ELEMENT-MDS Trial: How Well Does Luspatercept Prevent or Delay RBC Transfusion Dependency Onset?

In the wake of the COMMANDS study findings, clinical trials to evaluate luspatercept as treatment for anemia in patients with lower-risk myelodysplastic syndromes (MDS) continue. Among these is the actively enrolling ELEMENT-MDS trial, described in Blood.

Currently, efficacy and safety data for luspatercept in the management of anemia for patients who have erythropoiesis-stimulating agent (ESA)–naive lower-risk MDS but are not dependent on red blood cell (RBC) transfusions are lacking. The phase 3 randomized multicenter study addresses this lack by comparing luspatercept with epoetin alfa as treatment for MDS-associated anemia in this patient population. Key for the investigators conducting the study will be the degree to which luspatercept decreases progression to RBC transfusion dependency among these patients.

The investigators are seeking to enroll 360 adults with very low– to intermediate-risk MDS per the revised International Prognostic Scoring System (IPSS-R) who are experiencing MDS-associated anemia of moderate or worse severity. Participants in the study are to have baseline serum erythropoietin (sEPO) levels of no higher than 500 U/L, baseline hemoglobin no higher than 9.5 g/dL, and no RBC transfusions within 16 weeks of trial randomization.

The study period involves 5 weeks of screening and 96 weeks of treatment followed by an extension phase and a post-treatment follow-up period. Study participants will be randomized 1:1 to receive either luspatercept or epoetin alfa and will be stratified according to baseline sEPO level, ring sideroblast status, and IPSS-R risk category. Patients in the luspatercept arm will be administered the agent once every 3 weeks at a starting dose of 1.0 mg/kg, with escalation of up to 1.75 mg/kg permitted. Patients in the epoetin alfa arm will be administered the agent  once a week at a starting dose of 450 IU/kg, with escalation of up to 1,050 IU/kg permitted.

To evaluate luspatercept’s efficacy, the luspatercept and epoetin alfa arms will be compared in terms of proportions of patients who progress to transfusion dependency for 16 continuous weeks during weeks 1 through 96 of the study. The two arms will also be compared in terms of relative proportions of patients who have a hemoglobin increase of 1.5 g/dL or greater persisting for at least 16 weeks during weeks 1 through 48 of the study.

The luspatercept and epoetin alfa arms will also be compared in terms of respective proportions of patients who achieve transfusion independence lasting at least 24 weeks, as well as in rates of overall survival, transfusion-free survival, and progression to high-risk MDS or acute myeloid leukemia; time to progression to RBC transfusion dependence; and time to achievement of modified hematologic improvement-erythroid response. Quality of life measures will be included in the outcomes assessment, and adverse events will be logged and evaluated for any connections to the study agent.