription factors (RUNX1, BCOR) were also observed. High VAFs were seen in co-mutations of EZH2 (median 49%), TET2 (46%), and NRAS (46%). ASXL1 was most enriched in MDS/MPN (n=8, 35%) and MPN (n=3, 23%). Survival analysis showed better survival in ETNK1mut compared to ETNK1wt within AML (65 vs 19 months; p=0.2002) and MDS (107 vs 61 months; p=0.1993), although statistical significance was not reached. Conclusion ETNK1 mut frequently co-occur with mutations in epigenetic and splicing regulators, and demonstrate distinct molecular and cytogenetic features, including the absence of classic MDS-associated deletions and a high prevalence of translocations involving chromosome 1. ETNK1 was the dominant clone in a third of cases with a high co-mutation burden. Overall survival was better in ETNK1mut AML and MDS, but the difference was not statistically significant. These findings highlight the need for larger collaborative studies.

Abstract Background and Significance: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy with overlapping dysplastic and proliferative features, a high risk of leukemic transformation, and no disease-modifying therapies. Patients with proliferative CMML often present with symptomatic monocytosis, leukocytosis, splenomegaly, and systemic inflammation, which contribute to shortened survival and impaired quality of life. Hydroxyurea (HU), the standard cytoreductive agent, provides transient control of leukocytosis but has no known disease modifying properties. In the phase 3 DACOTA trial (Itzykson et al., JCO 2022), decitabine modestly delayed leukemic transformation compared to HU but did not improve event-free or overall survival and was associated with increased early mortality. HU achieved a clinical benefit rate (CBR) of approximately 15% (excluding stable disease), highlighting the urgent need for safer and more effective therapies. Pacritinib is a potent and selective multikinase inhibitor with a kinome profile that targets key mediators of clonal proliferation and inflammatory signaling relevant to CMML. It inhibits JAK2 (IC₅₀ = 6 nM) and IRAK1 (IC₅₀ = 13.6 nM)—critical drivers of cytokine-mediated growth and monocytic skewing—while sparing JAK1, potentially reducing myelosuppressive toxicity. Pacritinib also inhibits CSF1R (IC₅₀= 39.5 nM) which is involved in monocytic differentiation. Preclinical models demonstrate that dual inhibition of JAK2 and IRAK1 suppresses CMML colony formation and prolongs survival in xenografts. Furthermore, CSF1R inhibition may reduce monocyte-lineage bias in leukemic clones. Clinically, pacritinib is FDA-approved for intermediate- or high-risk myelofibrosis with severe thrombocytopenia (platelets <50 × 10⁹/L) based on evidence of significant spleen volume and symptom reduction with limited hematologic toxicity. These mechanistic and clinical data provide a strong rationale for evaluating pacritinib in advanced proliferative CMML, a setting characterized by both cytokine-driven proliferation and treatment-limiting cytopenias. Study Design and Methods PROSPERA (NCT07033598) is a collaborative multicenter, open-label, randomized phase 2 trial. Sixty-six patients with WHO-defined CMML-1 or CMML-2 will be enrolled. Eligible patients must have proliferative features (WBC ≥13 × 10⁹/L) and advanced disease as defined by ≥5 cm palpable splenomegaly, symptom burden (Myeloproliferative Neoplasm-Symptom Assessment Form Total Symptom Score MPNSAF-TSS ≥20), or thrombocytopenia (platelets <100 × 10⁹/L). Prior JAK inhibitor therapy is not allowed. The trial will be conducted at approximately six sites across the United States and United Kingdom, with enrollment anticipated to begin by the end of 2025. Participants will be randomized 2:1 to receive either pacritinib (200 mg orally twice daily) or HU (dosed as per investigator discretion) for 48 weeks. Patients in the HU arm may cross over to pacritinib at Week 24 if, in the opinion of the treating physician, they are not deriving clinical benefit (after assessment of the primary endpoint). Randomization will be stratified by prior cytoreductive therapy (none vs. prior HU or hypomethylating agents). The primary endpoint is CBR at Week 24, defined by modified IWG MDS/MPN criteria incorporating hematologic improvement, spleen volume reduction, and symptom response. Secondary endpoints include CBR at any time, duration of response, event-free survival, leukemia-free survival, and overall survival. Correlative studies will assess treatment-related changes in clonal dynamics, cytokine signaling, and hematopoietic composition using longitudinal peripheral blood and bone marrow sampling. Single-cell transcriptomic and immunophenotypic profiling will be employed to characterize pacritinib's impact on both the malignant clone and the surrounding immune microenvironment.

