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Luspatercept reduces the need for blood transfusions in anemic patients with myelodysplastic syndromes who require regular red blood cell transfusions

The phase III MEDALIST trial evaluated the potential of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts who require red blood cell (RBC) transfusions. The results of this trial were presented during the Presidential symposium of the 2018 annual meeting of the American Society of Hematology (ASH) and indicate that luspatercept was associated with a significantly reduced need for frequent blood transfusions. With luspatercept, 37.9% of patients were able to avoid RBC transfusions for at least eight weeks as compared to 13.2% of patients in the placebo arm. In addition, patients in the luspatercept arm achieved higher rates of erythroid response (HI-E) compared with the placebo arm. As such, luspatercept is a potential new therapy in the treatment armamentarium for patients with IPSS-R-defined very low-, low-, or intermediate-risk MDS associated anemia requiring frequent RBC transfusions.

MDS is associated with an erythroid maturation defect, characterized by ineffective erythropoiesis leading to anemia and RBC transfusion dependence. Currently, erythropoiesis-stimulating agents (ESAs) are the standard first-line treatment for anemia associated with lower-risk non-del(5q) MDS, however few treatment options exist for patients who are refractory/unresponsive to, or ineligible for ESAs. As such, there is an unmet clinical need for safe and effective treatment options to reduce RBC transfusion burden in patients with lower-risk non-del(5q) MDS. RBC transfusions increase hemoglobin only temporarily, and frequent transfusions are costly and time-consuming. In addition, RBCs can lead to iron overload, especially in the heart and liver. Luspatercept is a first-in-class erythroid maturation agent that binds to specific ligands of the TGFβ superfamily to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis.

The MEDALIST trial enrolled 229 adult patients with IPSS-R defined low-, very low-, or intermediate-risk MDS with ring sideroblasts. All patients had either failed to respond to ESAs or were ineligible for treatment with such drugs, and required RBCs at least every one to two months. Patients were randomized (2:1) to receive either luspatercept (starting dose 1.0 mg/kg with titration up to 1.75 mg/kg, if needed), or placebo, subcutaneously every 3 weeks for at least 24 weeks. The primary endpoint of the trial was RBC transfusion independence (RBC-TI) for ≥8 weeks between week 1 and week 24. In addition, the study assessed the rate of RBC-TI for ≥12 weeks between week 1 and 24 and evaluated the percentage of patients with a modified hematologic improvement-erythroid (mHI-E) response for any 56-day consecutive period (IWG 2006 criteria).

A significantly greater proportion of patients treated with luspatercept achieved the primary endpoint compared with placebo: 37.9% vs. 13.2% (p<0.0001). Also with respect to the secondary endpoints, luspatercept proved to be superior to placebo. The percentage of patients with RBC-TI ≥12 weeks was 28.1% in the experimental arm as compared to 7.9% with placebo (p=0.0002). With luspatercept, 52.9% of patients achieved a mHI-E response as compared to 11.8% in the placebo arm (p<0.0001). In other words, 52.9% of patients experienced either a significant reduction in the number of transfusions required or an increase in hemoglobin levels even without transfusions, compared with 11.8% of patients receiving placebo.

The most frequently reported adverse effects with luspatercept included fatigue and muscle pain, though it is difficult to determine whether these effects were related to the patients’ anemia or to the drug itself. Overall, the safety profile of luspatercept was consistent with what was reported in the phase 2 PACE-MDS study.

In summary, treatment with luspatercept resulted in a significantly greater proportion of patients who achieved RBC-TI compared with placebo, with an acceptable safety profile. These data support luspatercept is a potential new therapy for patients with IPSS-R-defined very low-, low-, or intermediate-risk MDS associated anemia who require RBC transfusions. For the moment it is unclear whether the drug would offer benefits for patients with higher-risk MDS or for lower-risk MDS patients without ring sideroblasts.

Reference

Fenaux P, Platzbecker U, Mufti GJ, et al. The MEDALIST trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusions. Presented at ASH 2018; Abstract 1.

Speaker Pierre Fenaux

fenaux

Pierre Fenaux, MD, PhD, Service d’Hématologie Séniors, Hôpital Saint-Louis, Université Paris 7, Paris, France

 

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