Reduced red blood cell transfusion dependence with luspatercept in patients with beta thalassemia

Beta-thalassemia is an inherited hemoglobinopathy associated with an erythroid maturation defect characterized by ineffective erythropoiesis and impaired RBC maturation. Results of the phase III Believe trial demonstrate that luspatercept is able to significantly reduce the need for blood transfusions in patients with this condition. In this trial, more than 1 in 5 patients treated with luspatercept experienced a reduction of 33% or more in the transfusion burden (defined as a reduction of ≥2 red blood cell [RBC] units) during weeks 13–24 after the start of therapy, the primary endpoint of the study. In patients treated with placebo, only 4.5% of patients obtained this milestone.In addition, more than 70% of patients who received luspatercept were able to cut blood transfusions by at least one-third over any consecutive 12-week period, while just under 30% of those who received a placebo were able to achieve the same result. Luspatercept was also well tolerated in this patient population.

Beta-thalassemia is a genetic blood disorder characterized by reduced production of the protein hemoglobin, and is associated with life-threatening complications such as severe anemia and organ damage. Although new treatments have emerged in recent years, including curative gene therapies, blood transfusions remain the standard of care and most accessible treatment for a vast majority of patients. Many patients with beta-thalassemia require transfusions every few weeks. This is not only a costly and time consuming procedure, patients who require frequent blood transfusions are also at risk of developing liver and heart problems due to a buildup of iron.

The Believe trial enrolled 336 adult patients with beta-thalassemia. Participants were mostly young, with a median age of 30 years, and required a median of six units of blood over a 12-week period before the trial. Patients were randomly assigned (2:1) to receive either luspatercept, at a starting dose level of 1.0 mg/kg with titration up to 1.25 mg/kg, or placebo, subcutaneously every 3 weeks for at least 48 weeks. The primary endpoint of the study was a ≥ 33% reduction in transfusion burden (with a reduction of ≥ 2 RBC units) during weeks 13–24, when compared with a 12-week baseline period. Secondary trial objectives included: a ≥33% reduction in RBC transfusion burden at weeks 37–48 and a ≥50% reduction in transfusion burden at weeks 13–24, or at weeks 37–48. Achievement of ≥33% reduction in RBC transfusion burden over any consecutive 12 weeks on study was also evaluated.

The results show that patients taking luspatercept were 5.8 times more likely to reach the primary endpoint. In fact, 48 of 224 (21.4%) patients in the luspatercept arm achieved the primary endpoint versus 5 of 112 (4.5%) patients receiving placebo (odds ratio: 5.79, p< 0.0001). In addition, 44 of 224 (19.6%) patients on luspatercept achieved a ≥33% reduction in RBC transfusion burden at weeks 37–48 compared with 4 of 112 (3.6%) patients receiving placebo (p< 0.0001). Of the 224 patients treated luspatercept, 17 (7.6%) and 23 (10.3%) achieved a ≥50% reduction in RBC transfusion burden at weeks 13–24 and 37–48, respectively, compared with 2 (1.8%) and 1 of 112 (0.9%) patients in the placebo arm (p= 0.0303 and p= 0.0017, respectively). Finally, 158 (70.5%) patients receiving luspatercept achieved a ≥33% RBC transfusion reduction over any consecutive 12 weeks compared with 33 (29.5%) patients randomised to placebo (p< 0.0001).

Reported adverse events included bone pain and thrombotic events, such as stroke, but the rates of these events did not differ significantly between patients taking luspatercept and those taking the placebo. No patient deaths were reported for those treated with luspatercept.

In conclusion, treatment with luspatercept resulted in significant reductions in RBC transfusion burden in adults with transfusion-dependent beta-thalassemia. Genetic variation is known to affect the severity of beta-thalassemia, so it may also affect the efficacy of treatments. In this respect, the Believe investigators plan to analyze whether genes or other factors affect how patients respond to luspatercept.

Reference

M.D. Cappellini, et al. The BELIEVE Trial: Results of a Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept in Adult Beta-Thalassemia Patients Who Require Regular Red Blood Cell (RBC) Transfusions. Presented at ASH 2018;Abstract 163