Luspatercept Effective in Patients with Lower-Risk Myelodysplastic Syndromes

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Patients with anemia and lower-risk myelodysplastic syndromes (MDS) in whom first-line erythropoiesis-stimulating agents (ESAs) are not effective generally become transfusion dependent. Luspatercept-aamt (Reblozyl), a recombinant fusion protein that binds transforming growth factor beta superfamily ligands to reduce SMAD2 and SMAD3 signaling, was approved by the FDA in November 2019 and has been studied in this patient population with promising results.

In a new study, researchers evaluated the safety and efficacy of luspatercept in patients with lower-risk MDS with ring sideroblasts who had been receiving regular red blood cell (RBC) transfusions and whose disease was refractory to or was unlikely to respond to ESAs or who had discontinued therapy because of an adverse event (Fenaux P, et al. N Engl J Med. 2020;-382:140-151).

The randomized, double-blind, placebo-controlled, phase 3 clinical trial MEDALIST included 229 patients with very low-risk, low-risk, or intermediate-risk MDS with ring sideroblasts who had been receiving regular RBC transfusions. Patients were randomized to luspatercept (N = 153), dosed at 1 mg/kg to 1.75 mg/kg, or to placebo (N = 76), administered subcutaneously every 3 weeks. The primary end point was transfusion independence for ≥8 weeks during weeks 1 through 24. The key secondary end point was transfusion independence for 12 weeks or longer, which was assessed during weeks 1 through 48 and weeks 1 through 24.

Transfusion independence for ≥8 weeks was achieved in 38% of patients in the luspatercept arm versus 13% in the placebo arm. In addition, 28% of patients in the luspatercept group achieved transfusion independence for ≥12 weeks versus 8% in the placebo group (during weeks 1-24, and 33% vs 12%, respectively, during weeks 1-48). By data cutoff, the median duration of the longest continuous response was 30.6 weeks with luspatercept versus 13.6 weeks with placebo.

The most common adverse events with luspatercept versus placebo were fatigue (27% vs 13%, respectively), diarrhea (22% vs 9%), asthenia (20% vs 12%), nausea (20% vs 8%), and dizziness (20% vs 5%). Overall, 65 patients who received luspatercept and 34 patients who received placebo had grade 3 or 4 adverse events.

“Patients with lower-risk myelodysplastic syndromes with ring sideroblasts for whom erythropoiesis-stimulating agents are not effective or are not an option have limited treatment options available beyond continued transfusions. Luspatercept significantly reduced the transfusion burden in a substantial proportion of these patients and was associated with mainly low-grade toxic effects,” concluded the researchers.

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