Myelofibrosis (MF) is a type of myeloproliferative neoplasm (MPN) that is associated with significant morbidity and mortality including progression to acute leukemia and cardiovascular disease (CVD). High-output heart failure (HOHF) has been previously associated with MF, though its impact on outcomes is unknown. To investigate the impact of HOHF on outcomes among patients with MF. This was a multicenter retrospective cohort study of MF patients from 2010-2024 with ≥ 1 transthoracic echocardiogram (TTE). Doppler estimation of cardiac index on TTE and pulmonary artery systolic pressure (PASP) was estimated and HOHF was defined as cardiac index of ≥ 3.54 L/min/m2 and PASP > 40 mmHg. Patients with vs without HOHF were compared. Primary outcome was death or leukemia transformation. Multivariable Cox proportional hazards regression was performed to explore association between HOHF and primary outcome. Of 114 patients included, 19 (16.7

Frameshift mutations in exon 12 of nucleophosmin 1 (NPM1 mut) are among the most common mutations in acute myeloid leukemia (AML) and have historically been considered favorable-risk in the absence of FLT3-ITD. In the European LeukemiaNet (ELN) 2024 risk-classification for patients treated with hypomethylating agents plus venetoclax (HMA + VEN), NPM1 mut is not considered favorable when co-occurring with signaling gene (SG) mutations (i.e., FLT3-ITD, NRAS, KRAS). However, due to limited numbers in the original analysis, the prognostic impact of SG mutations in NPM1-mutant AML remains unclear. We evaluated the prognostic significance of NPM1 mut with and without SG mutations in two independent cohorts of patients ≥ 60 years with ELN 2024 favorable- or intermediate-risk AML treated with HMA + VEN. Cohort 1 included 322 patients treated in the academic setting. NPM1 mut (n = 61) was associated with a nonsignificantly longer overall survival (OS) compared to NPM1 wild-type (NPM1 wt) (median, 53.05 vs. 17.03 months, p = 0.10). In multivariable analysis (MVA), SG mutations were not independently prognostic within the NPM1 mut subgroup. Cohort 2 included 816 patients from a real-world community-treated cohort. NPM1 mut (n = 124) had a longer OS compared with NPM1 wt (median, 15.3 vs. 14.4 months, p = 0.03). In MVA, NRAS, KRAS, and FLT3-ITD were independent unfavorable prognostic factors; NPM1 mut with, compared to without, SG co-mutation had a shorter OS (median, 9.4 vs. 31.6 months, p = 0.001). These findings suggest SG mutations negate the favorable impact of NPM1 mut in older patients treated with HMA + VEN. Prospective clinical trials are needed to investigate the use of combination therapies to improve outcomes in this high-risk subgroup.

Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), are chronic myeloid neoplasms associated with increased risk of cardiovascular disease (CVD). Statins are a common group of cholesterol-lowering medications recommended for the primary and secondary prevention of CVD, including arterial thrombotic events. Emerging evidence suggests that statins may reduce the risk of developing MPNs and their use may be associated with improved survival. However, the effect of statins on cardiovascular and hematologic outcomes among patients with MPNs remains uncharacterized. We conducted a multicenter retrospective cohort study of patients with MPNs who had at least 1 transthoracic echocardiogram (TTE) from 2010 to 2024. Inverse probability of treatment weighting (IPTW) competing-risk regression analysis was performed to assess the association between statin use at time of index TTE on major adverse cardiovascular events (MACE), MPN disease progression, and all-cause death. Patients with MPN were analyzed as a whole and separately by type (ET or PV and MF). A total of 669 patients were included, 43.9% were on statin use, 50.5% were female, 83.9% were White, 78.8% had JAK2 driver mutation, and 72.9% had class I guideline indication for statin therapy. There were 267 (39.9%) patients with PV, 234 (35.0%) with ET, and 168 (25.1%) with MF. After IPTW, statin use was associated with lower risk of MACE but not MPN disease progression or allcause death. Among patients with ET or PV, statin use was associated with lower risk of MACE but not MPN progression or all-cause death. Among patients with MF, there was no difference in MACE, leukemia progression, or all-cause death. Among patients with MPNs who underwent TTE, statin use was associated with lower risk of MACE, particularly among patients with ET or PV. However, there was no association between statin use and all-cause death or MPN disease progression. Statin therapy is underused in this patient population. Further studies are needed to explore the utility of statin therapy in patients with MPN and identify patients who would benefit most from statin therapy.

