Gore, Steven D.

Abstract Myelodysplastic syndromes (MDS) are clinically and biologically diverse disorders, emphasizing the need for personalized treatment approaches. The International Working Group for Prognostication of MDS (IWG_PM) recently introduced a molecular classification, referred to as the MDS taxonomy, that categorizes patients into 16 subgroups based on 21 gene mutations, 6 cytogenetic abnormalities, and loss of heterozygosity (LOH) at TP53 and TET2 loci. This study sought to validate and enhance the clinical relevance of the MDS taxonomy by analyzing a large retrospective cohort ( n = 5136) and transcriptomic data from a prospective cohort ( n = 477). The taxonomy successfully identified subgroups with distinct clinical characteristics and disease progression patterns. However, incorporating gene interactions from taxonomy subgroups did not improve the prognostic performance of the Molecular International Prognostic Scoring System (IPSS‐M). We further assessed whether the taxonomy could guide management in patients receiving disease‐modifying therapies. Except for the “ TP53 ‐complex” subgroup, taxonomy classifications were not predictive of hypomethylating agent response or transplant outcomes. Nonetheless, they correlated with overall survival, suggesting that while both IPSS‐M and the taxonomy capture disease biology, other non‐genetic factors may influence treatment response. RNA sequencing confirmed the biological distinctiveness of the taxonomy groups. Transcriptomic profiling of CD34+ bone marrow cells revealed unique, homogeneous gene expression patterns, particularly within the AML‐like, bi TET2 , SF3B1 , and TP53 ‐complex subgroups. Further integration of multi‐omics data may refine MDS classification, improving clinical decision‐making and guiding the development of targeted therapies.

ABSTRACT The epidemiology of myelodysplastic syndromes/neoplasms (MDS) is challenging to define due to inconsistent reporting, complex diagnostic procedures, and evolving diagnostic criteria. Using the National MDS Natural History Study—a prospective cohort with centrally adjudicated histopathology and genetic variant review—we characterized the landscape of MDS across the United States and identified differences across demographics. Among 2115 participants, 64% (1346) had an MDS spectrum condition, including MDS (24%), MDS/myeloproliferative neoplasm (5%) and precursor conditions—clonal cytopenia of undetermined significance (22%) and idiopathic cytopenia/dysplasia of undetermined significance (13%). The median age was 74 years, and participants were predominantly male (66%), White (91%), and Non‐Hispanic (92%). Myeloid‐associated variants were detected in 68% of participants, most commonly in TET2, DNMT3A, ASXL1, SF3B1, and SRSF2 . Black, compared to White, participants were younger at diagnosis (69 vs. 74 years, p = 0.01), had equal or increased prevalence of higher‐risk MDS, lower hemoglobin, and higher peripheral blood blasts, yet were less likely to receive MDS‐directed therapy (14% vs. 42%, p = 0.008). Black and Hispanic participants had fewer detectable gene mutations than White participants. Females had lower variant allele frequencies and fewer RNA splicing gene mutations than males. After multivariable adjustment, TP53 mutations, MDS diagnosis, and higher‐risk disease were associated with worse progression‐free and overall survival; age was also associated with overall survival. Black race trended toward improved progression‐free survival. These findings highlight the need for enhanced understanding of MDS pathogenesis across patient groups and refined prognostic tools to improve personalized management of MDS spectrum conditions. Trial Registration: ClinicalTrials.gov identifier: NCT02775383

Abstract Background: DNA methyltransferase (DNMT) isoforms 1, 3A and 3B are enzymes that regulate DNA methylation, controlling gene expression, chromatin stability and genetic imprinting. We have previously shown that DNMT3A protein expression in early triple negative breast cancer (TNBC) is associated with more aggressive clinicopathologic features (higher tumor grade, tumor proliferation and frequency of nodal metastases) and worse clinical outcomes in the absence of chemotherapy (Leon-Ferre et al, SABCS 2024). Pre-clinically, we have shown that DNMT3A protein expression predicts sensitivity to DNMT inhibitors (Yu J et al., J Clin Invest 2018), and that DNMT inhibitor treatment leads to downregulation of DNMT3A, enhanced expression of