Abstract Background and Significance: CMML is a myeloid neoplasm characterized by hematopoietic stem and progenitor cell (HSPCs) monocytic bias, leading to downstream monocyte expansion that plays a key role in disease maintenance and progression. Monocytes in CMML express high surface expression of the homing C-C chemokine receptor 2 (CCR2), which promotes malignant monocyte survival. Expansion of CCR2+ monocytic progenitors drives acute transformation in CMML and contributes to venetoclax resistance in AML. For these reasons, CCR2 is a potential novel therapeutic target in CMML and monocytic AML. The CyTAC platform was designed to enable targeting of cell surface antigens that demonstrate limited or ineffective binding to conventional therapeutic antibodies. A CyTAC is a heterobivalent small molecule that binds to both a target of choice and to a fully humanized monoclonal antibody. STX-0712 comprises a CCR2 CyTAC which potently binds to CCR2 on malignant cells, and a CyTAC humanized ADCC-enabling monoclonal antibody, which when combined eliminates target cells via enhanced effector-mediated killing in the presence of NK cells. We have demonstrated that treatment with STX-0712 ex vivo results in human target engagement and pharmacodynamic activity, and in vivo leads to depletion of CCR2 MO1 monocytes in a potent and dose-dependent manner in CMML and AML (ASH 2024). Therapeutic depletion of CCR2+ malignant monocytes presents a novel opportunity to develop a potential disease-modifying targeted therapeutic agent. We have designed a first-in-human, phase 1 clinical trial to evaluate the effect of CCR2 CyTAC in patients with refractory/resistant CMML, and relapsed/refractory monocytic or monocytic predominant AML. Study Design and Methods This is a phase 1, first-in-human, open-label, multicenter clinical trial based in the USA to evaluate STX-0712 as a monotherapy in patients with CMML and AML who have no remaining treatment options known to confer clinical benefit. STX-0712 will be administered as a single intravenous (IV) infusion every 3 weeks (additional regimen schedules may be explored) until evidence of disease progression, death, intolerance to study medication, or withdrawal of consent. The study consists of a dose-escalation and dose-expansion part and includes two cohorts: Cohort 1 (refractory/resistant CMML) and Cohort 2 (relapsed/refractory monocytic or monocytic predominant AML). Dose escalation will begin in participants with CMML using the Bayesian Optimal Interval (BOIN) design, with a minimum of three patients enrolled at each dose level. Backfilling of up to two cleared dose levels will be initiated once efficacious exposure levels are reached and at least one CMML participant has achieved a complete remission (CR) or a partial remission (PR), marrow response, or clinical benefit as defined by the MDS/MPN IWG 2015 criteria. In the AML cohort, backfilling may begin once at least one participant has achieved a response defined by ELN 2022 criteria. Dose expansion will occur upon completion of dose escalation in each cohort, using a Simon 2-stage adaptive design. Approximately 47 CMML and 58 AML patients may be enrolled in this phase 1 study. The primary objectives of the study are to evaluate the safety and tolerability of STX-0712 and to determine the minimal safe and biologically effective dose, recommended phase 2 dose (RP2D), and/or maximum tolerated dose (MTD), and to characterize dose-limiting toxicities (DLTs). Secondary objectives include evaluation of preliminary antitumor activity, pharmacokinetic (PK) parameters, and pharmacodynamic effects of STX-0712 on CCR2+ malignant cells in blood and bone marrow. Key exploratory endpoints include: (1) assessment of changes in CCR2+ tumor cells following STX-0712 dosing, (2) evaluation of candidate biomarkers, (3) characterization of T cells, B cells and NK cells at baseline and over the course of treatment, and (4) to explore the effects of STX-0712 on patient-reported outcomes using the CMML Symptoms Assessment Tool (MPN-SAF-TSS scoring system) and the EuroQoL 5 Dimension 5 level (EQ-5D-5L) for AML. Enrollment for Cohort 1 (CMML) began in March 2025, and the study is ongoing. Clinical Trial Information: NCT06950034

