Padron, Eric

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

PURPOSE Chronic myelomonocytic leukemia (CMML) is a rare myeloid neoplasm characterized by clinical heterogeneity and is associated with poor outcomes. To date, limited molecular information has been incorporated into disease classification and risk stratification. We aimed to integrate genomic features into the clinical decision-making process for CMML. PATIENTS AND METHODS We analyzed a retrospective cohort of 3013 patients with CMML (training set) and a prospective population of 516 patients (validation set). Using an innovative framework for multimodal data analysis, we developed molecular-based disease taxonomy and prognostication. RESULTS Unsupervised clustering identified nine entities with distinct genomic features and outcomes ( P < .001), including splicing machinery, transcription factors, signal transduction and tyrosine kinase pathways aberrations, and high-risk molecular signatures. Notably, 15% of patients showed molecular/clinical overlap with other myeloid neoplasms. We integrated molecular and clinical information to build the international CMML Prognostic Scoring System (iCPSS), incorporating mutations in nine genes together with hematologic parameters and cytogenetic abnormalities. The iCPSS identified five groups with distinct probability of overall and leukemia-free survival in both training and validation cohorts ( P < .001), outperforming existing prognostic models. Importantly, 55% of patients were reassigned to higher or lower risk groups by the iCPSS. Decision analysis demonstrated that iCPSS could refine the optimal timing of allogeneic transplantation at the individual level; compared with conventional prognostic tools, iCPSS-based decision modeling changed transplantation strategy in 31% of cases, resulting in a significant gain-in-life expectancy for eligible patient population ( P < .001). A federated learning platform was implemented to enable continuous, privacy-preserving model update across multiple centers. CONCLUSION Molecular information improves CMML classification and prognostication, supports more effective clinical decision making, and potentially refines the design of clinical trials.

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: Chronic myelomonocytic leukemia (CMML) is a universally fatal adult myeloid neoplasm with a median survival of 32 months and no approved therapies that alter its natural history. Although most patients initially present asymptomatically, disease progression (DP) is inevitable and its biological triggers remain poorly understood. Anecdotes and small case series suggest that acute inflammatory events (AIE) may precipitate hyperleukocytosis and DP in some patients, but fragmented care in the U.S. has hindered large-scale retrospective analyses. To address this gap, we launched a prospective, multi-institutional observational study to systematically evaluate the relationship between AIEs and DP. Our aim is to identify modifiable, cell-extrinsic stressors that contribute to disease destabilization and inform strategies for prolonging the indolent phase of CMML. Methods: We enrolled patients with WHO-defined CMML in a clinically asymptomatic state, defined by: (1) MPN-SAF TSS &lt;20, (2) no CMML-directed therapy, (3) no symptomatic splenomegaly, and (4) transfusion independence. Key exclusions included active malignancy, uncontrolled infection, or inability to attend monthly visits. Over 24 months, participants underwent monthly interviews to document AIEs, including flares of chronic illness e.g. gout, infections, surgery procedures, cardiovascular events, and trauma. AIE severity was graded by hospitalization status. Blood samples were collected at each visit, with bone marrow collected when clinically indicated. Cytokine profiling was performed using Olink Reveal assays, and genomic data were integrated to assess mutation-specific inflammatory patterns. DP was defined by worsening symptoms (MPN-SAF TSS ≥20 with ≥50% increase), new transfusion needs, therapy initiation, symptomatic splenomegaly, or transformation to CMML-2/AML. Descriptive statistics summarized baseline and AIE data. Progression-free (PFS) and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression models. Results: A total of 102 patients were enrolled over 2 years, with a median follow-up of 1 year (range, 0.5–1.5). The median age was 72 years; 71 were male and 31 female. By FAB criteria, 38 had myeloproliferative-type CMML, and 8 met WHO 2022 criteria for CMML-2. CPSS-Mol risk distribution was: 49.0% low, 26.5% intermediate-1, 37.3% intermediate-2, and 3.99% high. A total of 260 AIE were recorded in 77 patients. The most common AIEs were surgical procedures (n=115 events in 53 patients), flares of chronic disease (n=99 in 38), and infections (n=87 in 47). DP occurred in 28 patients: 18 met symptom-defined criteria, 13 met disease-defined criteria, and 3 met both. Longitudinal labs showed significant post-AIE increases in WBC (6.29 → 7.73 ×10⁹/L, p = 0.02) and platelets (112 → 131 ×10⁹/L, p = 0.03), with no change in hemoglobin (p = 0.27). Progressors had significantly lower hemoglobin than non-progressors (11.6 vs. 12.7 g/dL, p = 0.037), with no differences in WBC or platelet counts (p &gt; 0.5). Among those with DP, 25 of 28 had at least one AIE. AIE presence was significantly associated with DP (OR 3.76, p = 0.04). Flares of chronic disease conferred a threefold increased risk of DP (OR 3.37, p = 0.008) and remained an independent risk factor after adjusting for CPSS-Mol risk (OR 3.6, p = 0.009). Severe AIEs requiring hospitalization trended toward higher risk but were not statistically significant (OR 2.3, p = 0.09). Among the 44 patients with genomic data, all AIE-positive patients (29/29) harbored at least one epigenetic regulator mutations (TET2, DNMT3A, ASXL1, IDH1/2), compared to 12/15 AIE-negative patients (p = 0.034). Signaling mutations (JAK2, CBL, NRAS, KRAS) were also enriched in AIE-positive cases (11/29 vs. 1/15, p = 0.035). No significant differences were found in spliceosome or tumor suppressor mutations. No genomic features distinguished progressors from non-progressors, regardless of whether there was an AIE. Conclusion: In this interim analysis of a prospective multi-institutional CMML cohort, AIE were significantly associated with DP. Ongoing work is aimed at sequentially annotating genomic alterations and profiling secreted factors before and after AIEs. While this study continues to accrue and mature, these findings support inflammation as a modifiable driver to CMML biology and progression and lay the groundwork for future studies investigating inflammatory or supportive interventions to delay disease evolution.