(A) Immunoblots confirming MEF2C overexpression in MOLT4 cells. (B) Eight-day growth curves for control vs MEF2C OE MOLT4 cells. (C) Co-treatment with ziftomenib (0.3 µM) and CDK1/2 inhibitor (0.3 µM) in control vs MEF2C OE MOLT4 cells.

Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by progressive bone marrow fibrosis and extramedullary hematopoiesis. Patients with MF are at increased risk of heart failure (HF) and pulmonary hypertension (PH), which are associated with morbidity and mortality. Ruxolitinib is used in MF to palliate symptom. Whether treatment with ruxolitinib impacts risk of HF hospitalization or new PH in MF is unknown. This was a retrospective cohort of MF patients without prior HF. Outcomes were HF hospitalization or new PH and all-cause death. A total of 144 patients were included, 46 (31.9%) were on ruxolitinib, 40.3% were female and 78.5% were White race. Ruxolitinib treatment was associated with lower risk of HF hospitalization or new PH (adjusted subhazard ratio 0.27, 95% CI 0.10-0.73) but not all-cause death (adjusted HR 0.85, 95% CI 0.42-1.72). Prospective, randomized studies are needed to confirm the impact of ruxolitinib on cardiovascular outcomes among patients with MF.

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, biTET2, 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.

Myeloproliferative neoplasms (MPNs) are associated with pulmonary hypertension (PH). Recent studies have demonstrated associations between PH and adverse cardiovascular outcomes and MPN disease progression. However, risk factors for development of PH and the pathophysiology of PH in MPNs remain unclear. We conducted an analysis of a multicenter retrospective cohort of patients with MPN with ≥ 2 transthoracic echocardiograms (TTEs) after MPN diagnosis. Patients with low probability of PH on the first TTE after MPN diagnosis were included. Backward stepwise Cox proportional hazards regression modeling was performed to identify risk factors for high probability of PH on subsequent TTE. Impact of incident high probability of PH on subsequent TTE, on major adverse cardiovascular event (MACE), hematologic progression, and death was examined using multivariable competing risk or Cox proportional hazards regression. After backward stepwise modeling, age at MPN, non-JAK2 driver mutations, polycythemia vera (PV) and myelofibrosis (versus essential thrombocythemia), leukocytosis, and elevated HFA-PEFF score were associated with increased risk of incident high probability of PH. Incident high probability of PH was associated with increased risk of MACE, hematologic progression, and death. Further studies are needed to evaluate the role of prospective screening for PH in patients with MPNs and further delineate pathophysiology of PH in patients with MPNs.