immune-related pathways, and halted tumor growth, particularly in combination with immunotherapy and paclitaxel. Methods: This is a phase 1, open-label, multicenter study evaluating the safety and recommended phase 2 dose (RP2D) of the oral DNMT inhibitor ASTX727 + paclitaxel + pembrolizumab in metastatic TNBC. ASTX727 is an oral fixed dose combination (FDC) tablet of 35 mg decitabine (active agent) and 100 mg cedazuridine (a cytidine deaminase inhibitor that prevents decitabine degradation in the bowel and liver, allowing oral delivery). The study consists of two parts: Part 1 is a dose-finding cohort, using a 3+3 design, with 5 dose levels (Table), and its primary objective is to determine the RP2D. Part 2 is an expansion cohort (n=6), with the primary objective to confirm tolerability of the regimen at the RP2D. Secondary objectives are to record the antitumor activity of the regimen, describe the AE profile, explore the association of baseline gene expression profiles with clinical benefit, and to evaluate impact of treatment on tumor and ctDNA methylation. Exploratory objectives will evaluate the association of baseline DNMT3A protein expression and antitumor activity, and the impact of treatment on the tumor and peripheral blood immune phenotype. Eligible patients are adults 18 years or older with metastatic TNBC (ER/PR ≤10%, and HER2-negative per ASCO/CAP guidelines), independent of PD-L1 expression. Patients are allowed to have received 0-3 prior lines of systemic therapy in the metastatic setting, including prior immune checkpoint inhibitors in the early and/or metastatic settings. Patients must be eligible for taxanes and have adequate organ and bone marrow function. Patients with treated brain metastases are eligible if previously treated without evidence of progression after 4 weeks. Leptomeningeal carcinomatosis is not allowed. Patients must have an ECOG performance status of ≤2 and have no gastrointestinal disorders impacting absorption of oral medications. As of June 20, 2025, the study is enrolling patients, with 10 patients dosed in the dose-finding phase. Citation Format: R. Leon-Ferre, D. M. Zahrieh, P. P. Advani, D. Quiroga, K. V. Giridhar, P. J. Dizona, D. Stover, X. Wang, A. J. Tevaarwerk, G. M. Choong, S. Yasir, K. R. Kalari, J. Foldi, R. Parajuli, M. H. Hackney, H. K. Chew, R. Wajeeha, H. Bear, E. Sharon, B. Ko, G. I. Shapiro, S. Gore, L. Pelosof, L. Wang, M. P. Goetz. Trial in progress: Phase 1 Study Targeting DNA Methyltransferases in Metastatic Triple-Negative Breast Cancer (NCI Protocol #10546) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-07-20.

Abstract Patients at risk for progression from myeloid precursor states (idiopathic cytopenia of undetermined significance [ICUS] and clonal cytopenia of undetermined significance [CCUS]) to myelodysplastic syndrome (MDS) are not well defined. Epidemiologic risk factors, clonal changes for MDS development, and evolution from one MDS state to another were available in the MDS Natural History Study (NHS), a prospective cohort enrolled at diverse US sites. Extensive clinical data and biospecimens were collected at baseline and follow-up. A total of 1177 (56%) individuals with MDS or MDS-related precursor conditions (ICUS/idiopathic dysplasia of undetermined significance [IDUS], CCUS, and MDS/myeloproliferative neoplasm overlap) were enrolled and diagnosed in the MDS NHS. The median age was 74 years, with 89% aged ≥60 years, and most were male patients. Median follow-up time was 1.6 years and was similar among ICUS/IDUS, CCUS, and MDS. During follow-up period, 68% of participants terminated the study, 35% died, and 38% had disease progression. Using a refined clinical definition of progression, the greatest proportion of progression was observed among higher-risk-MDS (116 [73%]), followed by lower-risk-MDS (170 [52%]); fewer progression events were observed among participants with CCUS (65 [22%]) and ICUS/IDUS (46 [17%]). Predictors of progression are delineated, including female sex, higher quantity of mutations, the presence of TP53 mutation, and poor/very poor cytogenetic score. Based on these prospective data, guidelines for clinical management including monitoring and surveillance are outlined. The MDS NHS provides real-world data to illustrate how clinical and genotypic differences inform the classification, disease course, and approach to therapy, with informed monitoring guidelines for patients. This trial was registered at www.ClinicalTrials.gov as NCT02775383.

