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Findings presented at the 2026 European Hematology Association (EHA) Congress highlighted the continued progress across the spectrum of myelodysplastic syndromes (MDS), from improving anemia management in lower-risk disease, to refining transplant strategies and investigating novel therapies for higher-risk disease. During the VJHemOnc Post-EHA MDS Highlights webinar, leading MDS experts discussed abstracts selected by the webinar chair Amer Zeidan, MBBS, MHS, Yale School of Medicine, New Haven, CT. Below, we have highlighted five studies we believe will be the most clinically impactful.
MAXILUS: Maximum-dose luspatercept achieves durable transfusion independence in lower-risk MDS/SLL
Anemia and red blood cell (RBC) transfusion dependence remain major causes of morbidity in patients with lower-risk MDS (LR-MDS). Luspatercept has become an established treatment option for transfusion-dependent LR-MDS,1 but whether initiating treatment at the maximum approved dose can improve treatment outcomes has remained an important question.2
During EHA 2026 and the Post-EHA MDS Highlights webinar, Matteo Della Porta, MD, IRCCS Humanitas Research Hospital, Milan, Italy, presented the primary analysis of the Phase IIIb MAXILUS study (NCT06045689) evaluating luspatercept initiated at 1.75 mg/kg in patients with non-del(5q) LR-MDS requiring RBC transfusions.2
The global, multicenter study enrolled 106 patients who were erythropoiesis-stimulating agent (ESA)-naïve (n=53) or ESA relapsed/refractory or intolerant (R/R/I; n=53). All patients received luspatercept at the maximum approved starting dose every three weeks. The primary endpoint was RBC transfusion independence for ≥8 weeks and a concurrent mean hemoglobin increase of ≥1 g/dL during the first 24 weeks of treatment.2
Luspatercept demonstrated sustained transfusion independence in both treatment cohorts. Among ESA-naïve patients, the primary endpoint was achieved by 81.1% of patients, while 83.0% achieved RBC transfusion independence lasting ≥8 weeks, and 75.5% maintained transfusion independence for ≥12 weeks. Sustained RBC transfusion independence for ≥12 weeks was also achieved in 72.7% of patients without ring sideroblasts and 85.7% of patients with baseline serum erythropoietin concentrations ≤200 IU/L. Modified erythroid hematologic improvement was achieved in 86.8% of ESA-naïve patients.2
In the ESA-R/R/I cohort, the primary endpoint was achieved by 62.3% of patients. RBC transfusion independence lasting ≥8 and ≥12 weeks was achieved by 67.9% and 50.9%, respectively, while modified erythroid hematologic improvement was achieved in 77.4% of patients. Sustained RBC transfusion independence for ≥12 weeks was also achieved in 40.0% of patients without ring sideroblasts and 58.3% of those with baseline serum erythropoietin concentrations ≤200 IU/l. 2
The safety profile was consistent with previous experience of luspatercept. Grade 3–4 treatment-emergent adverse events (TEAEs) occurred in 66.0% of ESA-naïve patients and 54.7% of ESA-R/R/I patients. Progression to higher-risk MDS (HR-MDS) occurred in 3.8% of patients in each cohort, and no patients progressed to acute myeloid leukemia (AML) during follow-up.2
The combined findings from MAXILUS support initiating luspatercept at the maximum approved starting dose in patients with transfusion-dependent LR-MDS, with durable transfusion independence observed across both ESA-naïve and ESA-treated patients.