Azacitidine (Aza) plus venetoclax (Ven) is standard treatment for older/unfit patients with newly diagnosed (ND) acute myeloid leukemia (AML). The approved 28-day (D) Ven schedule is associated with prolonged cytopenias, causing frequent dose reductions and cycle delays. Retrospective studies show similar efficacy and reduced toxicity with abbreviated Ven dosing, but prospective data is lacking. We conducted OPTI-AML(NCT03013998), a prospective randomized phase 2 trial comparing 28D Ven (AV28) versus 14D (AV14) with Aza (75mg/m²x7D) for C1-2 in genomically agnostic ND-AML patients ≥60 years. The primary endpoint was complete remission (CR) rate achieved at any time with two cycles of therapy. Between 2023-2025, 169 patients received AV28 (n=83) or AV14 (n=86). CR across two cycles was 49.4% (AV28) versus 43% (AV14); difference of 6.4% [90%CI:-6.1% to 19.0%], not meeting non-inferiority criteria. Patients with NPM1/ IDH2 mutations had higher CR rates with AV28 (60.9% vs. 33.3%), while CR rates were equivalent (45%) for other subgroups. Composite CR rates were 80.7% (AV28) versus 68.6% (AV14) and MRD negativity was similar (77.6% vs. 76.5%). Although AV28 had more frequent treatment interruptions, count recovery after C2, grade ≥3 adverse events and early mortality were similar. In conclusion, the study did not demonstrate non-inferiority of AV14 compared with AV28 during C1-2 in an unselected ND-AML cohort. However, as the confidence interval for the difference covered 0, CR rate for AV28 was not significantly different than AV14. Certain subgroups may benefit from prolonged Ven exposure, but these findings require validation in larger studies, especially as triplet regimens evolve.

BACKGROUND:For patients with acute myeloid leukemia (AML) who are 75 years of age or older or who are ineligible for intensive induction chemotherapy, azacitidine or decitabine plus venetoclax is the standard of care, but parenteral administration imposes a burden on patients and providers. Oral decitabine-cedazuridine, approved in Europe for AML, has pharmacokinetic properties equivalent to those of intravenous decitabine but provides limited survival benefit as monotherapy. METHODS:In this phase 1-2, open-label, multicenter, nonrandomized trial, we assigned patients with newly diagnosed AML who were 75 years of age or older or who were ineligible for intensive chemotherapy to receive oral decitabine-cedazuridine plus oral venetoclax. To mitigate myelosuppression observed in phase 1, schedule adjustments were encouraged in phase 2b after bone marrow blast clearance. The primary end points were the venetoclax area under the curve from 0 to 24 hours and maximum observed concentration with or without decitabine-cedazuridine (measures of drug interaction) on days 5 and 15 of cycle 2 (phase 1-2a) and complete response (phase 2a-b). RESULTS:A total of 189 patients were enrolled (30 patients in phase 1, 58 patients in phase 2a, and 101 patients in phase 2b). No drug-drug interactions were observed between decitabine-cedazuridine and venetoclax. In the pivotal phase 2b, the percentage of patients with a complete response was 47% (95% confidence interval [CI], 36 to 57), the percentage with a complete response or complete response with incomplete hematologic recovery was 63% (95% CI, 53 to 73), and median overall survival was 15.5 months (95% CI, 7.6 to could not be estimated). Common adverse events of grade 3 or higher in phase 2b were anemia (in 30% of the patients), neutropenia (in 26%), and febrile neutropenia (in 25%). Mortality was 3% at 30 days and 10% at 60 days. CONCLUSIONS:Among patients with newly diagnosed AML who were ineligible for intensive chemotherapy, all-oral decitabine-cedazuridine plus venetoclax caused no drug interactions and resulted in a complete response in nearly half the patients, with myelosuppressive effects. (Funded by Taiho Oncology; ASCERTAIN-V ClinicalTrials.gov number, NCT04657081.).

