Effect of Luspatercept in β-Thalassemia Patients with β0/β0 Genotype: A Subgroup Analysis of the BELIEVE Study

Introduction: β-thalassemia is an inherited hemoglobinopathy caused by mutations in the HBB gene that encodes β-globin. Patients (pts) homozygous for mutations that severely reduce or silence expression of HBB (β⁰/β⁰ genotype) do not produce any functional β-globin, resulting in an imbalance of globin chains, ineffective erythropoiesis, and severe anemia. Pts with a β⁰/β⁰ genotype require frequent, lifelong red blood cell (RBC) transfusions to address their anemia. However, regular RBC transfusions are associated with increased risk of morbidities and mortality. As such, interventions that can reduce dependence on RBC transfusions are important for improving outcomes in this pt population.

Results from the phase 3 BELIEVE study showed that a higher percentage of pts with transfusion-dependent β-thalassemia who received luspatercept experienced reductions in RBC transfusion burden than pts receiving placebo in the first 48 weeks (wk) of the study (Cappellini MD, et al. N Engl J Med 2020;382:1219-1231) and the efficacy of luspatercept has been shown to persist with longer-term treatment (Cappellini MD, et al. HemaSphere 2022;6 [Suppl 3]. Abstract 270).

The aim of this post-hoc sub-analysis was to investigate the long-term efficacy of luspatercept in pts with β⁰/β⁰ genotypes from the BELIEVE trial.

Methods: Pts ≥ 18 years of age with β-thalassemia or hemoglobin E/β-thalassemia (compound β-thalassemia mutation and/or multiplication of α-globin genes allowed) and requiring regular RBC transfusions (6-20 RBC units in the 24 wk prior to randomization, no transfusion-free period > 35 days) were randomized 2:1 to receive luspatercept (1.0-1.25 mg/kg) or placebo subcutaneously every 3 wk. Response was defined as ≥ 33% or ≥ 50% reduction from baseline in RBC transfusion burden during any 12- or 24-wk interval over the entire study period. Genotyping was performed if this information was not included in the pt's medical history.

Results: Of the 336 pts enrolled in the BELIEVE study, 103 had a β⁰/β⁰ genotype. HBB mutations represented in the β⁰/β⁰ subgroup were: c.17_18delCT; c.20delA; c.25_26delAA; c.27dupG; c.52A>T; c.84_85insC; c.92G>A; c.92+1G>A (IVS1-1); c.92+1G>T (IVS1-1); c.92+2T>G; c.93-15T>G (IVS1-116); c.112delT; c.114G>A; c.118C>T; c.126_129delCTTT; c.135delC; c.217dupA; c.315+1G>A (IVS2-1); c.315+1G>T (IVS2-1); c.316-2A>C (IVS2-849); and deletion of HBB. In the intent-to-treat (ITT) population, 224 pts received luspatercept, 68 of whom had a β⁰/β⁰ genotype.

Median (range) duration of treatment for pts receiving luspatercept was 153.57 (1.7-215.0) wk. In the ITT luspatercept population, 173 (77.2%) pts achieved ≥ 33% reduction in RBC transfusion burden and 112 (50.0%) pts achieved ≥ 50% reduction in RBC transfusion burden during any 12-wk interval over the entire study period (Figure 1A). For pts with a β⁰/β⁰ genotype, 52 (76.5%) achieved ≥ 33% reduction in RBC transfusion burden and 36 (52.9%) achieved ≥ 50% reduction during any 12-wk interval.

Transfusion burden reductions of ≥ 33% and ≥ 50% over any 24-wk interval were reported in 116 (51.8%) and 53 (23.7%) pts in the ITT population, respectively. Of the pts with a β⁰/β⁰ genotype, 36 (52.9%) achieved ≥ 33% reduction and 11 (16.2%) achieved ≥ 50% reduction in RBC transfusion burden during any 24-wk interval.

Responses in the β⁰/β⁰ subgroup were also evaluated by splenectomy status (n = 40 splenectomized and n = 28 non-splenectomized pts). Of the splenectomized pts, 34 (85.0%) achieved ≥ 33% reduction in RBC transfusion burden and 27 (67.5%) ≥ 50% reduction during any 12-wk interval; 18 (64.3%) and 9 (32.1%) non-splenectomized pts, respectively, achieved these responses (Figure 1B). Over any 24-wk interval, 24 (60.0%) and 8 (20.0%) splenectomized pts achieved ≥ 33% reduction and ≥ 50% reduction in RBC transfusion burden, respectively. For non-splenectomized pts, reductions in RBC transfusion burden of ≥ 33% and ≥ 50% were reported in 12 (42.9%) and 3 (10.7%) pts, respectively.

Conclusion: Pts with a β⁰/β⁰ genotype in the BELIEVE trial experienced similar reductions in RBC transfusion burden with luspatercept as the overall ITT luspatercept population. Furthermore, greater proportions of splenectomized pts with a β⁰/β⁰ genotype achieved reductions in RBC transfusion burden than β⁰/β⁰ pts who were not splenectomized. These longer-term data demonstrate the efficacy of luspatercept in a pt population with more severe disease.

Sheth:Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Forma: Consultancy, Research Funding; Fulcrum: Consultancy; CRISPR/Vertex: Other: Member of Clinical Trial Steering committee; Chiesi: Consultancy; Agios: Consultancy, Research Funding. Hermine:Inatherys: Research Funding; BMS: Honoraria, Research Funding; Novartis: Research Funding; Kite/Gilead: Honoraria; AB Science: Current equity holder in private company, Honoraria, Research Funding. Taher:Agios: Consultancy, Research Funding; Imara: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ionis Pharmaceuticals: Consultancy, Research Funding; Vifor Pharma: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Kuo:Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding; Alexion: Consultancy, Honoraria; Bioverativ/Sanofi/Sangamo: Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy; bluebird bio: Consultancy; Celgene/BMS: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Porter:Agios: Consultancy, Honoraria; VIFOR: Honoraria; bluebird bio: Consultancy, Honoraria; Silence Therapeutics: Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Protagonism: Honoraria; La Jolla Pharmaceuticals: Honoraria; Celgene: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Piga:Chiesi: Honoraria; Celgene: Honoraria. Coates:Agios: Consultancy; BMS Pharma: Consultancy; Vifor: Consultancy; Bluebird: Consultancy; Chiesi: Consultancy; Forma: Consultancy. Kattamis:IONIS: Consultancy; ViFOR: Consultancy; VERTEX: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Chiesi: Honoraria; AMGEN: Consultancy; AGIOS Pharmaceuticals: Consultancy. Felber Medlin:Bristol Myers Squibb: Current Employment, Current holder of stock options in a privately-held company. Kuo:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Holot:BMS: Current Employment. Cappellini:Silence: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Vertex: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.