Luspatercept Reduced RBC Transfusion in Adults with β-Thalassemia

Luspatercept produced a clinically meaningful reduction of red blood cell (RBC) transfusions and was generally well tolerated in patients with adult β-thalassemia, according to results of the BELIEVE study presented at the 60^th ASH Annual Meeting and Exposition.

The results were presented by Maria Domenica Cappellini, MD, of the University of Milan, Italy.

β-thalassemia is a hereditary hemoglobinopathy that occurs due to a globin chain synthesis production defect, leading to ineffective erythropoiesis and anemia. Despite undergoing iron chelation therapy, many patients with the condition experience multiple morbidities because of iron toxicity (including increased mortality).

Luspatercept is a first-in-class erythroid maturation agent in development for adults with anemia from β-thalassemia or myelodysplastic syndrome.

The phase 3, double-blind BELIEVE study was designed to determine the efficacy and safety of luspatercept in adult β-thalassemia patients requiring regular RBC transfusions (ClinicalTrials.gov identifier: NCT02604433). Eligible patients were aged 18 or older, had β-thalassemia or hemoglobin (Hb) E/β‑thalassemia, and required regular transfusions of 6–20 RBC units in the 24 weeks prior to randomization with no transfusion-free period ≥ 35 days during that time.

The researchers enrolled 336 patients and randomly assigned them 2:1 to receive either luspatercept (n=224), at a starting dose level of 1.0 mg/kg with titration up to 1.25 mg/kg, or placebo (n=112) subcutaneously every 3 weeks for ≥ 48 weeks. Patients in both treatment arms continued to receive RBC transfusions and iron chelation therapy to maintain the same baseline Hb level. (At 48 weeks, crossover was permitted; the study is now open-label and will follow patients for 5 years; post-treatment follow-up will be 3 years).

The primary endpoint was a reduction in transfusion burden of 33% or greater, with a reduction of ≥ 2 RBC units during weeks 13–24, when compared with a 12-week baseline period. The groups had similar baseline characteristics.

“A significantly greater proportion of luspatercept-treated patients achieved a 33% reduction from baseline in transfusion burden during weeks 13 to 24 than those in the placebo group,” Cappellini said. Forty-eight patients in the luspatercept group met the primary endpoint compared with five patients in the placebo arm (21.4% vs. 4.5%; odds ratio=5.79, P<.0001).

Further, 19.6% of patients receiving luspatercept achieved a ≥ 33% reduction in RBC transfusion burden at weeks 37–48 compared with only 3.6% receiving placebo (P<.0001). Of 224 patients receiving luspatercept, 7.6% and 10.3% of patients achieved a ≥ 50% reduction in RBC transfusion burden at weeks 13–24 and 37–48, respectively, compared with only 1.8% and 0.9% of patients receiving placebo (P=.0303 and P=.0017, respectively).

The difference of mean change from baseline in transfusion burden from week 13 to week 24 was 1.35 units (P<.0001). Additionally, the majority (70.5%) of patients receiving luspatercept achieved a ≥ 33% RBC transfusion reduction over any consecutive 12 weeks compared with less than one-third (29.5%) of patients receiving placebo (P<.0001); statistically significant differences were also noted for all other transfusion burden reduction endpoints.

“All the primary endpoint subgroup analyses favors luspatercept,” Cappellini said. All key secondary endpoints of erythroid response were met, and were also statistically significant in favor of luspatercept.

Adverse events (AEs) observed in the study were generally consistent with previously reported phase 2 data, with similar numbers of patients reporting at least one AE of any grade in both arms. Treatment-emergent AEs leading to dose delay or dose reduction were similar between treatment arms, with the exceptions of bone pain, arthralgia, and dizziness, which were more pronounced in the luspatercept arm. Cappellini said these AEs were mild and did not require treatment. No patient deaths were reported for those treated with luspatercept.