Rethinking Immune Therapies for Myelodysplastic Syndromes

​ ‌​ ‌ ⁢ Updated June 13, 2025
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MILAN—The European Hematology Association’s (EHA) Specialized Working Group on MDS convened at⁤ the EHA 2025 Congress to⁣ address the ongoing ‌challenges of immune-based treatments⁤ for myelodysplastic syndromes⁢ (MDS). Experts are ⁢reevaluating core strategies, ⁢including clinical trial endpoints, patient selection,⁢ and the timing of ⁤interventions, suggesting a need for ​a shift in how these therapies are developed and used.

Myelodysplastic syndromes are a diverse group ⁤of ‌disorders affecting myeloid stem and progenitor cells, characterized by ineffective blood cell ‍production, reduced blood cell counts, and a risk of progressing to acute myeloid leukemia. Immune dysregulation is believed to​ play ⁤a meaningful role in MDS ​development, raising hopes that modulating immune responses⁢ in the bone marrow could change the course of the disease. However, immune-based interventions have largely failed to produce significant clinical results.

Currently, only​ a few therapies targeting inflammation and immune activation are approved for MDS, including antithymocyte globulin, with or without cyclosporine A, lenalidomide, and ‌luspatercept. A⁤ growing number of‍ investigational agents are under​ study, including ‌cytokine inhibitors, signaling pathway inhibitors, immune checkpoint inhibitors, bispecific and trispecific antibodies, and CAR-T cell therapies.

Anne Sophie Kubasch, MD, a hematologist at the University Medical Hospital Leipzig, Germany, presented findings from the CANFIRE trial of canakinumab and the LUCAS‍ trial of emavusertib. Neither study met its primary endpoint of hematologic improvement in erythroid cells per International Working Group (IWG) 2018 criteria. However, some patients continued treatment due to perceived clinical benefits, such as reduced fatigue, biomarker changes, or delayed hematologic responses. Kubasch questioned whether hematologic ⁢improvement in erythroid cells is the most appropriate endpoint for immunomodulatory agents.

“We can argue that current⁣ IWG endpoint criteria are‍ too rigid⁤ for ‌immune modulation trials,” Kubasch said. “Late or gradual responses may go undetected.” She​ suggested future trials incorporate patient-reported outcomes and quality-of-life metrics as co-primary endpoints.

Kubasch⁤ also questioned ⁤whether⁤ the right patients are ⁤being selected for immunotherapy. She ‌cited a recent transcriptomic analysis⁢ that identified two immune subtypes based on the expression‌ of six genes: hyperactive (HIC) and moderate (MIC)⁢ immune clusters. The HIC group had greater activation of immune-related pathways. Kubasch hypothesized that only MIC patients were being enrolled in trials, contributing to negative results.She ‍proposed a stepwise stratification approach including baseline assessment,genetic⁢ stratification,and immune transcriptomic profiling.

Valeria Santini,⁤ MD, of the University of Florence Medical‍ School, Italy, focused⁤ on immunosuppressive therapy,​ emphasizing that ‍immune dysfunction in MDS ⁤is dynamic and changes during the disease course. She said precise immune profiling is needed at both the ​subtype and patient level. Santini noted that optimization of immunosuppressive therapy is hampered⁣ by the lack⁢ of prospective ⁤randomized ‍trials and heterogeneity in study populations.

Lionel⁣ Adès, MD, PhD, of Saint-Louis ⁣Hospital, Paris, commented that while the rationale ⁣for immune modulation is strong, clinical evidence remains weak. “Maybe we don’t ⁣have the right drugs or combinations. Maybe we’re using them too late in the ‍disease course,” Adès said.He noted that immune therapies frequently enough require extended ​treatment periods before activity can be detected, while traditional MDS trial endpoints‍ focus on earlier timepoints.

Adès pointed to ‌the ‌EHA-sponsored i4MDS Consortium and data from the STIMULUS MDS ‌2 study, which evaluated sabatolimab plus azacitidine as a first-line therapy in MDS. Although the trial failed to show ⁢a survival advantage subgroup analysis revealed a benefit among female patients.⁣ “This is something ​very ‌interesting,” Adès said, suggesting this finding could be valuable for stratifying future trials by sex.

Kubasch reported relationships with ‍BMS,Curis,Jazz,Johnson & Johnson,and Novartis. Santini reported serving on advisory boards for ⁣AbbVie, Ascentage, BMS, ‍Geron, GSK, Keros, Novartis, Servier, and Takeda. Adès disclosed research⁤ support from BMS/celgene and AbbVie, and advisory roles with AbbVie, Amgen, BMS, ‌Jazz, Novartis, Roche, and Takeda.

What’s next

The i4MDS Consortium aims ⁤to deepen the understanding of MDS immunobiology, ⁢perhaps leading to more effective immune-based therapies and ⁢improved patient outcomes. Future⁣ research will likely ‍focus on identifying the right‌ drugs,combinations,and timing of interventions,as well as stratifying patients based on immune profiles and other factors.