ASSESSMENT OF RESPONSE TO LUSPATERCEPT BY Β-GLOBIN GENOTYPE IN ADULT PATIENTS WITH Β-THALASSEMIA IN THE BELIEVE TRIAL
Author(s): ,
Maria Domenica Cappellini
Affiliations:
Fondazione IRCCS Ca' Granda Policlinico Hospital,University of Milan,Milan,Italy
,
Olivier Hermine
Affiliations:
Imagine Institute,INSERM U1163, University of Paris,Paris,France;Department of Hematology,Necker Hospital, Assistance Publique-Hôpitaux de Paris,Paris,France
,
Antonio Piga
Affiliations:
Department of Clinical and Biological Sciences,University of Turin,Turin,Italy
,
Vip Viprakasit
Affiliations:
Siriraj Hospital,Mahidol University,Bangkok,Thailand
,
Pencho Georgiev
Affiliations:
St George University Hospital for Active Treatment,Plovdiv,Bulgaria;Medical University of Plovdiv,Plovdiv,Bulgaria
,
Kevin H. M. Kuo
Affiliations:
Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Division of Hematology, Department of Medicine,University of Toronto,Toronto, ON,Canada
,
Thomas Coates
Affiliations:
Children's Center for Cancer and Blood Diseases,Children's Hospital Los Angeles,Los Angeles, CA,United States;USC Keck School of Medicine,Los Angeles, CA,United States
,
Ersi Voskaridou
Affiliations:
Thalassemia and Sickle Cell Center of Laiko General Hospital,Athens,Greece
,
Hong Keng Liew
Affiliations:
Hospital Sultanah Bahiyah,Alor Setar,Malaysia
,
Idit Pazgal-Kobrowski
Affiliations:
Comprehensive Center of Thalassemia,Rabin Medical Center, Beilinson Hospital,Petah Tikva,Israel
,
Gian Luca Forni
Affiliations:
Centro della Microcitemia e Anemie Congenite e del Dismetabolismo del Ferro, Ospedale Galliera,Genoa, Italy,Italy
,
Silverio Perrotta
Affiliations:
Università della Campania,Luigi Vanvitelli,Caserta,Italy
,
Abderrahim Khelif
Affiliations:
Farhat Hached Teaching Hospital,Sousse University,Tunisia
,
Ashutosh Lal
Affiliations:
University of California San Francisco Benioff Children's Hospital,Oakland, CA,United States
,
Antonis Kattamis
Affiliations:
First Department of Pediatrics,National and Kapodistrian University of Athens,Athens,Greece
,
Farrukh Shah
Affiliations:
Department of Haematology,Whittington Health NHS Trust,London,United Kingdom
,
John Porter
Affiliations:
University College London, University College London Hospitals,London,United Kingdom
,
Abderrahmane Laadem
Affiliations:
Bristol-Myers Squibb,Summit, NJ,United States
,
Jeevan K. Shetty
Affiliations:
Celgene International, A Bristol-Myers Squibb Company,Boudry,Switzerland
,
Wen-Ling Kuo
Affiliations:
Bristol-Myers Squibb,Summit, NJ,United States
,
Jennie Zhang
Affiliations:
Bristol-Myers Squibb,Summit, NJ,United States
,
Dimana Miteva
Affiliations:
Celgene International, A Bristol-Myers Squibb Company,Boudry,Switzerland
,
Tatiana Zinger
Affiliations:
Celgene International, A Bristol-Myers Squibb Company,Boudry,Switzerland
,
Daniel Sinsimer
Affiliations:
Bristol-Myers Squibb,Summit, NJ,United States
,
Chrystal Louis
Affiliations:
Bristol-Myers Squibb,Summit, NJ,United States
,
Peter G. Linde
Affiliations:
Acceleron Pharma,Cambridge, MA,United States
Ali T. Taher
Affiliations:
Department of Internal Medicine,American University of Beirut Medical Center,Beirut,Lebanon
(Abstract release date: 05/14/20) EHA Library. Domenica Cappellini M. 06/12/20; 295114; S295
Dr. Maria Domenica Cappellini
Dr. Maria Domenica Cappellini
Contributions
Abstract

Abstract: S295

Type: Oral Presentation

Session title: New therapeutic approaches for thalassemia

Background
β-thalassemia is a genetic blood disorder caused by mutations that downregulate (β+) or silence (β0) expression of the gene (HBB) that encodes β-globin. Reduced expression of normal β-globin (β) leads to ineffective erythropoiesis, anemia and, in transfusion-dependent patients (pts), frequent and lifelong red blood cell (RBC) transfusions. Luspatercept, a first-in-class erythroid maturation agent approved for adult pts with β-thalassemia who require regular RBC transfusions, binds several TGF-β superfamily ligands to diminish Smad2/3 signaling and enhance late-stage erythropoiesis.