EPO-PRETAR: Early ESA initiation improves erythroid responses without delaying transfusion dependence/SLL
The timing of ESA therapy remains an important clinical consideration in LR-MDS. While ESAs are widely used to treat anemia, it remains unclear whether initiating treatment before patients become transfusion dependent improves long-term outcomes.1,3
During EHA 2026 and the Post-EHA MDS Highlights webinar, Sophie Park, MD, PhD, CHU Grenoble Alpes, Grenoble, France, presented final results from the multicenter, open label, randomized, Phase III EPO-PRETAR trial (NCT03223961) comparing early versus delayed initiation of epoetin (EPO) alfa in patients with non-transfusion-dependent LR-MDS. Eighty-four patients were randomized to receive EPO alfa either immediately after study enrollment (Arm A) or only when hemoglobin dropped to the threshold for RBC transfusions (<9 g/dL; Arm B).3
The primary endpoint was time to development of transfusion dependence, and the study did not meet its primary endpoint. Time to transfusion dependence was similar between treatment strategies (HR 0.90; 95% CI: 0.48–1.68, p=0.74), with comparable rates of transfusion dependence observed over 24 and 36 months between Arm A and Arm B (24 months: 26.2% versus 31.7%; 36 months: 43.4% versus 39.2%, respectively.)3
Overall survival (OS) and progression free survival (PFS) rates were similar between treatment arms. OS was 47% in Arm A and 41% in Arm B (HR 0.84; 95% CI: 0.44–1.61; p=0.60). Median PFS was 51.0 versus 38.0 months, respectively (HR 0.91; 95% CI: 0.51–1.63; p=0.75), with comparable 36‑month PFS rates (57.0% versus 58.3%). In addition, AML transformation, and quality-of-life (QoL) outcomes did not significantly differ between the two treatment arms.3
Earlier treatment initiation produced higher early hematologic responses. After 12 weeks of EPO alfa treatment, erythroid hematologic improvement was achieved in 85% of patients receiving early treatment compared with 55% of those receiving delayed treatment (risk ratio 1.57; 95% CI: 1.12–2.20; p=0.003). Median duration of response also numerically favored earlier treatment (32.7 versus 24.9 months), although this difference did not reach statistical significance.3
Treatment was well tolerated with no unexpected safety signals observed. There were also no differences in QoL trajectories between the two treatment strategies.3
These findings suggest that while earlier initiation of ESA therapy increases the likelihood of achieving an early erythroid response, the timing of treatment should be individualized according to patient symptoms, preferences, and treatment goals rather than the expectation of delaying transfusion dependence.3
First-in-class NEK7 inhibition with ofirnoflast demonstrates multilineage hematologic responses in lower-risk MDS
Although therapies such as ESAs and luspatercept have improved anemia management in LR-MDS, many patients continue to experience persistent cytopenias, highlighting the need for treatments that address the underlying disease biology.1 Hyperactivation of the NEK7-dependent NLRP3 inflammasome has emerged as a key driver of ineffective hematopoiesis, providing the rationale for investigating the first-in-class oral NEK7 inhibitor ofirnoflast.4
During EHA 2026 and the Post-EHA MDS Highlights webinar, Varun Bafna, MBBS, Star Superspeciality Clinic and Hospital, Kolhapur, India, presented results from the open-label, single-arm, Phase II trial evaluating ofirnoflast in ESA-refractory, intolerant or ineligible LR-MDS.4
Thirty-seven patients received treatment, of whom 30 were evaluable for efficacy, after seven patients were subsequently found to be ineligible or did not complete the planned treatment period. Patients represented multiple WHO-defined MDS subtypes, including MDS with low blasts, MDS/MPN, del(5q), SF3B1-mutated, and MDS with increased blasts. In addition, 49% of patients had a high transfusion burden at baseline.4
Ofirnoflast demonstrated multilineage clinical activity, as the overall hematologic improvement rate reached 67%, including erythroid responses in 63% of patients, platelet responses in 60%, and neutrophil responses in 50%. Among transfusion-dependent patients, 55% achieved RBC transfusion independence lasting ≥8 weeks, with a median duration of 28.5 weeks. In addition, 75% of non-transfusion-dependent patients achieved erythroid hematologic improvement, and the median maximum hemoglobin increase among responder reached 4.2g/dL. Morphologic responses included complete remission (CR) in 30% of evaluable patients and marrow CR in one additional patient. Responses were observed across all WHO-defined MDS subtypes and mutation profiles.4
Supporting the proposed mechanism of action, pharmacodynamic analyses after 16 weeks of treatment demonstrated reductions in inflammatory markers, including TNF-α and oxidized DNA. In addition, improvements were seen in QoL metrics, with the greatest gains in hematologic improvement responders being in overall QOL-E score, fatigue and social/family well-being domains.4
Treatment-related adverse events (TRAEs) occurred in 27% of patients, with only two Grade ≥3 TRAEs reported (hypertension and leukopenia). No treatment-related serious adverse events occurred, and only one patient discontinued treatment because of a TRAE (leukocytosis).4
Although these findings are from a single-arm Phase II study, they provide early clinical evidence that targeting inflammasome biology via NEK7 inhibition may represent a novel therapeutic strategy for lower-risk MDS, warranting further investigation in larger studies.