Abstract Background Myelodysplastic syndromes (MDS) develop from the acquisition of somatic mutations over years or decades. While some mutations are random stochastic events, others derive from extrinsic agents that promote genomic instability, including environmental exposures. Agent Orange (AO) is a phenoxy herbicide used by the U.S. military as a defoliant during the Vietnam War (1962-71), often diluted with gasoline to promote aerosolization, contaminated with the carcinogen dioxin during the manufacturing process, and linked to various cancers. We studied AO as a risk factor for MDS. Methods The prospective National Heart, Lung, and Blood Institute National MDS Natural History Study includes patients (pts) with suspected or recently diagnosed MDS enrolled from 6/2016-6/2024. Bone marrow samples underwent central pathology review, resulting in diagnoses including MDS, MDS/myeloproliferative neoplasm overlap (MDS/MPN), or clonal cytopenia of undetermined significance (CCUS). Pts completed detailed assessment for AO exposure and other risk factors for MDS development. Associations between AO exposure, mutation prevalence, and key covariates (demographics, diagnosis, military service, clinical history, cytogenetics and smoking) were assessed using univariate tests of association, multivariable regression and Cox regression models for survival and progression. Results Among 2115 enrolled pts, 1191 (56%) had a myeloid malignancy or precursor condition and 130 (6.1%) reported AO exposure, the majority (96%) male. Compared to unexposed pts, AO exposed pts were more likely to derive from the 1945-54 birth cohort (p<.001), of age to serve in Vietnam, and to have an ultimate diagnosis of MDS or CCUS vs. a non-clonal diagnosis (57% vs. 44%, p=.046). AO exposure was more common among Blacks (12% vs 6%, p=.02), specifically Black males (21% vs 9%, p=.006). AO exposure was marginally associated with International Prognostic Scoring System (IPSS)-R poor-risk cytogenetics (p=.066) and lower baseline platelet count (p=.072). In multiple regression analyses, risk of AO exposure was significantly higher for the 1945-1954 birth cohort (OR [95% CI]=10.3 [4.4-30.6], p<.001), among those with military service (OR=24.1 [11.9-55.8], p<.0001), and for Blacks vs Whites (OR=2.6 [1.2-5.5], p=.017). The crude risk of AO exposure trended higher for patients with MDS compared to idiopathic cytopenia of undetermined significance (ICUS; OR=2.1 [0.9-6.0],p=.13), but not in multivariable analysis (OR=1.3 [0.5-4.4, p=.60]). AO exposure trended toward an association with younger age at MDS diagnosis (p=.06) and toward having a prior primary malignancy (49% vs. 41%, p=.09): Compared to non-AO exposed pts, AO exposed pts had higher rates of prior prostate cancer (16% vs. 8%), notable given its documented association with AO exposure. AO exposure was not associated with a history of or intensity of cigarette smoking (p=.67). After accounting for age, diagnosis, sex, and military service, AO exposure was significantly associated with increased numbers of pathogenic variants in 53 genes (OR=1.2 [1.0-1.4], p=.02) and with having Very Poor/Poor risk IPSS-R cytogenetics (OR=3.7 [1.2-11.1], p=.02). AO exposed and non-exposed pts had similar overall survival (HR=1.1 [0.8-1.7], p=.50), but those exposed to AO had a higher risk of disease progression in the first two years following diagnosis (HR =1.9 [1.2-2.8], p=.004). AO exposed pts appeared more likely to have del (5q) (15% vs. 8%) and del (20q) (13% vs. 5%) karyotypic abnormalities, and TP53 (7.7% vs. 4.5%), STAG2 (5.1% vs. 2.8%), and NRAS mutations (3.4% vs. 1.7%), although sample sizes were small. Focusing on gene pathways, AO exposed pts appeared more likely to have abnormalities in RAS signaling (10.3% vs. 5.7%), cell cycle (7.7% vs. 4.5%), and cohesion complex pathways (6.0% vs. 3.1%), but less likely to have abnormalities in cytokine receptor pathways (0% vs. 4.5%). ConclusionsIn our representative national cohort of pts with at least one cytopenia, and for the first time, we demonstrated that AO exposure is associated with younger age at MDS diagnosis, ultimate MDS diagnosis, genetic complexity of MDS, increased risk of disease progression, and with Black race, despite Black individuals comprising just 16% of men who served in the Vietnam War and being less likely to have MDS than white individuals. AO should formally be recognized as a risk factor for the development of MDS.