Abstract Background: While mutations in the fms-like tyrosine kinase 3 (FLT3) gene are well-established adverse drivers in acute myeloid leukemia (AML), their role in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) remains insufficiently defined. Methods: We conducted a retrospective multicenter study of 115 patients with FLT3-mutated (FLT3mut) MDS (n=63) or CMML (n=52), comparing their clinical, genomic, and therapeutic characteristics at diagnosis or first referral to 677 FLT3 wild-type (FLT3wt) controls (MDS n=388; CMML n=289) using multivariate analyses and propensity score matching (PSM). Results: FLT3mut MDS and CMML exhibited a proliferative phenotype with higher leukocyte and neutrophil counts and lower platelet levels (p&lt;0.02); in MDS, median white blood cell counts remained below 13,000/µL. In MDS, FLT3mut cases were enriched in the MDS with increased blasts subtype (57% vs 39%, p=0.01) and favorable-risk cytogenetics (64% vs 41%, p&lt;0.01). Genomically, FLT3mut MDS showed higher frequencies of NRAS, KRAS, PTPN11, RUNX1 and CBL co-mutations (p&lt;0.05), and a markedly lower prevalence of TP53 mutations (2% vs 36%, p&lt;0.001). In CMML, FLT3mut cases were more often transfusion-dependent (50% vs 23%, p&lt;0.01), classified as CMML-2 (39% vs 25%, p=0.04), and enriched in ASXL1 (68% vs 47%; p&lt;0.01) and SETBP1 (24% vs 8%; p&lt;0.01) mutations. Notably, they exhibited multi-hit TET2 mutations less frequently than FLT3wt CMML (27% vs 53%, p=0.01). After adjusting for age, sex, and allogeneic stem cell transplantation, FLT3 mutations were independently associated with worse outcomes. To further assess the prognostic impact of FLT3 mutations, we conducted PSM analyses using a 1:1 ratio of FLT3mut to FLT3wt patients, adjusting for key clinical and biological confounders. In MDS, matching was based on age, sex, bone marrow blast percentage, and cytogenetic risk category; in CMML, variables included age, CMML-2 subtype, peripheral blood counts, normal karyotype, and ASXL1 mutation status. After matching, FLT3mut MDS cases showed significantly shorter overall survival (OS; 19.9 vs 44.2 months, p=0.046) and leukemia-free survival (LFS; 13.8 vs 37.1 months, p=0.023) compared to FLT3wt patients. Similarly, in CMML, FLT3mut patients experienced inferior OS (30.4 vs 67.2 months, p=0.017) and LFS (17.2 vs 65.6 months, p=0.014). Competing risk models confirmed a markedly increased cumulative incidence of AML transformation in both FLT3mut MDS and CMML (p&lt;0.001), without significant differences in the risk of non-leukemic death. Among FLT3mut cases, tyrosine kinase domain mutations (FLT3-TKD) were associated with superior survival compared to internal tandem duplications (FLT3-ITD; MDS hazard ratio [HR]: 0.28, p=0.003; CMML HR: 0.34, p=0.012). FLT3 allelic ratio (AR), assessed by conventional PCR in 63 patients (MDS n=34, CMML n=29), provided additional prognostic value. An AR ≥0.21 identified a subgroup with significantly shorter OS (MDS: 24.4 vs 38.8; CMML: 6.7 vs 30.4 months) and LFS (MDS: 9.0 vs 18.5 months; CMML: 5.8 vs 30.4 months; all p&lt;0.05), supporting the utility of quantitative FLT3 assessment in clinical risk stratification. FLT3 inhibitors (FLT3i) were administered in combination with hypomethylating agents (HMA) to 16 (27%) FLT3mut MDS and 15 (33%) CMML patients. Compared to HMA, FLT3i treatment was associated with higher overall response rates (MDS: 69% vs 22%, p&lt;0.01; CMML: 73% vs 35%, p=0.06). Molecular clearance, defined as post-treatment reduction in AR to ≤0.01, was observed more frequently with FLT3i than with HMA (MDS: 56% vs 10%, p=0.03; CMML: 60% vs 20%, p=0.09). FLT3 clearance was associated with prolonged survival. In MDS, median OS and LFS were 66.0 vs 14.5 (p=0.12) and 29.0 vs 9.9 months (p=0.056), respectively; in CMML, it was 37.6 vs 14.6 months for both OS (p=0.043) and LFS (p=0.032). Conclusions: This study expands the current understanding of FLT3mut MDS and CMML by characterizing their clinical, molecular, and therapeutic features in the largest multicenter cohort reported to date. These cases exhibit a proliferative phenotype, frequent co-mutations in RAS pathway genes, and an elevated risk of leukemic transformation. Quantitative assessment of FLT3 allelic burden refines prognostication beyond mutation status alone. The observed associations between FLT3 inhibitor use, molecular clearance, and improved outcomes support further evaluation of targeted strategies in selected patients.