T-lineage acute lymphoblastic leukemia (T-ALL) lacks effective targeted therapies, with poor outcomes in relapsed/refractory (R/R) disease. HOXAhigh T-ALL is biologically aggressive and often resistant to standard therapy. Menin inhibitors, recently approved for KMT2A-rearranged leukemias, may be effective in T-ALL, but biomarkers of response remain undefined. This study aims to evaluate the efficacy of menin inhibition in T-ALL and identify molecular predictors of sensitivity. We tested menin inhibitors (ziftomenib, revumenib, and VTP50469) in 14 primary T-ALL samples and 8 cell lines, representing HOXAhigh and HOXAlow genotypes. In vitro sensitivity assays, xenograft mouse models, transcriptomics, proteomics, and phosphoproteomics were used to characterize drug response. MEF2C modulation experiments and combination studies with cyclin-dependent kinase (CDK) 1/2 and ERK1/2 inhibitors were performed in vitro and in vivo. Menin inhibitors suppressed leukemic growth in a subset of HOXAhigh and HOXAlow primary human T-ALL samples. Similarly, ziftomenib was effective in reducing tumor burden in xenografts without major toxicity. Upon treatment, we observed downregulation of canonical menin targets (HOXA, MEIS1, and MEF2C) and upregulation of T-cell differentiation programs. Phosphoproteomic studies identified MEF2C S222 phosphorylation-mediated by CDK1/2 and ERK1/2-as a predictor of ziftomenib sensitivity in T-ALL. MEF2C overexpression promoted proliferation and ziftomenib resistance, whereas its knockdown impaired growth. Ziftomenib synergized with CDK1/2 and ERK1/2 inhibitors in vitro and improved survival in xenografted mice. In conclusion, a subset of T-ALL, defined by high p-MEF2C S222, is sensitive to menin inhibition. Combining ziftomenib with CDK or ERK inhibition offers synergistic efficacy, supporting biomarker-driven clinical trials of this strategy in R/R T-ALL.

6547 Background: We and others have reported the antileukemic activity of a 10-day regimen of the hypomethylating agent (HMA), decitabine (DEC), in high-risk acute myeloid leukemia (AML). Venetoclax (VEN), at a standard (std) dose of 400 mg, combined with HMA, at a std schedule, has improved AML outcomes. We aimed to investigate the safety of adding VEN to the 10-day regimen of DEC and explore the effects of BCL2 inhibition on the immune repertoire. Methods: This was a multicenter, investigator-initiated, dose-escalation study in adults with high-risk AML defined as, disease with a TP53 mutation, adverse-risk cytogenetics or relapsed/refractory (R/R). Patients (pts) were naïve to HMA and VEN. The primary endpoint was to establish the maximum tolerated dose (MTD) of VEN when combined with a 10-day DEC schedule. Dose-limiting toxicities (DLT) were evaluated during cycle 1. In the absence of a DLT, 3-6 evaluable pts were enrolled per dose level (DL) or until the 400mg DL of VEN was reached (Table 1). Peripheral blood mononuclear cells (PBMCs) were isolated before and after treatment. Shifts in the immune landscape and BCL2 family expression were profiled with spectral flow cytometry. Results: 14 pts were enrolled, with a median age of 66.5 years (range 19-77); including 9 pts (64%) with R/R AML, 8 (57%) with adverse-risk cytogenetics and 6 (43%) with a TP53 mutation. One pt had a DLT at DL1, due to grade (G) 4 neutropenia and persistent marrow aplasia in the absence of leukemia beyond day 42. One patient with R/R AML and pre-existing elevated alanine aminotransferase (ALT) secondary to known graft-versus-host disease developed G2 ALT elevation. 3 pts were then enrolled at DL-1, before reescalation back up to DL1. 2 pts at DL1 were deemed not eligible for DLT evaluation, requiring an additional 2 pts enrolled at DL1, without DLT, to confirm safety. The MTD was determined to be DL2 (400 mg). 5 pts (36%) had a complete remission (CR) or CR with incomplete count recovery (CRi). Non-hematologic or infectious G1-2 toxicities included fatigue (43%), diarrhea (43%) and decreased appetite (36%). 1 pt died of suspected sepsis outside of the DLT evaluation period. 7 pts had serial PBMCs available for multiparameter flow cytometric immune and BCL2 family profiling. Of these, 3 responders had strong induction of BCL2 in CD4+/CD8+ lymphocytes and B cells after 1 cycle and were enriched for a population of “senescent” CD8+ T cells that had relatively low expression of coinhibitory markers (PD-1, LAG3, TIM3). Conclusions: A 10-day DEC+VEN regimen is feasible in high-risk AML, with myelosuppression being the major DLT. The recommended phase 2 dose is 400mg VEN (DL2), but responses were also seen at 200mg. The immune profile of responders have demonstrated intriguing patterns that merit investigation in a larger HMA+VEN cohort. Clinical trial information: NCT03844815 . DL DEC dose(D1-10)mg/m2 VEN dose (D1-21)mg # of pts DLT CR CRi No Response -1 15 100 3 0 0 0 3 1 20 200 8 1 1 3 4 2 20 400 3 0 0 1 2