Abstract Background: MyeloMATCH is an NCI-sponsored initiative for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) employing a Master Screening and Reassessment Protocol (MSRP) to assign patients (pts) to a pt and disease biology-specific clinical trial. Several trials evaluating initial therapies are currently open, while subsequent trials dedicated to eradicating measurable residual disease during consolidation and including stem cell transplant are being developed. A pt enrolled at diagnosis may be followed longitudinally and be eligible for trials in sequential tiers throughout the treatment course. We report key data concerning the first cohort of pts enrolled on the MSRP. Methods: After pts with suspected AML or MDS consent for the MSRP, blood and marrow are sent to the myeloMATCH Molecular Diagnostics Network (MDNet) of central CLIA labs operating under a single Investigational Device Exemption to rapidly define molecular, cytogenetic, and immunophenotypic characteristics. These data are catalogued by a bioinformatics team (MATCHBox) and reviewed daily to assign participants to an available trial based on pt and disease features. A Tier Advancement Pathway (TAP) allows standard of care therapy with potential for assignment to subsequent myeloMATCH trials. Since activation in May 2024, 550 patients age≥18 were enrolled on the MSRP from 76 institutions: 48 Academic, 14 NCORP, 11 community, 3 VA. There are currently 4 open randomized AML trials (≥age 60 or unfit with mutant FLT3, ≥age 60 IDH2 mutant AML, fit age<60 ELN 2017 intermediate-risk AML, fit age<60 ELN 2017 adverse risk) and 1 MDS trial(IDH2 mutant). Patients not eligible for an open protocol were assigned to TAP. Results: Of the 550 pts consented, 491 completed screening assays; 49 had no or incomplete samples; 10 withdrew before completed analysis. Median cytogenetic turnaround time (TAT) was 69 hours (91% within 72 hours), and median Next Generation Sequencing (NGS) TAT from receipt was 49 hours (95% within 72 hours). Seventy-six pts (of 491 with assay data) were not assigned due to non-AML or non-MDS diagnoses, the most common being: B-ALL [n=11], MPN [9], benign marrow [9], APML [7], and MPAL [6]. The AML/MDS verified cohort was 415 pts, 366 (89.2%) patients with AML (45% age <60) and 49 (11.8%) with MDS. The median age at screening was 63 years (range:18-95) and 186 (45%) were female. Eighty-two percent identified as White, 7.5% Black, 3% Asian, 7% unknown, and 9% as Hispanic. The most frequent mutations in the AML pts were NPM1 (24.0%), DNMT3A (22.7%), TET2 (19.9%), NRAS (18.0%), FLT3 (18.0% ITD, TKD 7.1%), TP53 (14.5%), and CEBPA (8.7%); IDH1/2 mutation rates were 8.2% and 13.7%, respectively. Co-mutations include FLT3/NPM1 (9.8%), NPM1/IDH2 (4.4%), IDH1/2 and any RAS (3.8%). Karyotypes were normal in 40.4%, complex 20.8%, inv(16) 6.0%, MLL/KMT2A 4.6% and t(8;21) 1.9%. 29% had favorable risk disease, 29% intermediate, and 42% adverse (ELN 2017). In MDS, mutations included: TP53 (36.7%), RUNX1 (20.4%) ASXL1 (20.4%), TET2 (18.4%), spliceosome mutations (SRSF2, SF3B1, U2AF1 and ZRSR2, 28.6%) andIDH1/2 in 4.1% and 6.1%, respectively. Karyotypes were normal in 24.5%; complex in 40.8%. By IPSS-R, 2.4% were low, 73.8% intermediate, 2.4% high, and 21.4% very high risk. 82/415 (20%) pts were assigned to initial therapy protocol, with an increase in assignment rate to 44% in the most recent two months. 71/415 pts (16%) were enrolled in one of the MyeloMATCH studies. Three-hundred forty-four pts (80%) were assigned and enrolled to TAP (296 AML, 48 MDS) for potential assignment to subsequent tier trials. In the TAP AML pts, 99 (33%) have completed initial treatment, including intensive chemotherapy (IC) in 62% of pts and hypomethylating agents/venetoclax (HMA/VEN) in 38%. In pts <60 years of age, 87% received IC v. 13% with HMA/VEN, in >60 34% IC v. 66% HMA/VEN and in age 60-75 42% IC v. 58% HMA/Ven. Conclusion: MyeloMATCH has screened over 500 pts from academic and community sites in the US and Canada in 14 months, meeting the TAT goal of sample acquisition to results of <72 hours. Assignment to treatment protocols has substantially increased recently. As additional trials open (12 in development) we expect the percentage of pts enrolled on MSRP who go on to therapeutic trials will markedly increase, thereby allowing a personalized medicine approach for a broad group of US and Canadian adult pts with AML and MDS.