Abstract Excessively restrictive inclusion and exclusion criteria in clinical trials are one of many barriers to clinical trial enrollment for patients with myelodysplastic syndromes/neoplasms (MDSs). Many organizations are developing efforts to increase clinical trial eligibility; yet, several recent publications focused on patients with MDS suggest that many patients with this disease may be excluded from clinical trials unnecessarily. Clinical trial eligibility should reflect the phase of the study and risks of the agent being studied. Phase 3 trials should be less restrictive than early-phase trials to represent the real-world population as closely as possible. We hypothesize that many clinical trials, particularly phase 3 trials, have unnecessarily restrictive eligibility criteria. This study aims to evaluate the most common eligibility criteria according to phase of trial and to determine whether criteria correspond with drug safety signals. We identified MDS clinical trials registered on ClinicalTrials.gov from 1 January 2000 to 1 September 2023 and analyzed the eligibility criteria of 191 therapeutic MDS trials. We found that categorical inclusion and exclusion criteria are remarkably similar in representation across trial phases. Additionally, only 13% of trials are concordant with drug safety signals, suggesting that the eligibility criteria are often arbitrary. On behalf of the icMDS (International Consortium for Myelodysplastic Syndromes), an association of international MDS experts, we provide a position statement on restrictive eligibility criteria for MDS clinical trials that should be avoided with the aim of removing barriers to clinical trial enrollment.

Abstract “Nonclassical” myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) represent a heterogeneous group of malignancies characterized by a wide range of clinical manifestations. Unlike classical MPNs, there is no standardized management approach for these conditions, particularly concerning the indications for and management of allogeneic hematopoietic cell transplantation. To address this gap, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee and the Chronic Malignancies Working Party (CMWP) have collaborated to develop shared guidelines aimed at optimizing the selection and management of patients with these rare forms of neoplasms. A comprehensive review of the literature from the publication of the revised fourth edition of the (2016) World Health Organization classification onward was conducted. A multidisciplinary group of experts in the field convened to produce this document, which was developed through multiple rounds of draft circulation. Key recommendations include the early identification of potential transplant candidates, particularly in cases of chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL)/CEL, not otherwise specified (CEL-NOS), myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions with FGFR1, JAK2, ABL1, and FLT3 rearrangements, MDS/MPN with neutrophilia/atypical chronic myeloid leukemia, and MDS/MPN, NOS. For patients with MPN, NOS/MPN unclassifiable, standard recommendations for myelofibrosis should be applied. Similarly, in MDS/MPN with thrombocytosis, transplantation is recommended on the basis of established MDS guidelines. Given the current lack of robust evidence, this document will serve as a valuable resource to guide future research activities, providing a framework for addressing critical unanswered questions and advancing the field.