Abstract Myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are a diverse group of hematopoietic stem cell neoplasms associated with an increased risk of hematologic progression to secondary MF or leukemia and cardiovascular disease (CVD). Elevated total cholesterol levels are traditional CVD risk factors. Patients with MPNs may have reduced cholesterol levels, potentially reflecting an underlying hypermetabolic state. The impact of serum total cholesterol on clinical outcomes in patients with MPNs has not yet been evaluated. We performed a multicenter retrospective cohort study of patients with MPNs who had transthoracic echocardiogram (TTE) with available serum lipid levels at time of TTE not on statin therapy. Patients were categorized by total cholesterol level (≥150, 120-149, and <120 mg/dL). Outcomes evaluated were MPN disease progression to secondary MF or acute leukemia, major adverse cardiovascular events, and all-cause mortality. Multivariable competing-risk regression modeling was performed. A total of 305 patients were included of whom 54.4% had total cholesterol ≥150 mg/dL, 21.3% had 120 to 149 mg/dL, and 24.3% had <120 mg/dL. After a median follow-up of 50.8 months, total cholesterol <120 mg/dL was associated with increased risk of MPN disease progression (adjusted subhazard ratio, 3.00; 95% confidence interval [CI], 1.36-6.63), heart failure hospitalization (aSHR, 3.76; 95% CI, 1.77-7.96), and all-cause death (adjusted hazard ratio, 1.87; 95% CI, 1.06-3.30) vs ≥150 mg/dL. Among patients with MPN, low total cholesterol levels were associated with increased risk of MPN disease progression and death especially among patients with ET or PV.

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.

Patients with myeloproliferative neoplasms (MPNs) are at increased risk for cardiovascular disease. Although thrombosis is a well-recognized complication, emerging evidence indicates that nonthrombotic conditions, including heart failure (HF) and pulmonary hypertension (PH), are also prevalent and associated with adverse cardiovascular and hematologic outcomes. Clinical and preclinical data suggest a shared pathophysiology linking MPNs to the development and progression of cardiomyopathy, HF, and both precapillary and postcapillary PH. Recent studies further support a bidirectional relationship, in which HF and PH are associated with hematologic progression and vice versa. Elucidating the mechanisms underlying these interactions may uncover novel therapeutic targets and inform clinical management. Here, the authors review the pathophysiology and impact of HF and PH in patients with MPNs.

