Longitudinal Effect of Luspatercept Treatment on Iron Overload and Iron Chelation Therapy (ICT) in Adult Patients (Pts) with β-Thalassemia in the Believe Trial

Introduction: Regular red blood cell (RBC) transfusions are the main supportive treatment for chronic anemia due to β-thalassemia. Transfusion-dependent pts require ICT to prevent iron overload from RBC transfusions, and associated complications. Thus, there is a clinical need to reduce transfusions and iron burden in pts with anemia due to β-thalassemia. Luspatercept, an erythroid maturation agent, is approved by the FDA for treatment of anemia in adult pts with β-thalassemia who require regular RBC transfusions. The phase 3, double-blind, randomized, placebo (PBO)-controlled BELIEVE study is evaluating the efficacy and safety of luspatercept in adult pts with β-thalassemia requiring regular RBC transfusions (NCT02604433; Cappellini MD, et al. N Engl J Med 2020;382:1219-31). Here we assess the effect of long-term luspatercept use on iron loading and ICT use in the BELIEVE trial. Methods: Pts were ≥ 18 years with β-thalassemia or hemoglobin (Hb) E/β-thalassemia (compound β-thalassemia mutation and/or multiplication of α-globin genes was allowed) and required regular RBC transfusions (defined as 6-20 RBC units in the 24 wks prior to randomization with no transfusion-free period > 35 days). Pts were randomized 2:1 to luspatercept 1.0 mg/kg (up to 1.25 mg/kg allowed) or PBO subcutaneously every 3 wks for ≥ 48 wks. Pts in both treatment arms continued to receive RBC transfusions to maintain target pretransfusion Hb levels, as well as ICT (deferasirox, deferoxamine, and deferiprone alone or in combination) per product label and physician practice prior to randomization. After study unblinding, pts randomized to PBO were eligible to cross over to luspatercept in an open-label phase. Risk for iron overload-related complications was evaluated by stratifying pts into categories based on serum ferritin (SF) level (< 1,000 μg/L, 1,000 to < 2,500 μg/L, ≥ 2,500 μg/L), liver iron concentration (LIC; ≤ 3 mg/g dw, > 3 mg/g dw), and myocardial iron (by T2* MRI; ≤ 20 ms, > 20 ms). Long-term changes in SF and ICT use were assessed in luspatercept pts remaining on treatment up to data cutoff (July 1, 2019) or study discontinuation, whichever was earlier. Results: Of 336 pts enrolled, 224 were randomized to luspatercept and 112 to PBO. Mean baseline SF, LIC, and myocardial T2* for luspatercept vs PBO arms were 2,097 vs 1,845 μg/L, 12.0 vs 10.1 mg/g dw, and 33.5 vs 34.8 ms, respectively. Overall, 97.3% of pts received ICT at baseline. As of July 1, 2019, 67.9% of pts initially randomized to luspatercept were still receiving treatment at the end of 2 years; 92 (82.1%) PBO pts crossed over to luspatercept after study unblinding. Of 141 luspatercept-treated pts with baseline mean SF ≥ 1,000 μg/L, 24 (17.0%) pts achieved post-baseline mean SF < 1,000 μg/L when assessed over Wks 1−24, vs 3 (5.0%) PBO-treated pts. During Wks 73−96, 26/56 (46.4%) luspatercept pts with baseline mean SF ≥ 1,000 μg/L achieved post-baseline mean SF < 1,000 μg/L (Figure A). At Wks 24 and 48, 5/120 (4.2%) and 13/134 (9.7%) luspatercept pts, respectively, shifted from LIC > 3 mg/g dw at baseline to ≤ 3 mg/g dw, vs 4/61 (6.6%) and 4/68 (5.9%) PBO pts; 15/105 (14.3%) of luspatercept pts shifted from LIC > 3 mg/g dw at baseline to ≤ 3 mg/g dw at Wk 96. 6/30 (20.0%) pts receiving luspatercept shifted from myocardial iron T2* ≤ 20 ms at baseline to > 20 ms at Wk 48 (vs 1/11 [9.1%] PBO pts); at Wk 96, 6/24 (25.0%) luspatercept-treated pts shifted from ≤ 20 ms to > 20 ms. During Wks 1-12, mean daily deferasirox dose in luspatercept pts was 1,477.08 mg (mean change from baseline +136.27 mg) and 1,516.28 mg (mean change from baseline +131.80 mg) in PBO pts. No significant difference was seen between luspatercept and PBO arms during the first 48 weeks, however, the proportion of patients receiving ≥ 1 ICT gradually declined in both luspatercept responders (defined as pts achieving ≥ 33% reduction in transfusion burden from baseline during Wks 13−24) and non-responders over time (Figure B). Both luspatercept responders and non-responders also experienced a gradual decrease in mean daily dose of deferasirox over time (Figure C). Conclusions: Compared with PBO-treated pts, a higher proportion of luspatercept-treated pts shifted to lower SF, LIC, and myocardial iron levels during the first 48 wks, indicative of lower risk of iron overload complications. Long-term luspatercept treatment led to an increasing proportion of patients with SF < 1,000 μg/L and decreasing trends of overall ICT use and deferasirox dosage. Figure 1 Disclosures Hermine: Celgene BMS: Consultancy, Research Funding; AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding; Alexion: Research Funding; Roche: Consultancy; Novartis: Research Funding. Cappellini:CRISPR Therapeutics, Novartis, Vifor Pharma: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Taher:Novartis Pharmaceuticals: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ionis Pharmaceuticals: Consultancy; Vifor Pharma: Consultancy, Research Funding; Silence Therapeutics: Consultancy. Coates:Sangamo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios pharma: Consultancy, Honoraria; Celgene, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; apo pharma (Chiesi Pharma): Consultancy, Honoraria; Vifor Pharma: Consultancy, Honoraria. Viprakasit:BMS, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Agios Pharmaceuticals, Ionis Pharmaceuticals, La Jolla Pharmaceuticals, Protagonist Therapeutics, Vifor Pharma: Consultancy, Research Funding. Voskaridou:ADDMEDICA Company: Consultancy, Research Funding; NOVARTIS Company: Research Funding; GENESIS Company: Consultancy, Research Funding; PROTAGONIST Company: Research Funding; ACCELERON Company: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Lal:Chiesi USA: Consultancy; Novartis: Research Funding; Celgene, BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; La Jolla Pharmaceutical Company: Research Funding; bluebird bio, Inc.: Research Funding; Insight Magnetics: Research Funding; Terumo Corporation: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharmaceuticals: Consultancy. Perrotta:Acceleron Pharma: Research Funding; Celgene, BMS: Honoraria; Novartis: Honoraria, Research Funding. Kattamis:Genesis Pharma SA: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apopharma/Chiesi: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ionis: Membership on an entity's Board of Directors or advisory committees; Vertex: Membership on an entity's Board of Directors or advisory committees; Vifor: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy. Shetty:BMS: Current Employment, Current equity holder in publicly-traded company. Zhang:BMS: Current Employment. Tian:BMS: Current Employment. Miteva:BMS: Current Employment. Zinger:Celgene International, A Bristol-Myers Squibb Company: Current Employment. Tang:BMS: Current Employment, Current equity holder in publicly-traded company. Backstrom:BMS: Current equity holder in publicly-traded company; Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company. Porter:Agios Pharmaceuticals: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Protagonist Therapeutics: Honoraria; Silence Therapeutics: Honoraria; La Jolla Pharmaceuticals: Honoraria; Vifor Pharmaceuticals: Honoraria; bluebird bio, Inc.: Consultancy, Honoraria.