COMMANDS Trial: Luspatercept Efficacy and Long-Term Outcomes in ESA-Naive Lower-Risk MDS

The COMMANDS trial continues to provide compelling evidence supporting the use of luspatercept in erythropoiesis-stimulating agent–naive patients with low-risk myelodysplastic syndromes (MDS). The study's primary end point—a composite of achieving a hemoglobin increase of at least 1.5 g/dL and transfusion independence for 12 weeks or more—was met by 60% of patients in the luspatercept arm, with updated data later showing an even higher response rate of 76.4%. Notably, transfusion independence in some patients exceeded 130 weeks, and longer-term follow-up revealed over 30% of patients maintained this independence for more than 1.5 years.

Subgroup analyses, though not powered for statistical significance, showed a consistent benefit of luspatercept across patients regardless of erythropoietin levels, transfusion burden, SF3B1 mutation status, or ring sideroblast presence. Additional data highlighted that 77% of patients achieved both a hemoglobin ≥10 g/dL and transfusion independence, and 80% of these responders required dose escalation. Importantly, increasing the dose did not lead to higher rates of adverse events, even among patients who began treatment with hemoglobin <8 g/dL.

Perhaps the most intriguing update came from recent overall survival (OS) data. While the OS difference between treatment arms has not yet reached statistical significance, the 5-year OS rate was higher for luspatercept (54%) compared to ESA (41.8%), suggesting a potential long-term survival benefit. Furthermore, the duration of transfusion independence with luspatercept has now extended to 187 weeks, with no new safety concerns. There was also a slight trend toward lower progression to high-risk MDS, while acute myeloid leukemia rates remained similar between groups. These findings position luspatercept as a potentially transformative option in the frontline setting for low-risk MDS.