The MEDALIST Trial: Are We on the Podium for Lower-Risk MDS?

The myelodysplastic syndromes (MDS) are a diverse group of malignant hematopoetic stem cell disorders characterized by ineffective hematopoiesis, blood cytopenias, and an increased risk of transformation into acute myeloid leukemia (AML).¹  The revised International Prognostic Scoring System (IPSS-R) is a commonly used clinical prognostic tool that utilizes variables from the blood and marrow to place patients into one of five risk groups, based on risk of mortality and transformation to AML.²  For patients with “lower-risk” MDS, which comprises the IPSS-R very-low, low, and intermediate-risk groups, the disease is characterized by a low risk of transformation into AML, a relatively prolonged survival, but a high prevalence of anemia.³  Over time, approximately 40 percent of patients will need frequent red blood cell (RBC) transfusions.

The first-line treatment for transfusion-dependent patients with lower-risk MDS (those without the chromosome abnormality of deletion 5q) are the erythropoiesis-stimulating agents (ESAs).⁴  For such patients who do not respond to or are ineligible to receive ESAs, there are few treatment options for chronic anemia.⁵  Accordingly, the identification and translation of novel therapies capable of improving the marrow function in patients with MDS has the potential to significantly improve quality of life and overall outcomes for patients with MDS.

Luspatercept is a novel recombinant fusion protein that consists of a modified extracellular domain of the human activin receptor type IIB (ActRIIB) linked to the human immunoglobulin G1 Fc domain.⁶  It binds to select transforming growth factor-β superfamily ligands and neutralizes them, and consequentially inhibits erythropoiesis in the marrow and modulates late-stage erythroid differentiation.⁷  Importantly, the mechanism of action seems to be independent of erythropoietin regulation. In November 2019, the U.S. Food and Drug Administration (FDA) approved luspatercept for the treatment of anemia in adult patients with β-thalessemia who require regular RBC transfusions, and luspatercept is being studied for treatment of MDS-associated anemia.⁸  The safety and efficacy of luspatercept was tested in a single-arm phase II study of 58 patients with lower-risk MDS with anemia.⁹  Sixty-three percent of patients demonstrated an erythroid response, and 38 percent were transfusion independent for 8 weeks or longer. Patients with the ring sideroblast phenotype had the optimal responses, however, with 69 percent achieving an erythroid response and 42 percent becoming transfusion independent for 8 weeks or longer. Based on these promising phase II results, a randomized phase III trial (NCT02631070) was initiated to test luspatercept for the treatment of anemia in patients with lower-risk MDS with ringed sideroblasts who were transfusion dependent.

In the current article, Dr. Pierre Fenaux and colleagues report on the prospective, international, multicenter, double-blind, placebo controlled, phase III MEDALIST trial. The trial enrolled 229 patients in 65 trial sites in 11 countries. Eligible patients had lower-risk MDS and were RBC transfusion dependent, defined as receiving at least two or more red cell units per eight weeks. Additionally, each patient’s anemia had to be classified as refractory to or unresponsive to ESAs, or they had to have discontinued ESAs due to a prior adverse effect. Patients were randomly assigned in a 2:1 ratio to receive luspatercept or placebo, at a dose of 1 mg/kg administered subcutaneously every three weeks for 24 weeks. The dose of luspatercept could be escalated during the treatment to 1.75 mg/kg. The MDS disease assessment was performed at 24 weeks after the start of study treatment and then every 6 months thereafter. The primary endpoint was transfusion independence for 8 weeks or longer during weeks 1 through 24. Important secondary endpoints were transfusion independence greater than 12 weeks during the first 24 weeks and also within the first 48 weeks. Patients were observed for three years following the last dose of study treatment for AML progression and overall survival.

Thirty-eight percent of patients in the luspatercept group achieved the study’s primary endpoint of at least eight weeks without the need for transfusion compared to 13.2 percent in the placebo group (p<0.001). The median duration of transfusion independence was 30.6 weeks in the luspatercept group and 13.6 weeks in the placebo group. For the key secondary endpoint, 28 percent of patients in the luspatercept group achieved red cell transfusion independence for 12 weeks or longer compared to 8 percent in the placebo group. Also, during weeks 1 through 24, an erythroid response was observed in 53 percent of patients in the luspatercept group compared to 12 percent in the placebo group. The adverse events most frequently reported in the luspatercept treatment group were fatigue, diarrhea, asthenia, nausea, dizziness, and back pain. The risk of progression to higher risk MDS was low (1 patient in each treatment group), as was the development of AML (2 percent in the luspatercept group and 1 percent in the placebo group) in the three-year study period. Long-term follow-up of the patient cohorts is ongoing, however.