Reflecting on the broader implications of these findings, Dr Bafna commented:
“This is the first clinical validation that targeting NEK7 can suppress inflammasome signaling and restore hematopoiesis across multiple cell lineages.”
PALOMA: CPX-351 improves event-free survival as bridging therapy before allogeneic transplantation in higher-risk MDS
Allogeneic stem cell transplantation (alloHCT) remains the only potentially curative treatment for patients with HR-MDS. However, the optimal strategy for bridging patients to transplantation remains uncertain, with both hypomethylating agents and intensive chemotherapy commonly used in clinical practice.5
During the Post-EHA MDS Highlights webinar, Madlen Jentzsch, MD, University of Leipzig Medical Center, Leipzig, Germany, presented results from the Phase II PALOMA study (NCT04061239) comparing CPX-351 with conventional care regimens (CCR) before alloHCT in patients with HR-MDS or oligoblastic AML.5
The multicenter, open-label study randomized 150 patients to receive CPX-351 (n=75) or CCR, consisting of either azacitidine (n=23) or conventional induction chemotherapy (n=52), with the intention of proceeding to alloHCT within six months.5
The primary endpoint of event-free survival (EFS) was met. After a median follow-up of 38 months, median EFS was not reached in the CPX-351 arm, compared with 11.1 months for conventional care (p=0.0263). A pre-planned interim analysis of OS numerically favored CPX-351; median OS was not reached compared with 35.4 months for CCR, although the difference was not statistically significant at the time of analysis.5
Primary refractory disease occurred less frequently in the CPX-351-treated arm than in the CCR arm (8 versus 17 patients), while similar proportions of patients proceeded to alloHCT across both treatment arms (85.1% versus 86.4%, respectively).5
The safety profile was consistent with the expected toxicities associated with intensive therapy. The most common Grade ≥3 adverse events (AEs) in the CPX-351 and CCR arms were thrombocytopenia (65 versus 55 patients), leukopenia (55 patients versus 46 patients), and febrile neutropenia (44 versus 35 patients), with no unexpected safety signals identified.5
The PALOMA study showed that CPX-351 improved EFS as first-line bridging therapy before alloHCT in patients with HR-MDS and oligoblastic AML, supporting further evaluation of this approach in transplant-eligible patients.
