Clinical Summary:

• Design/Population: The phase 3 COMMANDS trial compared first-line luspatercept with epoetin alfa in erythropoiesis-stimulating agent-naïve patients with transfusion-dependent lower-risk myelodysplastic syndromes, with updated follow-up extending beyond 3 years. 
• Key Outcomes: Luspatercept produced higher rates and longer duration of red blood cell transfusion independence and hemoglobin response than epoetin alfa. Overall survival continued to trend in favor of luspatercept, and fewer patients progressed to higher-risk myelodysplastic syndromes. 
• Clinical Relevance: The sustained erythroid responses and favorable long-term survival trend strengthen the evidence supporting luspatercept over epoetin alfa as first-line treatment for erythropoiesis-stimulating agent-naïve patients with transfusion-dependent lower-risk myelodysplastic syndromes.

Updated results from the phase 3 COMMANDS trial demonstrated sustained red blood cell transfusion independence and hemoglobin improvement with luspatercept in erythropoiesis-stimulating agent-naïve patients with transfusion-dependent lower-risk myelodysplastic syndromes, with an overall survival (OS) trend continuing to favor luspatercept after more than 3 years of follow up. 

These results were presented by Guillermo Garcia-Manero, MD, MD Anderson Cancer Center, Houston, Texas, at the Society of Hematologic Oncology (SOHO) Annual Meeting in Houston, Texas.

In this trial, 363 adult patients were randomized 1:1 to receive either 1.0 to 1.75 mg/kg of luspatercept once every 3 weeks (n = 182) or 450 to 1050 IU/kg of epoetin alfa once weekly for at least 24 weeks (n = 181). Randomization was stratified by baseline transfusion burden, ring sideroblast status, and serum erythropoietin level.

At analysis, median OS was not reached with luspatercept and 46 months with epoetin alfa, corresponding to a numerical reduction in the risk of death with luspatercept (hazard ratio [HR], 0.78).  Similar OS trends were observed across patient subgroups.

Red blood cell transfusion independence lasting at least 12 weeks was achieved by 76.4% of patients receiving luspatercept and 55.8% of patients receiving epoetin alfa. When accompanied by a mean hemoglobin level of at least 10 g/dL, corresponding rates were 60.4% and 39.2%, respectively. 

Responses were also substantially more durable with luspatercept. Median cumulative duration of red blood cell transfusion independence lasting at least 12 weeks was 184.4 weeks with luspatercept and 95.1 weeks with epoetin alfa (HR, 0.54). Transfusion independence lasting at least 2.5 years was achieved by 25.3% of patients and 10.5% of patients, respectively. 

A mean hemoglobin increase of at least 1.5 g/dL was achieved by 80.2% of patients receiving luspatercept and 58.6% receiving epoetin alfa. Median duration of hemoglobin response was 72.9 weeks and 47.9 weeks, respectively (HR, 0.61). 

Exploratory biomarker analyses identified associations between improved OS and baseline markers of favorable immune function among patients receiving luspatercept. Markers of cardiovascular function were associated with improved OS in both treatment arms, while less aggressive disease and preserved megakaryopoiesis were associated with improved OS among patients receiving epoetin alfa. 

At data cutoff, 17.6% of patients receiving luspatercept and 7.8% receiving epoetin alfa remained on treatment. Dose escalation occurred in 84.6% and 83.2% of patients, respectively. 

No new safety concerns emerged with longer follow-up. Deaths from any cause occurred in 36.3% of patients receiving luspatercept and 43% receiving epoetin alfa. Progression to higher-risk myelodysplastic syndromes was less frequent with luspatercept (3.3% vs 7.3%), while progression to acute myeloid leukemia was comparable between groups (4.9% vs 5.5%).

As Dr Garcia-Manero concluded, “long-term follow-up demonstrated improved OS trends and sustained responses with luspatercept vs [epoetin alfa], overall and in subgroups… reinforcing superior clinical benefit as first-line treatment.” 

Source:

Garcia-Manero G, Porta MG Della, Zeidan AM, et al. Updated overall survival and long-term transfusion independence from the phase 3 COMMANDS trial in erythropoiesis-stimulating agent-naïve patients with lower-risk myelodysplastic syndromes. Presented at the 2026 SOHO Annual Meeting; September 9-12, 2026; Houston, Texas. Abstract MDS-113.