Abstract Introduction:A comprehensive integration of significantly mutated genes and pathways with molecular subgroups is lacking in adult B-ALL. Furthermore, the genomic drivers underlying each subgroup remain to be identified.We aimed to perform genomic analysis on a large cohort of patients with adult B-ALL, and to correlate genomic markers with achievement of MRD negativity enabling blinatumomab randomization, and with subsequent response to blinatumomab. Methods:For genomic analysis, we studied 569 adults with newly diagnosed B-ALL registered for initial screening on the ECOG-ACRIN-led E1910 trial (NCT02003222), which evaluated the addition of blinatumomab to standard consolidation chemotherapy. The median age was 52 yrs (range 30 to 71 yrs), with 52% males. Analysis was performed on tumor and matched-normal samples using whole transcriptome sequencing (RNA-seq; tumor only; n=569), whole exome sequencing (n=490), whole genome sequencing (n=131), and single nucleotide polymorphism array (n=445). B-ALL cases were classified into 22 molecular groups. Outcome analysis was limited to patients enrolled and treated on E1910 (n=319). Results: Driver genes (n=268) were identified by the mutation-significance detection tool dNdScv or by the presence of pathogenic variants in known cancer genes, with NUP188 identified as a novel driver gene. Recurrently mutated pathways included: B-cell development (46%), cell cycle (44%), epigenetic regulation (30%), other transcriptional regulation (27%), Ras signaling (25%), RNA machinery (17%) and JAK-STAT signaling (8%). A high frequency of high-risk subtypes was observed including BCR::ABL1 (20%), BCR::ABL1-like (18%), low hypodiploid (14%) and KMT2A (12%). Using tSNE analysis, we identified a new cluster of cases (n=20, 3.5%) lacking a known subgroup driver, with overexpression of CEBPA (n=13) or CEBPB (n=7), distinct from CEBPE/ZEB2, termed “CEBP-altered” ALL (CEBPalt). Five of 13 cases with high CEBPA expression harbored an IGH::CEBPA rearrangement and one harbored a RXRA::CEBPA enhancer hijacking alteration. Of the 7 cases with high CEBPB expression, 5 harbored IGH::CEBPB, and two of these had concomitant clonal BCR::ABL1 fusions. To identify additional mechanisms of CEBP deregulation, in situ Hi-C coupled to H3K27 acetylation immunoprecipitation (HiChIP) was performed on 5 cases. Four cases showed evidence of de novo CEBPA enhancer activity. In two cases, we identified novel insertions (12 and 34nt) ~2kb downstream of CEBPA. A novel translocation and enhancer hijacking event between LINC00426 and the 5' UTR of CEBPB was identified in the remaining case. Overall, we confirmed genomic alterations of CEBPA or CEBPB in 16 of 20 cases with available material. Thus, we have identified a new molecular subgroup of adult B-ALL characterized by genomic alterations that drive enhancer hijacking and oncogenic deregulation of CEBPA/CEBPB. Several subgroups were enriched in patients that failed induction chemotherapy (n=62) or were MRD-positive (n=63) compared to those that achieved MRD-negative status (n=194): BCR::ABL1-like (30 vs 14%, p<0.001), KMT2A (18 vs 9%, p=0.03) and BCL2/MYC (5 vs 1%, p=0.06). Conversely, the following subgroups were enriched in patients that achieved MRD-negativity: PAX5alt (6 vs 18%, p=0.002), TCF3::PBX1 (0 vs 5%, p=0.01) and ZNF384 (2 vs 6%, p=0.08) Within each molecular subgroup we compared the survival of patients who achieved MRD-negative status after induction and were randomized to receive blinatumomab plus chemotherapy (n=93) or chemotherapy only (n=91). Although numbers were low, blinatumomab improved relapse-free survival for patients with hyperdiploid, PAX5alt, BCR::ABL1-like and KMT2A ALL compared to chemotherapy alone. Clonal hematopoiesis of indeterminate potential (CHIP)-related gene mutations were identified in 121 of 417 cases analyzed (29% total: somatic 74%, remission 31%, both 5%). TP53 mutations were most frequent (n=65 patients), with the majority identified in patients with low hypodiploid (n=52). Interestingly, patients with CRLF2 rearrangements collectively harbored the highest number of other CHIP gene mutations (n=13), including DNMT3A (n=4), TET2 (n=3) and ASXL1 (n=3). Conclusions:We provide a comprehensive landscape of genomic alterations in adult B-ALL and identify a new group characterized by deregulation of CEBPA/CEBPB (CEBPalt). We also provide insights into the efficacy of blinatumomab in different molecular subgroups of adult B-ALL.