Mesutoclax plus azacitidine: Early Phase I data support next-generation BCL-2 inhibition in myeloid malignancies/SLL
Novel BCL-2 inhibitors continue to be explored in myeloid malignancies following the success of venetoclax in AML. However, responses in MDS have been more modest, prompting investigation of next-generation BCL-2 inhibitors with the potential to improve efficacy while maintaining manageable safety.6
Although presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting rather than EHA 2026, emerging data evaluating mesutoclax, a novel, highly selective BCL-2 inhibitor were presented during the Post-EHA MDS Highlights webinar.6
Huafeng Wang, MD, Zhejiang University School of Medicine, Hangzhou, China, presented updated results from the ongoing global, Phase I, ICP-CL-01205 trial (NCT06656494) evaluating mesutoclax (ICP-248) plus azacitidine. The ongoing study enrolled 59 patients with myeloid malignancies, including 12 with newly diagnosed MDS and 39 patients with newly diagnosed AML. The dose-escalation phase established mesutoclax 100 mg and 125 mg as the recommended doses for expansion.6
Among the 10 response-evaluable MDS patients, the overall response rate (ORR) was 100% according to IWG 2006 criteria including CR in 20% of patients and marrow CR in 80%. The composite complete remission (cCR) rate was 70%, including CR in 30% of patients, despite the majority having received only one treatment cycle.6
Among the 35 response-evaluable AML patients, the cCR rate was 85.7%, including a centrally assessed CR rate of 65.7%. Among patients achieving cCR, 86.7% became MRD negative, while the six-month OS rate was 94.1%.6
Treatment was generally well tolerated. Across the pooled MDS and AML population, no dose-limiting toxicities or tumor lysis syndrome were observed. The most common Grade ≥3 TEAEs were decreased neutrophil count (62.7%), decreased platelet count (50.8%), and anemia (33.9%). No TEAEs led to treatment discontinuation.6
Discussing the broader implications of these findings, Dr Wang noted that mesutoclax had been designed to address several limitations associated with existing BCL-2 inhibitors, including prolonged cytopenias and early mortality (discussed during webinar presentation).
The preliminary activity observed in treatment-naïve MDS supports continued evaluation of mesutoclax in combination with azacitidine. Larger studies will be needed to determine whether these initial early responses translate into durable clinical benefit.
Together, the findings from these EHA abstracts reflect the increasingly personalized management of MDS, spanning optimization of established therapies, development of novel biologically targeted approaches, and refinement of transplant strategies. As several of these approaches move into later-phase development, they have the potential to further refine standards of care across the MDS treatment landscape.
References
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Merz AMA, Uwe Platzbecker U. Treatment of lower-risk myelodysplastic syndromes. Haematologica. 2025;110(2):330–338.
- Della Porta M, Díez Campelo M, Santini V, et al. Luspatercept (luspa) initiated at the maximum-approved dose in patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) who require transfusions: Primary analysis from MAXILUS. Abstract S173. Presented at the European Hematology Association (EHA) 2026 Congress; June 11–14 2026; Stockholm, Sweden.
- Park S, Slama B, Moldovan M, et al. Early versus delayed ESA in lower-risk non-transfusion-dependent MDS: Final Phase III EPO-PRETAR results on transfusion dependence and erythroid response. Abstract S17. Presented at the European Hematology Association (EHA) 2026 Congress; June 11–14 2026; Stockholm, Sweden.
- Bafna V, Kumar Nath U, Shah S, et al. Ofirnoflast, a first-in-class NEK7 inhibitor, induces robust transfusion independence and multilineage hematological improvement in lower-risk myelodysplastic syndrome (LR-MDS): Phase 2 results. Abstract S174 Presented at the European Hematology Association (EHA) 2026 Congress; June 11–14 2026; Stockholm, Sweden.
- Platzbecker U, Crysandt M, Kaufmann M, et al. CPX-351 versus standard of care as bridging to allo-HCT in patients with higher-risk myelodysplastic neoplasms or oligoblastic acute myeloid leukemia: Results of the randomized Phase 2 PALOMA study. Abstract S170. Presented at the European Hematology Association (EHA) 2026 Congress; June 11–14 2026; Stockholm, Sweden.
- Wang H, Jiang Q, Zhao X, et al. Safety, tolerability, and efficacy of mesutoclax (ICP-248) in combination with azacitidine in patients with myeloid malignancies. Abstract 6506. Presented at the 2027 American Society of Clinical Oncology (ASCO) Annual Meeting; May 29–June 2 2026; Chicago, IL, USA.
