COMMANDing Anemia in Lower-risk Myelodysplastic Syndromes: Luspatercept Versus Erythropoiesis-stimulating Agents

Erythropoiesis-stimulating agents (ESAs) have been the mainstay of treatment for anemia in patients with lower-risk myelodysplastic syndromes (MDS) who have an endogenous serum erythropoietin level less than 500 U/L in the absence of a chromosome 5q deletion.¹  Based on the results of the phase III MEDALIST trial, luspatercept-aamt was approved by the U.S. Food and Drug Administration (FDA) in 2020 for the treatment of anemia in patients with lower-risk, transfusion-dependent MDS exhibiting ring sideroblasts (RS) and those with MDS/myeloproliferative neoplasms exhibiting ring sideroblasts (RS) and thrombocytosis after failure of an ESA.²  Luspatercept is a recombinant fusion protein that binds transforming growth factor beta (TGF-β) superfamily ligands, thereby decreasing SMAD2 and SMAD3 signaling and promoting erythropoiesis.³  The MEDALIST trial focused specifically on lower-risk MDS with RS (MDS-RS) based on prior data showing particular efficacy in this population, but patients with lower-risk MDS without RS may also respond to this agent.^2,4  Whether luspatercept should be considered an alternative to ESAs in patients with previously untreated transfusion-dependent MDS, regardless of RS status, has remained unknown.

Uwe Platzbecker, MD, and co-investigators recently published the interim results of the phase III COMMANDS study (NCT03682536). This international, open-label trial included adult patients (≥18 years old) with transfusion-dependent MDS classified as very low, low, or intermediate risk based on the Revised International Prognostic Scoring System (IPSS).⁵  Eligibility criteria included a requirement of two to six units of packed red blood cells (PRBCs) over the eight weeks preceding enrollment and an endogenous serum erythropoietin level under 500 U/L. Patients who had received prior treatment with ESAs, luspatercept, or hypomethylating agents were excluded. Patients were randomized to receive either luspatercept every three weeks at a starting dose of 1.0 mg/kg or epoetin alfa every week at a starting dose of 450 IU/kg. Both agents were delivered subcutaneously, and doses of both were increased if necessary. The primary endpoint was PRBC transfusion independence for at least 12 weeks, accompanied by a mean hemoglobin increase of at least 1.5 g/dL. Secondary endpoints included PRBC transfusion independence for at least 12 weeks and at least 24 weeks, hematologic improvement with erythroid response (HI-E) per International Working Group criteria, PRBC transfusion burden, time to response, and duration of response.

A total of 356 patients were randomized to treatment with luspatercept or epoetin alfa. The median age was 74 years, and a notable majority of patients in the study (73%) had RS. Significantly more patients in the luspatercept group (59%) than in the epoetin alfa group (31%) met the primary endpoint (common risk difference in response rate: 26.6, 95% CI 15.8-37.4, p<0.0001). A subgroup analysis of RS-positive patients revealed that 65% of patients in the luspatercept group and 26% of those in the epoetin alfa group met the primary endpoint. When the same analysis was conducted for RS-negative patients, 41% of patients in the luspatercept group and 46% in the epoetin alfa group met the primary endpoint. Among patients who had achieved PRBC transfusion independence for at least 12 weeks, the median duration of transfusion independence was 127 weeks in the luspatercept group versus 77 weeks in the epoetin alfa group (nominal p=0.005). In the luspatercept group, the most common adverse events (AEs) of any grade included fatigue (15%), diarrhea (15%), hypertension (13%), peripheral edema (13%), and nausea (12%). The most common grade 3/4 AE was hypertension (8%). There was no difference in the rate of progression to acute myeloid leukemia between the two groups.