Abstract Introduction Defining the epidemiology of myelodysplastic syndromes/neoplasms (MDS) and precursor conditions, such as clonal cytopenia of undetermined significance (CCUS), is challenging due to inconsistent reporting, complex diagnostics, and evolving criteria. The National MDS Natural History Study (NHS) overcomes these challenges through central pathology review, prospective follow-up, and a nationally representative cohort enrolled at the time of suspected MDS, enabling robust analysis across the myeloid disease spectrum. We analyzed clinical, genetic, and pathologic features in NHS participants by race, ethnicity, and sex to characterize disease variation across populations. Methods The NHS (NCT02775383) enrolled individuals undergoing evaluation for suspected MDS from June 2016–July 2024 at 102 US sites. Participants underwent bone marrow assessment with centralized, adjudicated histopathology review. Those meeting WHO 2016 criteria for MDS, MDS/myeloproliferative neoplasm (MPN), CCUS, idiopathic cytopenia/dysplasia of undetermined significance (ICUS/IDUS), or oligoblastic AML were followed longitudinally. Demographics, comorbidities, exposures, and clinical data were collected at baseline and every 6 months. Deep DNA sequencing was performed on baseline marrow, with pathogenic variants manually curated (53 genes). Statistical analyses assessed associations using chi-squared, Fisher's exact, Kruskal-Wallis, logistic regression, and Cox models. A p-value <0.05 was considered significant. Results Among 2,021 participants, 1,174 (58%) were diagnosed with MDS or precursor conditions. Median age was 74 years (yrs) and 66% were male. Most identified as Non-Hispanic White (NHW, 92%), with 4% Black and 4% Hispanic. The most common diagnoses were MDS (42%) and CCUS (37%). Pathogenic somatic mutations were identified in 84% (774/918) of MDS/CCUS, with TET2 (26% of 918), DNMT3A (21%), and ASXL1 (16%) most frequent. Median follow-up was 1.8yrs and consistent across race, ethnicity, and sex (p≥0.6). Black, compared to NHW, participants were younger (69 vs 74 yrs, p=0.006) and trended toward more females (47% vs 34%, p=0.09) and more MDS diagnoses (51% vs 41%, p=0.07). Black participants showed more advanced disease (e.g., lower hemoglobin, higher peripheral blood blasts, higher variant allele frequencies (VAFs) of pathogenic mutations), yet received less MDS-directed treatment (14% vs 41%, p=0.01). Black, compared to NHW, participants had more mutations in RUNX1, TP53, BCOR, and DNMT3A, but fewer in TET2 and ASXL1. Hispanic, compared to Non-Hispanic, participants had fewer known pathogenic mutations, leading to more ICUS (19% vs 5%, p=0.02). Females, compared to males, were younger at diagnosis (72 vs 75yrs, p<0.001), had more ICUS/IDUS (20% vs 10%, p<0.001), fewer pathogenic mutations, especially in splicing/chromatin modifier genes (U2AF1, SRSF2, ASXL1, ZRSR2), more DNMT3A mutations, and lower VAFs (0.27 vs 0.33, p<0.001). Median overall survival (OS) was 6.4yrs, and shorter in MDS (4.2yrs) than CCUS (not reached). Worse OS was associated with age (adjusted hazard ratio (aHR) 1.06), MDS (vs CCUS; aHR 1.89), higher-risk disease by IPSS-R/CCRS (aHR 2.15), and TP53 mutations (aHR 2.17) (all p<0.001). A trend toward improved OS in Black participants was attenuated after adjustment (aHR 0.79, p=0.6). Progression (e.g., worsening of disease, increase in transfusion dependency, death) occurred in 53% of participants. Worse progression-free survival (PFS) was associated with MDS diagnosis (aHR 2.59), higher-risk disease by IPSS-R/CCRS (aHR 2.17), and TP53 mutations (aHR 1.86) (all p<0.001). Despite more advanced disease and less MDS therapy, Black participants trended toward improved PFS (aHR 0.62, p=0.14), while age was borderline significant (aHR 1.01, p=0.05). Conclusions For the first time, we show that among individuals evaluated for suspected MDS at sites across the US, 58% had MDS or precursor conditions. Differences across demographics underscore the heterogeneity of MDS. Black participants presented with more advanced MDS, received less treatment, but trended toward improved outcomes, particularly PFS, even after adjustment, suggesting biological rather than access-to-care differences driving disparities. These findings highlight the complex interplay of sex, race, and genetics in shaping MDS outcomes and reinforce the need for diverse, large-scale studies to improve risk stratification and personalized care.