Background: Parenteral DNA methyltransferase inhibitors (DNMTi) such as azacitidine and decitabine (DEC), including an attenuated 3-day regimen, are recommended in the NCCN Guidelines for patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) with clinically significant cytopenias. However, parenteral administration requires frequent clinic visits, which imposes a substantial burden on pts, particularly those requiring long-term therapy. Oral DMTIs offer more flexible dosing and maintenance of pts' autonomy. Oral DEC-cedazuridine (DEC-C) is a fixed-dose combination tablet containing DEC (35 mg) and cedazuridine (100 mg). ASTX727-03 (NCT03502668) is a randomized, open-label, multicenter, phase 1/2 clinical trial evaluating safety, efficacy, and pharmacokinetics (PK) of various DEC-C doses and regimens in pts with LR-MDS. Phase 1 identified a 5-day regimen of DEC 10 mg/cedazuridine 100 mg as the optimized low-dose (LD) regimen. Phase 2 compares this LD regimen with the attenuated standard-dose (SD) regimen. Here, we report phase 2 results on efficacy, safety, PK, and pharmacodynamic (PD) data. Methods: Adults (aged ≥18 years) with International Prognostic Scoring System (IPSS) low-risk or Intermediate-1 MDS, ECOG PS 0−2, and ≥1 cytopenia or red blood cell (RBC) transfusion dependence were randomized 1:1 to receive oral DEC-C LD (10 mg x 5 days) or SD (35 mg x 3 days). The primary endpoint was hematologic response. Secondary endpoints included PK, PD (by LINE-1 demethylation), time to bone marrow blasts >5%, leukemia-free survival (LFS), overall survival (OS), and safety. Results: As of October 31, 2024, 81 pts were treated (LD arm: n=40; SD arm: n=41) and completed a median of 8.8 months on treatment. At cutoff, 17 (42.5%) and 12 (28.6%) LD and SD pts, respectively, were still continuing the study; 9 (22.5%) and 6 (14.6%) pts respectively, had discontinued treatment due to hematopoietic stem cell transplant. Median age was 70 (LD) and 75 (SD) years; 75.0% (LD) and 68.3% (SD) had IPSS Int-1 risk MDS and 60.0% vs 41.5% had IPSS-Molecular Lower-Risk MDS (very low, low, or moderate-low). Low-risk prognostic scoring system risk distribution was similar: Category 1 (2.5% vs 4.9%), Category 2 (47.5% vs 46.3%), and Category 3 (50.0% vs 48.8%). After a median follow-up of 29.3 months, median OS was 23.9 months (95% confidence interval [CI]: 13.0, not estimable [NE]) in the LD arm vs 26.0 months (95% CI: 19.4, 28.5) in the SD arm. Median LFS was 23.8 months (95% CI: 13.0, NE) and 25.7 months (95% CI: 17.8, 26.5), respectively. Hematologic improvement per International Working Group 2006 criteria was achieved in 27.5% (LD) and 26.8% (SD) of pts. Among RBC transfusion–dependent pts, 52.4% (LD) and 37.5% (SD) achieved ≥56-day independence and 47.6% (LD) and 20.8% (SD) achieved ≥112-day independence. Pts received a median of 10 (LD) and 9 (SD) cycles. Delayed cycles occurred in 72.5% (LD) vs 82.9% (SD) of pts; dose reductions occurred in 40.0% (LD) and 46.3% (SD) of pts. Both treatment regimens caused a decrease in blood counts, reaching a nadir before recovering in each cycle. Neutropenia was more pronounced during early cycles and was more severe in the SD arm. Blood counts across all lineages remained stable or improved through ≥12 cycles with the LD arm, suggesting a more favorable safety and tolerability profile. Grade ≥3 adverse events (AEs) occurred in 85.0% and 90.2% of pts in the LD and SD arms, respectively; treatment discontinuation due to AEs occurred in 2.5% and 17.1% of pts, respectively. Most commonly reported treatment-emergent AEs were anemia (42.5% LD, 39.0% SD), fatigue (32.5% LD, 43.9% SD), and thrombocytopenia (37.5% LD, 39.0% SD). Three deaths occurred in the trial: 2 in the LD arm, which were both unrelated to study treatment, and 1 in the SD arm (Pseudomonal bacteremia in Cycle 1), which was treatment related. Total AUC0–24 was 199 ng*h/mL in the LD arm and 465 ng*h/mL in the SD arm; AUC for all cycles of the LD arm was approximately half of the SD arm. Maximal % LINE-1 demethylation rate was lower with LD than SD, but narrowed by Cycle 3. Conclusion: LD oral DEC-C demonstrated comparable clinical benefit to SD oral DEC-C, with improved safety and tolerability, including fewer dose modifications and less severe myelosuppression. These findings support LD DEC-C as a potential optimal regimen for pts with LR-MDS. Clinical trial registration: NCT03502668