Clinical benefit of luspatercept in ESA-naive patients with very low-, low-, or intermediate-risk MDS: post-hoc data from COMMANDS

At ASH 2025, Prof Valeria Santini, hematologist at the hematology department of the University of Florence, presented the results of an ad hoc analysis of the COMMANDS trial focusing on clinically meaningful predictors of response to first-line therapy in transfusion-dependent patients with lower-risk myelodysplastic syndromes (MDS). The analysis compared luspatercept with erythropoiesis-stimulating agents (ESAs/EPO), the historical standard of care, and explored outcomes according to baseline characteristics reflecting earlier versus more advanced disease stages, namely hemoglobin level, serum erythropoietin (sEPO) concentration, and transfusion burden.

The COMMANDS trial was designed to evaluate achievement of red blood cell transfusion independence (TI) lasting at least 12 weeks. Across all predefined subgroups, luspatercept demonstrated consistently higher response rates and longer duration of benefit compared with EPO. Among patients with baseline hemoglobin ≥8 g/dL, transfusion independence was achieved in 86% of luspatercept-treated patients vs. 74% of those receiving EPO. In patients with hemoglobin <8 g/dL, representing more advanced disease, response rates remained higher with luspatercept (69%) compared with EPO (43%). Importantly, the median duration of transfusion independence was substantially longer with luspatercept, reaching 150 weeks versus 75 weeks with EPO in patients with higher baseline hemoglobin.

Serum EPO level, a known predictor of ESA response, showed a similar pattern. In patients with EPO ≤100 U/L, transfusion independence rates were 87% with luspatercept vs. 71% with EPO, with a longer median response duration for luspatercept (143 vs. 95 weeks). In patients with EPO >200 U/L, a subgroup of patients who are known to respond poorly to ESAs, luspatercept still induced TI in 54% of patients compared with only 19% in the EPO arm.

Finally, analyses by transfusion burden confirmed superior outcomes with luspatercept both in patients with lower transfusion requirements (2 units/8 weeks) and in those with higher burden, again with a longer durability of response among patients treated with luspatercept.

Overall, these findings suggest that earlier intervention, particularly with luspatercept, yields higher and more durable responses in transfusion-dependent lower-risk MDS, supporting timely treatment selection rather than delaying therapy until disease progression.