Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes

N Engl J Med. 2020 Jan 9;382(2):140-151. doi: 10.1056/NEJMoa1908892.


Background: Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor β superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study.

Methods: In a double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48.

Results: Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group (P<0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28% vs. 8% for weeks 1 through 24, and 33% vs. 12% for weeks 1 through 48; P<0.001 for both comparisons). The most common luspatercept-associated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time.

Conclusions: Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event. (Funded by Celgene and Acceleron Pharma; MEDALIST number, NCT02631070; EudraCT number, 2015-003454-41.).

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / adverse effects
  • Activin Receptors, Type II / therapeutic use*
  • Adult
  • Aged
  • Aged, 80 and over
  • Anemia, Sideroblastic / drug therapy*
  • Anemia, Sideroblastic / therapy
  • Double-Blind Method
  • Erythrocyte Transfusion*
  • Female
  • Hematinics / adverse effects
  • Hematinics / therapeutic use*
  • Hemoglobins / analysis
  • Humans
  • Immunoglobulin Fc Fragments / adverse effects
  • Immunoglobulin Fc Fragments / therapeutic use*
  • Infusions, Subcutaneous
  • Male
  • Middle Aged
  • Myelodysplastic Syndromes / drug therapy*
  • Myelodysplastic Syndromes / therapy
  • Recombinant Fusion Proteins / adverse effects
  • Recombinant Fusion Proteins / therapeutic use*


  • Hematinics
  • Hemoglobins
  • Immunoglobulin Fc Fragments
  • Recombinant Fusion Proteins
  • luspatercept
  • Activin Receptors, Type II

Associated data

  • EudraCT/2015-003454-41