Abstract Introduction: Standardized reporting of clinical trials results for MDS is essential to improve clinical interpretation and cross-study comparison. However, reporting of patient characteristics, response criteria, and endpoints in publications is often inconsistent; there is no systemic analysis of MDS trial reporting available. We conducted a systematic review of published MDS trial manuscripts on behalf of the international consortium for MDS (icMDS) to assess variability in reporting practices. Methods We searched ClinicalTrials.gov to identify all clinical trials registered for adults (≥18 years) with MDS that reported results between 2015-2024. Clinical trials that included acute myeloid leukemia (AML) or MDS/myeloproliferative neoplasms (MPN) were included if they enrolled ≥5 MDS patients. We excluded trials without an MDS cohort; non-therapeutic trials; trials focused on transplant interventions; or those which enrolled solid malignancies or other hematologic malignancies (chronic myeloid leukemia or lymphoid diseases). Finally, trials were required to have a manuscript available on Larvol, PubMed, or Google Scholar. Trials were categorized by disease risk (lower-risk [LR] vs. higher-risk [HR]) and trial phase (early phase [EP] vs. late phase [LP]). Results We identified 502 MDS trials on ClinicalTrials.gov, of which 351 did not meet inclusion criteria and 79 lacked a manuscript. A total of 72 trials (32 EP, 40 LP) with 80 publications (34 EP, 46 LP) were analyzed. Frequently reported baseline characteristics included age (100% EP, 100% LP), disease risk (74% EP, 74% LP), Eastern Cooperative Oncology Group performance status (85% EP, 72% LP), prior treatments (71% EP, 67% LP), and RBC transfusion dependency (32% EP, 70% LP). Less frequently reported characteristics included blood counts (hemoglobin [Hb; 38% EP, 54% LP], platelet count [38% EP, 54% LP], neutrophil count [24% EP and LP]) and bone marrow blasts (29% EP, 43% LP). Although disease risk was widely reported, definitions varied: IPSS and IPSS-R were each reported in 54% of manuscripts, while IPSS-M appeared in only 3%. Cytogenetic risk was separately reported in 39% of manuscripts (38% EP, 39% LP), and mutational data in 45% (47% EP, 43% LP). Responses per IWG 2006 criteria were reported in 84% of manuscripts. The primary endpoint involved safety/tolerability in 85% of EP manuscripts, though definitions were variable; recommended phase 2 dose was the most common (26% of EP manuscripts). In LP trials, primary endpoints were risk-specific: transfusion independence (TI) in 77% of LR, overall response rate (ORR) in 28% of HR, and complete remission (CR) or overall survival (OS) in 22% of HR. In HR manuscripts, CR was reported in 100%, ORR in 73%, hematologic improvement (HI) in 48%, RBC-TI in 23%, and OS in 80%. However, seven different definitions were used for ORR: CR + marrow CR + partial remission + HI per IWG 2006 was most common (35%). Event-free survival was reported in 25%; progression-free survival and relapse-free survival in 13%; and leukemia-free survival in 5%. Early mortality rate was reported in 35% (18% EP, 56% LP) and transplant rate in 58% (50% EP, 67% LP). Only 47% of HR and 90% of LR manuscripts identified HI-eligible patients. In LR-MDS, RBC-TI was reported in 72% of manuscripts but used six definitions. The most common were RBC-TI ≥8 weeks at any time during treatment (24%), ≥8 weeks within 28 weeks of treatment (13%), ≥8 weeks with Hb increase ≥1.0 (4%), ≥12 weeks with Hb increase ≥1.5 (4%), and ≥16 weeks within 24 weeks of treatment (12%). The remainder did not report RBC-TI, did not define it, or used a custom definition not used in another trial. HI was reported in 80% of LR papers with most of those reporting HI using IWG 2006 criteria (90%). Conclusion Reporting of baseline characteristics, response criteria, and outcomes is inconsistent in MDS clinical trials, with wide variability in response definitions, including ORR and TI. This heterogeneity limits interpretability, hampers historical comparisons and may obscure efficacy signals. Our findings highlight the need for standardized reporting guidelines to ensure clarity and consistency in MDS trial publications. As a next phase of this effort, we will conduct a formal Delphi process among icMDS experts to establish consensus recommendations for minimal and optimal MDS clinical trial reporting in manuscripts by disease risk (LR/HR) and trial phase (EP/LP).

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.