COMMANDS Trial Shows Improved Transfusion Independence with Luspatercept in LR-MDS

Luspatercept improved the rate of transfusion independence and increased hemoglobin levels compared with epoetin alfa in patients with lower-risk myelodysplastic syndromes (MDS) who had not previously received erythropoiesis-stimulating agents (ESA), according to an interim analysis of the phase III COMMANDS trial.

Uwe Platzbecker, MD, of the University Hospital Leipzig, and colleagues conducted the study and published results from the interim analysis in The Lancet. Researchers also presented results from the study during the 2023 European Hematology Association Congress and the 2023 American Society of Clinical Oncology Annual Meeting.

The COMMANDS trial is an open-label, randomized control trial that is being conducted at 142 sites in 26 counties. It enrolled adults with MDS classified as very low, low, or intermediate risk per the Revised International Prognostic Scoring System. All patients were ESA-naïve and required red blood cell transfusions.

Dr. Platzbecker and colleagues randomly assigned patients 1:1 to receive luspatercept (n=178) or epoetin alfa (n=178). They stratified patients by baseline red blood cell transfusion burden, endogenous serum erythropoietin concentration, and ring sideroblast status. The median patient age was 74 years and most patients (56%) were men.

Patients in the luspatercept arm received the treatment subcutaneously once every three weeks. The starting dose of luspatercept was 1 mg/kg and could be titrated up to 1.75 mg/kg. Patients in the epoetin alfa arm received the treatment subcutaneously once a week. The starting dose of epoetin alfa was 450 IU/kg body weight with possible titration up to 1,050 IU/kg for a maximum permitted total dose of 80,000 IU.

The study’s primary endpoint was red blood cell transfusion independence for at least 12 weeks with a concurrent mean hemoglobin increase of at least 1.5 g/dL during weeks one through 24, assessed in the intention-to-treat population. The study’s investigators assessed safety in patients who received at least one dose of the study treatment.

The interim efficacy analysis included 147 patients who received luspatercept and 154 who received epoetin alfa who completed 24 weeks of treatment or discontinued earlier.

More than half (59%) of patients receiving luspatercept reached the primary endpoint, while 31% of patients receiving epoetin alfa achieved the primary endpoint (common risk difference on response rate 26.6; 95% CI, 15.8-37.4; P<.0001).

The median treatment exposure was 42 weeks in patients receiving luspatercept, while it was 27 weeks in those receiving epoetin alfa.

The most frequently reported grade 3 or 4 treatment-emergent adverse events (AEs) with luspatercept were hypertension, anemia, dyspnea, neutropenia, thrombocytopenia, pneumonia, COVID-19, myelodysplastic syndromes, and syncope. The most frequently reported grade 3 or 4 treatment-emergent AEs with epoetin alfa were anemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia.

The most common suspected treatment-related AEs in the luspatercept group were fatigue, asthenia, nausea, dyspnea, hypertension, and headache. No suspected treatment-related AEs were reported in the epoetin alfa group. One patient death, which occurred after a diagnosis of acute myeloid leukemia was “considered to be related to luspatercept treatment,” which the patient received for 44 days, according to the study’s authors.

“In this interim analysis, luspatercept improved the rate at which red blood cell transfusion independence and increased hemoglobin were achieved compared with epoetin alfa in ESA-naive patients with lower-risk myelodysplastic syndromes,” Dr. Platzbecker and colleagues concluded. “Long-term follow-up and additional data will be needed to confirm these results and further refine findings in other subgroups of patients with lower-risk [MDS], including nonmutated SF3B1 or ring sideroblast-negative subgroups.”

Reference

Platzbecker U, Della Porta MG, Santini V, et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Lancet. 2023. doi:10.1016/S0140-6736(23)00874-7