Luspatercept-aamt Reduces RBC Transfusion Burden in Patients With Rare Blood Disorder

Maria Domenica Cappellini, MD

Data from the BELIEVE trial showed that luspatercept-aamt (Reblozyl), a first-in-class erythroid maturation agent designed to regulate late-stage red blood cell maturation, reduced the need for red blood cell (RBC) transfusions across every subgroup of patients with β-thalassemia.¹

“A greater proportion of luspatercept-treated patients achieved the primary endpoint: a reduction equal to or more than 33% from baseline during week 13 and 24 compared to placebo,” said lead author Maria Domenica Cappellini, MD, professor of internal medicine at the University of Milan in Milan, Italy. She presented the findings during the 2020 European Hematology Association Congress. “That was achieved regardless of β-globin subtype.”

b-thalassemia is a rare blood disorder that is caused by a genetic defect in hemoglobin; it is also associated with ineffective erythropoiesis, which leads to a production of fewer and less healthy RBCs and often leads to severe anemia.

In the double-blind, placebo-controlled, multicenter, BELIEVE study (NCT02604433), investigators explored the safety and efficacy of luspatercept-aamt in adult patients with b-thalassemia who regularly required RBC transfusions. The primary endpoint of the trial was a greater than or equal to 33% reduction in transfusion burden, with a reduction of a greater than or equal to 2 RBC units, during weeks 13 to 24, when compared with a 12-week baseline period.

Overall, 103 patients had the more severe β⁰/β⁰ genotype, 87 had genotype β⁰/β⁺, 84 had genotype β⁺/β⁺, 9 had at least 1 unmutated β, and 52 had HbE/β-thalassemia.

In the β⁰/β⁰ subtype, 13.2% of patients in the experimental arm achieved the primary endpoint compared with 5.7% of those assigned to placebo (P = .271). Similarly, patients assigned to luspatercept-aamt had better outcomes in the β⁰/β⁺ (25.4% vs 3.6%; P = .015), β⁺/β⁺ (27.6% vs 0.0%; P = .004), and the HbE/β-thalassemia (19.4% vs 9.5%; P = .341) subgroups.

“This subanalysis of the BELIEVE study showed clinical meaningful reductions in blood transfusion burden that were sustained for a long period of time, 24 weeks, across all b-globin genotypes, including the β⁰/β⁰ genotype,” Cappellini said.

For any 12-week period, 70.6% of patients in the experimental arm with the β⁰/β⁰ genotype, achieved a greater than or equal to 33% reduction in transfusion burden compared with 31.4% of those assigned to placebo (P <.001). Similarly, patients assigned to luspatercept-aamt had better outcomes in the β⁰/β⁺ (67.8% vs 35.7%; P = .005), β⁺/β⁺ (72.4% vs 26.9%; P <.001), and the HbE/β-thalassemia (71.0% vs 19.0%; P <.001) subgroups.

For any 24-week period, 38.2% of patients in the experimental arm with the β⁰/β⁰ genotype achieved the primary endpoint compared with just 2.9% of those assigned to placebo (p<.001). Again, the results were consistent across the β⁰/β⁺ (39.0% vs 0.0%; P <.001), β⁺/β⁺ (46.6% vs 0.0%; P <.001), and the HbE/β-thalassemia (38.7% vs 4.8%; P <.007) subgroups.

Investigators then assessed the rate of greater than or equal to 50% reduction in RBC transfusion burden during any 12- and any 24-week period. They again found that patients receiving luspatercept-aamt had better results regardless of β-globin genotype.

“This is quite important because it shows a consistent and persistent response,” Cappellini said.

A total 336 patients were randomly assigned to receive either luspatercept-aamt at a starting dose level of 1.0 mg/kg with titration up to 1.25 mg/kg (n=224), or placebo (n=112) delivered every 3 weeks for at least 48 weeks; 332 patients were treated on protocol. Those in both arms continued to receive RBC transfusions and iron chelation therapy to maintain the same baseline Hb level.

The median patient age was 30 years (range 18-66) and 58% of patients were female. Additionally, patients received a median of 6 RBC units in the 12 weeks before treatment, and 58% of patients in each arm had undergone splenectomy. Investigators observed the β⁰/β⁰ genotype in 30.4% and 31.3% of patients in the luspatercept-aamt and placebo arms, respectively.

Cappellini and colleagues published findings from the overall patient population in March. Those data showed that 21.4% of patients who received luspatercept-aamt achieved the primary endpoint compared with 4.5% of patients who received placebo (odds ratio, 5.79; 95% CI, 2.24-14.97; P <.001).²

In April 2020, the FDA approved luspatercept-aamt for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions based on data from BELIEVE.³

References

1. Cappellini MD, Hermine O, Piga A, et al. Assessment of response to luspatercept by β-globin genotype in adult patients with β-thalassemia in the BELIEVE trial. Presented at: the 2020 European Hematology Association Congress: Virtual; June 11-21, 2020. Abstract #S295.

2. Cappellini MD, Viprakasit V, Taher AT, et al. A phase 3 trial of luspatercept in patients with transfusion-dependent β-thalassemia. N Engl J Med. 2020;382(13):1219-1231. doi:10.1056/NEJMoa1910182

3. FDA approves luspatercept-ammt for anemia in adults with MDS. FDA. Press release. April 3, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-adults-mds