Background. Study of myeloid neoplasms (MN) has been rapidly transformed by genome characterization. Gene mutations have been reported to influence disease phenotype and risk of disease progression, and the evaluation of mutational status can provide valuable insights to improve the decision-making process. In this international study, we evaluated the clinical impact of mutational screening in patients with CMML, which is characterized by significant clinical and genomic heterogeneity, including a substantial proportion of patients with poor outcomes and unmet needs. Currently, only limited molecular information has been incorporated into CMML classification and prognostication. Methods. We retrospectively collected 3182 CMML patients. We used MOSAIC, an AI-based framework for multimodal analysis in rare cancers (PMID: 38875514) to develop innovative, molecular-based tools for classification and prognostication. An independent validation of the results on 516 prospectively collected patients was performed. Results. Bayesian Networs and Hierarchical Dirichlet Processes were used to identify genomic associations and define a CMML molecular classification. We identified 11 clusters with distinct clinical and genomic features, including splicing machinery, signal transduction and tyrosine kinase pathways aberrations, and high-risk molecular signatures (i.e., AML-like and TP53 mutations). Up to 15% of patients showed clear genomic overlap with other MN. Importantly, extensive multi-color flow cytometry on T lymphocytes, NK and myeloid cells (BD FACSymphony A5 Cell Analyzer) revealed specific immunologic and inflammation signatures associated with molecular subgroups. We then integrated molecular and clinical information to build an international CMML Prognostic Scoring System (iCPSS). We assessed the performance of different statistical and AI-based methods; L1-penalized Cox Model resulted as the best performing method. Selected features included hematological parameters (WBC, Hb, PLT and marrow blasts), cytogenetic abnormalities, and mutations in 10 genes (ASXL1, DNMT3A, EZH2, NRAS, RUNX1, SETBP1, STAG2, TET2, TP53, U2AF1). By Bayesian thresholds optimization, we identified 5 risk classes (i.e., very-low, low, intermediate, high and very-high) with median overall survival (OS) ranging from 99 to 9 months (P<.001), and median leukemia-free survival (LFS) ranging from 210 to 18 months (P<.001). iCPSS provided better patient discrimination across all clinical endpoints compared to currently available prognostic tools, with a Concordance Index (CI) for OS of 0.75 versus 0.62-0.64, respectively. Notably, compared to available scoring systems, up to 40% of patients were reassigned to higher or lower risk classes by the iCPSS. External validation on an independent prospective cohort confirmed that the performance of iCPSS is superior to existing prognostic models (CI for OS 0.71 vs 0.54-0.61, respectively) To demonstrate the clinical utility of iCPSS, we focused on 753 patients who underwent allogeneic stem cell transplantation (HSCT). In multivariable analysis, iCPSS stratified the probability of OS post-HSCT (P<.001) and identified groups of patients with different probabilities of disease relapse, ranging from 9% to 62% (P<.001). We employed a clinical- and genomic-based decision support system (PMID: 38723212) to determine the optimal timing of HSCT. Preliminary analyses indicated that higher-risk patients according to iCPSS (i.e., intermediate, high, and very high) benefit from an immediate HSCT strategy. Lower-risk patients (i.e., very low and low) had life expectancy maximized with delayed HSCT. Modeling decision analysis using iCPSS compared to conventional scores, resulted in a change in transplantation policy for a significant proportion of patients (up to 25%). Conclusion. Molecular information significantly improves the classification of CMML patients, providing a basis for refining diagnostic boundaries with other MN and for a more rational inclusion of patients in clinical trials. The iCPSS demonstrated superior performance over currently available scoring systems and improved HSCT decision making process.

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 > 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 < 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).

