FDA Approves Luspatercept for Myelodysplastic Syndrome-Associated Anemia

April 3, 2020

Article

The FDA granted approval to luspatercept-aamt as treatment of adult patients with anemia failing an erythropoiesis stimulating agent that requires 2 or more red blood cell units over 8 weeks, that is associated with very low- to intermediate-risk myelodysplastic syndromes, intermediate-risk myelodysplastic syndromes with ring sideroblasts or myelodysplastic/myeloproliferative neoplasm.

The FDA granted approval to luspatercept-aamt (Reblozyl) as treatment of adult patients with anemia failing an erythropoiesis stimulating agent (ESA) that requires 2 or more red blood cell (RBC) units over 8 weeks, that is associated with very low- to intermediate-risk myelodysplastic syndromes (MDS), intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or myelodysplastic/myeloproliferative neoplasm (MPNs).

The approval was based results from thephase III MEDALIST study of luspatercept in patients with lower-risk myelodysplastic syndromes. Results published in theNew England Journal of Medicineshowed that luspatercept reduced the severity of anemia in these patient populations, including patients refractory disease, those unlikely to respond, and/or those who were unable to tolerate ESA treatment.

Treatment with luspatercept led to RBC-transfusion independence (RBC-TI) for ≥8 weeks in 38% of patients compared with 13% of patients who received placeboP<.001), meeting the primary endpoint of the study.

The key secondary endpoint of RBC-TI for ≥12 weeks was met by a higher percentage of patients in the luspatercept group than in the placebo group at 28% versus 8% for weeks 1 through 24, and 33% versus 12% for weeks 1 through 48 (P<.001 for both). In an analysis that applied the International Working Group (IWG) 2018 criteria, 19% of luspatercept-treated patients compared with 4% of patients on placebo had RBC-TI for ≥16 weeks during weeks 1 through 24; these rates were 28% and 7%, respectively, during weeks 1 through 48.

The study met an additional secondary endpoint, which was hematologic improvement-erythroid (HI-E) for ≥8 weeks, as assessed by IWG 2006 criteria. In weeks 1 through 24, HI-E responses occurred in 53% of patients on luspatercept compared with 12% of those in the placebo group. Fifty-nine percent of patients treated with luspatercept had an HI-E response in weeks 1 through 48 versus 17% of patients on placebo. During the double-blind period, no significant changes in neutrophil or platelet counts were observed.

“In clinical trials, Reblozyl has shown to have significant benefit for the treatment of anemia in patients with myelodysplastic syndromes who have ring sideroblasts,” Guillermo Garcia-Manero, MD, professor and chief of Section of Myelodysplastic Syndromes, Department of Leukemia, University of Texas MD Anderson Cancer Center, said in a press release. “Anemia is a serious consequence of MDS, requiring the majority of these patients to receive regular red blood cell transfusions, which can lead to additional complications, such as iron overload, transfusion site reactions and infections. In our current environment, we are reminded of the significant burden frequent blood transfusions can have on individuals and the healthcare system.”

The double-blind, placebo-controlled, phase III MEDALIST trial included 229 patients who were categorized with International Prognostic Scoring System (IPSS)-Revised very low-, or intermediate-risk MDS with ring sideroblasts and required RBC transfusions. Patients were randomized to receive luspatercept at a dose of 1.0 to 1.75 mg/kg (n = 153) or placebo (76) subcutaneously every 3 weeks.

The median age was 71 years (range, 26-95) and 63% of patients were male. SF3B1 mutations were identified in 93% of patients in the luspatercept group and 86% of those on the placebo arm. Ninety-five percent of patients previously received ESAs and 48% had received prior iron chelation treatment. The data cutoff date was May 8, 2018.

Ninety percent (n = 52) of patients in the luspatercept group who had a response had their first response at the starting dose of 1.00 mg/kg, and 7% of patients responded after dose increases at 1.33 mg/kg (n = 2) and 1.75 mg/kg (n = 2).

RBC-TI for ≥8 weeks occurred in 80% of patients on luspatercept who received <4 units per 8 weeks, in 37% of those who received 4 to 6 units per 8 weeks, and in 9% of patients who received ≥6 units per 8 weeks. In the placebo group, these RBC-TI rates were 40%, 4%, and 3%, respectively.

Additionally, the authors noted that the RBC-TI rates with luspatercept at ≥8 weeks during weeks 1 to 24 were similar regardless of number of baseline mutations: 1 (36.4%), 2 (34.9%), 3 (42.4%), and 4 or 5 (33.3%).³

Regarding safety, the most common adverse events (AEs) found in ≥10% of the luspatercept and placebo arms were fatigue (27% vs 13%), diarrhea (22% vs 9%), asthenia (20% vs 12%), nausea (20% vs 8%), dizziness (20% vs 5%), and back pain (19% vs 7%). Grade ≥3 AEs occurred in 42% and 45% of patients on luspatercept and placebo, respectively; the most common were fatigue (5% with luspatercept and 3% with placebo) and injury (5% and 3%, respectively). Thirty-one percent of patients on luspatercept and 30% of those on placebo experienced ≥1 serious AE.

Longer-term analyses from MEDALIST were presented at the 2019 ASH Annual Meeting.⁴At a data cutoff date of July 1, 2019, results showed that the RBC-TI at ≥8 weeks was 47.7% with luspatercept and 15.8% with placebo (odds ratio [OR], 5.978; 95% CI, 2.840-12.581; P<.0001). At ≥6 units per 8 weeks, the RBC-TI was 21.2% with luspatercept and 6.1% with placebo (OR, 4.17; 95% CI, 0.89-19.60; P= .0547). In those who received 4 to 6 units per 8 weeks, the RBC-TI was 48.8% and 8.7% with luspatercept and placebo, respectively (OR, 10.00; 95% CI, 2.07-48.28; P= .0013). In patients who received <4 units per 8 weeks, the RBC-TI was 84.8% with luspatercept and 40.0% with placebo (OR, 8.36; 95% CI, 2.51-27.83; P= .0002).

Additionally, the longer follow-up showed that of the 73 patients treated with luspatercept achieving RBC-TI ≥8 weeks during the entire treatment period, 69.9% had ≥2 separate response periods, 38.4% of patients had ≥3 separate response periods, and 20.5% had ≥4 separate response periods.

Luspatercept is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.

The drug is also approved for the treatment ofanemia in adult patients with beta thalassemia who require regular RBC transfusions.

References

U.S. Food and Drug Administration (FDA) Approves Reblozyl® (luspatercept-aamt), the First and Only Erythroid Maturation Agent, to Treat Anemia in Adults with Lower-Risk Myelodysplastic Syndromes (MDS). Published April 3, 2020. https://bit.ly/2JEHtGG. Accessed April 3, 2020.
Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Eng J Med. 2020;382(2):140-151. doi: 10.1056/NEJMoa1908892.
Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes [supplementary appendix]. N Engl J Med. 2020;382(2):140-151. doi: 10.1056/NEJMoa1908892.
Fenaux P, Mufti GJ, Buckstein R, et al. Assessment of longer-term efficacy and safety in the phase 3, randomized, double-blind, placebo-controlled medalist trial of luspatercept to treat anemia in patients (pts) with revised International Prognostic Scoring System (IPSS-R) very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusions. Blood. 2019;134(suppl_1):841. doi: 10.1182/blood-2019-123064.