Abstract Background The expansion of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow is universally associated with adverse outcomes and disease progression in all chronic myeloid neoplasms, to include chronic myelomonocytic leukemia (CMML). However, HSPCs are a heterogeneous cellular compartment and the impact of its composition on clinical outcomes remains poorly defined. Single cell RNA-sequencing (scRNA-seq) represents an optimal strategy to annotate cellular composition but no large clinically annotated scRNA-seq datasets are currently available. To address this, we have embarked to generate a clinically annotated 500 patient CMML scRNA-seq atlas from CD34+ enriched BMNCs to establish among the largest clinically and genetically annotated single cell references for any chronic myeloid malignancy. Here we report the interim analysis of 113 clinically annotated cases that demonstrates massive reshaping of HSPC composition that is independently a predictor of overall survival. Methods Single-cell RNA expression profiling was performed on 113 CD34-enriched CMML BMNC samples using 10x Genomics GEM-X Universal 3' Gene Expression v4 (4-plex) chemistry. Libraries were sequenced on NovaSeq S4 flow cells in two runs, and data were processed using Cell Ranger to generate gene expression matrices. A total of 502,659 single cells from 113 samples were processed using Seurat. The upper threshold for gene count was defined as the mean number of detected genes plus two standard deviations data normalization was performed using the log-normalization method. Batch correction and integration were conducted with Harmony to mitigate technical variation across pools. Descriptive statistics were used to tabulate clinical and genetic parameters. KM curves, log-rank test, and cox regression were used to calculate survival, test for statistical differences, and perform multivariate analysis, respectively. Results To derive high resolution cell annotations, we employed the SingleR algorithm using a large hematopoietic reference of over 300,000 single cells (Zhang, X. Nature Immunology, 2024). Using this approach a diverse set of cell types were identified that included HSCs, 23 myeloid progenitors, 18 erythroid progenitors, and 18 lymphoid progenitors. This diverse cellular repertoire displayed massive reshaping relative to the normal CD34 enriched reference including a &gt;53x expansion of multilineage GMPs and a &gt;100x depletion of B-cell progenitors consistent with the known myeloid skewing seen in this disease. To understand whether expansion of specific progenitors was associated with outcomes we iteratively evaluated key progenitor populations and observed that expansions of HSC (HR 0.468 p&lt;0.005) and MEP (HR 0.485, p&lt;0.005) were associated with improved survival while GMP (HR 1.729, p=0.029) expansions were associated with inferior survival when using a cut point derived with a maximally selected ranks statistics approach. To achieve a more comprehensive metric of HSPC composition we explored GMP ratios to include GMP/HSC ratios and GMP/MEP ratios and observed that both were associated with inferior survival in univariate and multivariate when considering clinical and genetic features such as the CPSS-molecular prognostic score and FAB classification. When considering both GMP/HSC and GMP/MEP ratios in a multivariate model only GMP/MEP ratios and CPSS molecular remained independently prognostic. As an orthogonal approach, pseudotime projections were carried out using a reference map from Setty et al., 2019 to calculate differentiation potential and branch probabilities. This approach enabled both cell identity assignment and placement of cells along the hematopoietic differentiation trajectory. Samples were classified as monocyte-biased, MEP-biased, or normal-like, as previously described (Ferrall-Fairbanks et al. 2022) and demonstrated that increased GMP ratios are associated with a monocytic biased trajectory and that this trajectory is also associated with overall survival. Conclusion This study represents an interim analysis of among the largest scRNA-seq cohorts generated in chronic myeloid malignancies. This enabled us, for the first time, to demonstrate that HSPC composition is independently prognostic even when considering modern CMML prognostic models. As this cohort continues to increase, validation of these findings and examining the impact of therapy on HPSC composition in serial samples will be prioritized.

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 &lt;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&lt;0.001), had more ICUS/IDUS (20% vs 10%, p&lt;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&lt;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&lt;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&lt;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).