Introduction Knowledge of epidemiologic risk factors, clonal changes associated with MDS development from precursor states, and evolution from one MDS state to another (lower- (LR) or higher-risk (HR) disease or leukemia (AML)) are largely limited to retrospective studies, which may not reflect the true MDS spectrum. The MDS NHS is an established prospective cohort of patients (pts) with suspected MDS enrolled at diverse US sites. Extensive clinical data and biospecimens are collected at baseline and throughout follow-up (F/U), in real time, as pts are followed for life. Here, we assess rates and potential predictors of progression providing a foundation for precise stratification across the MDS spectrum, which may ultimately guide intervention. Methods At baseline, all MDS NHS pts have central pathology review and those assigned to MDS, MDS/MPN overlap, AML<30% blasts, or at-risk of MDS (AR-MDS: CCUS and other at-risk) are followed prospectively. We compared AR-MDS with LR-MDS (MDS and MDS/MPN overlap with IPSS-R ≤ 3.5) and HR-MDS (MDS and MDS/MPN overlap with IPSS-R > 3.5). We defined disease progression as any F/U diagnosis of worsening disease or documented disease-related death. Rates of disease progression were compared between groups using survival analysis methods for cumulative incidence incorporating non-disease death as a competing risk. Associations between progression and predictor variables were explored using univariate tests of association and multivariable survival (Cox regression) models for time-to-progression and logistic models for probability of progression (yes/no). Results The MDS NHS enrolled 2051 pts during June 2016-February 2024, with 54% (1111, above categories) followed prospectively. Median F/U is 1.7 yrs (IQR: 0.8-3.1 yrs, max: 7.9 yrs). For the current analysis, 582 MDS and 505 AR-MDS pts were included. Compared to AR-MDS, MDS patients were more often male (70% v 61%, p<0.01), older (median age: 75 v 72 years, p<0.01), and had lower baseline hemoglobin (median: 10.1 v 11.9 g/dL, p<0.001), platelets (median: 124 x109 v 146 x109 cells/L, p<0.001), and absolute neutrophil counts (median: 1.9 x109 vs 2.8 x109 cells/L, p<0.001). F/U time was similar among AR-MDS and MDS (median: 1.9 vs 1.6 yrs), with both groups having a 75th percentile of 3 yrs and maximum of 7 yrs. A total of 331 deaths were observed (30%), with 145 (44%) of these due to causes related to MDS (myeloid disease and/or cardiovascular disease). Overall, 18.5% had disease progression, with annual rates of 8% (MDS) and 2% (AR-MDS) (p<0.01). Among HR-MDS, progression rates were greatest in the 1st year following diagnosis (33%) and declined thereafter, whereas progression rates remained between 5-8% for LR-MDS and 1-3% for AR-MDS over 5 yrs of F/U. AR-MDS had similar rates of progression within the first 3 yrs from diagnosis as MDS with the lowest IPSS-R category. Among AR-MDS, low hemoglobin (hazard ratio, HR [95% CI]=3.2 [1.4-7.3], p<0.01) was significantly associated with progression. Among MDS, low hemoglobin (HR=4.0 [2.2-7.0], p<0.001), low platelet count (HR=3.1 [1.7-5.6], p<0.001) and higher numbers of mutations (HR=1.13 [1.0-1.2], p<0.01) were significantly associated with progression. Due to the low rate of progression in AR-MDS, meaningful comparisons of mutations could not be completed. In MDS, univariate analyses showed that somatic mutation prevalence in gene pathways for transcription, cell cycle and RAS signaling, and in genes TP53, BCOR, SF3B1, DDX41, PTPN11, SETBP1, and JAK2 were significantly associated with the probability of progression (p<0.05 in all). In multivariable models, adjusting for patient age, sex, and MDS risk level, the probability of progression (PP) was significantly higher among those with vs without somatic mutations in BCOR (PP=63% vs 29%, p=0.004), PTPN11 (PP=67% vs 29%, p=0.009), SETBP1 (PP=61% vs 30%, p=0.02), JAK2 (PP=59% vs 30%, p=0.02), DDX41 (PP=56% vs 30%, p=0.03) and TP53 (PP=43% vs 29%, p=0.04). Conclusions In this large prospective cohort of MDS and pts at risk for MDS, the annual rate of any disease progression was 8% among MDS and 2% among AR-MDS, lower than some retrospective series. Specific cytopenias and genetic factors associated with progression were identified. The MDS NHS provides an incomparable opportunity to address the critical clinical challenges of management and prevention of MDS progression across its spectrum.

Abstract Drug development for chronic myelomonocytic leukemia (CMML) has failed to parallel the recent success observed in related myeloid neoplasms. To address these shortcomings, the US Food and Drug Administration (FDA) held a “Mini-symposium on CMML: Current State of the Art and Trial Design” in September 2023. This symposium brought together a panel of key FDA regulators and academic experts in CMML drug development to discuss challenges and provide perspectives on future drug development for this disease. The panel explored unique challenges that underlie the lack of therapeutic advances in CMML to date and discussed relevant topics such as clinical trial design, study end points, and key regulatory considerations. This article summarizes the key points of discussion from this symposium to facilitate advancements in the field.