Long-term efficacy and safety of luspatercept for the treatment of anaemia in patients with transfusion-dependent β-thalassaemia (BELIEVE): final results from a phase 3 randomised trial

Cappellini MD 1 , Viprakasit V 2 , Georgiev P 3 , Coates TD 4 , Origa R 5 , Khelif A 6 Show all authors , Liew HK 7 , Tantiworawit A 8 , Chew LP 9 , Khalil A 10 , Ho PJ 11 , Kuo KHM 12 , Holot N 13 , Perin M 14 , Giuseppi AC 13 , Kuo WL 13 , Lai Y 13 , Medlin LF 14 , Bueno LM 14 , Kattamis A 15 , Taher AT 16

Affiliations 

  • 1 Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy. Electronic address: maria.cappellini@unimi.it
  • 2 Siriraj Hospital, Mahidol University, Bangkok, Thailand
  • 3 St. George University Hospital for Active Treatment and Medical University of Plovdiv, Plovdiv, Bulgaria
  • 4 Cancer and Blood Disease Institute, Children's Hospital Los Angeles and USC Keck School of Medicine, Los Angeles, CA, USA
  • 5 University of Cagliari, Ospedale Pediatrico Microcitemico 'A. Cao', Cagliari, Italy
  • 6 Department of Clinical Hematology, Farhat Hached Hospital and Ibn El Jazzar Faculty of Medicine, Sousse University, Sousse, Tunisia
  • 7 Department of Medicine, Hospital Sultanah Bahiyah, Alor Setar, Kedah, Malaysia
  • 8 Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
  • 9 Department of Medicine, Haematology Unit, Sarawak General Hospital, Kuching, Sarawak, Malaysia
  • 10 Department of Pediatric Hematology Oncology, Rambam Medical Center, Haifa, Israel
  • 11 Royal Prince Alfred Hospital and the University of Sydney, Sydney, NSW, Australia
  • 12 Division of Medical Oncology and Hematology, Department of Medicine, University Health Network and Division of Hematology, Department of Medicine, University of Toronto, Toronto, ON, Canada
  • 13 Bristol Myers Squibb, Princeton, NJ, USA
  • 14 Celgene International Sàrl, a Bristol-Myers Squibb Company, Boudry, Switzerland
  • 15 Thalassaemia Unit, First Department of Paediatrics, National and Kapodistrian University of Athens, Athens, Greece
  • 16 Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
Lancet Haematol, 2025 Feb 10.
PMID: 39947215 DOI: 10.1016/S2352-3026(24)00376-4

Abstract

BACKGROUND: Treatments to reduce red blood cell (RBC) transfusion burden among patients with transfusion-dependent β-thalassaemia remain limited. Here, we report long-term follow-up data from the phase 3 BELIEVE trial of luspatercept for transfusion-dependent β-thalassaemia.

METHODS: BELIEVE was a phase 3, randomised, double-blind, placebo-controlled study performed at 65 sites in 15 countries. The trial included adults with transfusion-dependent β-thalassaemia or haemoglobin E/β-thalassaemia and Eastern Cooperative Oncology Group score of 0-1. Patients were randomly assigned (2:1) using integrated response technology stratified by region to luspatercept (1·0-1·25 mg/kg) or placebo administered subcutaneously once every 21 days. After study unblinding, patients could receive luspatercept in the open-label extension phase (crossover allowed). The primary endpoint results (proportion of patients with reduction in transfusion burden of ≥33% and ≥2 RBC units during weeks 13-24) are described elsewhere; herein we present an update to the primary endpoint analysis consequent to late-reported transfusion events. We also report long-term efficacy (intention-to-treat population) and safety data (safety population) for patients followed up for approximately 3 years. This trial is registered on ClinicalTrials.gov (NCT02604433) and is completed.

FINDINGS: Between May 2, 2016, and May 16, 2017, 336 patients were randomly assigned to luspatercept (n=224) or placebo (n=112). The median age of patients was 30 years (IQR 23-40); 195 (58%) were female and 141 (42%) male. As of Jan 5, 2021, the median duration of treatment in the luspatercept group was 153·6 weeks (IQR 81·0-171·0) and median study follow-up was 163·1 weeks (140·5-176·2). Due to the difference in treatment duration between the luspatercept and placebo groups, no comparative analyses between the two groups were performed after week 96. Patients in the luspatercept group showed a sustained reduction in RBC transfusion burden from baseline through week 192, with mean decreases of 6·2 RBC units (SD 5·7) during weeks 97-144 and 6·4 RBC units (4·3) during weeks 145-192. In the luspatercept group, a 33% or greater reduction in transfusion burden from baseline was observed in 173 (77%) patients over any 12-week interval and in 116 (52%) patients over any 24-week interval. The median total duration of 33% or greater transfusion burden reduction response during any period of at least 12 weeks was 586·0 days (IQR 264·0-1010·0). The most common grade 3 or worse treatment-emergent adverse events (TEAEs) among all patients who received luspatercept (n=315, including 92 patients who crossed over after study unblinding) were anaemia (nine [3%]), increased liver iron concentration (seven [2%]), and bone pain (seven [2%]); serious TEAEs occurred in 71 (23%) patients. No treatment-related deaths occurred in any group during the study.

INTERPRETATION: These long-term results affirm luspatercept's efficacy in addressing key unmet needs of patients with transfusion-dependent β-thalassaemia with a manageable safety profile.

FUNDING: Celgene and Acceleron Pharma.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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