Aims
To explore the association between β-globin genotype and response to luspatercept in adult pts with β-thalassemia in the BELIEVE trial.

Methods
BELIEVE is a phase 3, double-blind, randomized, placebo (PBO)-controlled study evaluating the efficacy and safety of luspatercept in regularly transfused, adult pts with β-thalassemia (NCT02604433). Eligible pts were aged ≥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 transfusions of 6–20 RBC units in the 24 weeks prior to randomization, with no transfusion-free period >35 days. All pts provided informed written consent. Pts were randomized 2:1 to luspatercept 1.0 mg/kg (up to 1.25 mg/kg allowed) or PBO administered subcutaneously every 3 weeks for ≥48 weeks. Pts in both treatment arms continued RBC transfusions to maintain target pretransfusion Hb levels, as well as iron chelation therapy.

Results
Of the 336 pts randomized as part of the BELIEVE trial, 103 had genotype β00, 87 had genotype β0+, 84 had genotype β++, 9 had ≥1 unmutated β (includes β/β, β+/β, β0/β), and 52 had HbE/β-thalassemia.

The primary endpoint (≥33% reduction in RBC transfusion burden in Weeks 13–24, with a reduction of ≥2 units) was achieved with luspatercept vs PBO treatment by 9/68 (13.2%) vs 2/35 (5.7%; P=0.271) β00 pts, 15/59 (25.4%) vs 1/28 (3.6%; P=0.015) β0+ pts, 16/58 (27.6%) vs 0/26 (P=0.004) β++ pts, and 6/31 (19.4%) vs 2/21 (9.5%; P=0.341) HbE/β-thalassemia pts.

In the luspatercept arm, ≥33% reduction in transfusion burden during any 24 weeks was achieved by 26/68 (38.2%) β00 pts (vs 1/35 [2.9%] PBO; P<0.0001), 23/59 (39.0%) β0+ pts (vs 0/28 PBO; P=0.0001), 27/58 (46.6%) β++ pts (vs 0/26 PBO; P<0.0001), and 12/31 (38.7%) HbE/β-thalassemia pts (vs 1/21 PBO [4.8%]; P=0.007) (May 11, 2018 cutoff). With luspatercept treatment, 7/68 (10.3%) β00 pts (vs 1/35 [2.9%] PBO; P=0.193), 9/59 (15.3%) β0+ pts (vs 0/28 PBO; P=0.031), 10/58 (17.2%) β++ pts (vs 0/26 PBO; P=0.028), and 8/31 (25.8%) HbE/β‑thalassemia pts (vs 0/21 PBO; P=0.013) achieved ≥50% reduction in transfusion burden during any 24 weeks.

Least squares mean change (standard error) in RBC units transfused from baseline in Weeks 13–24 in luspatercept vs PBO arms, respectively, were −0.48 (0.205) vs 0.85 (0.288) for β00, −0.72 (0.273) vs 0.74 (0.395) for β0+, −0.90 (0.253) vs 0.71 (0.354) for β++, and −0.69 (0.416) vs 0.26 (0.469) for HbE/β-thalassemia pts.

Grade ≥3 treatment-emergent adverse events (TEAEs; ≥1) were reported in 18/68 (26.5%), 17/58 (29.3%), 14/58 (24.1%), and 14/31 (45.2%) luspatercept-treated β00, β0+, β++, and HbE/β-thalassemia pts, respectively. The incidence of specific adverse events was consistent with the overall population.

Conclusion
Although response rates were lower in pts with the most severe disease (β00), clinically meaningful reductions in transfusion burden were observed across genotypes.

Session topic: 27. Thalassemias

Keyword(s): Beta thalassemia, Clinical trial

Abstract: S295

Type: Oral Presentation

Session title: New therapeutic approaches for thalassemia

Background
β-thalassemia is a genetic blood disorder caused by mutations that downregulate (β+) or silence (β0) expression of the gene (HBB) that encodes β-globin. Reduced expression of normal β-globin (β) leads to ineffective erythropoiesis, anemia and, in transfusion-dependent patients (pts), frequent and lifelong red blood cell (RBC) transfusions. Luspatercept, a first-in-class erythroid maturation agent approved for adult pts with β-thalassemia who require regular RBC transfusions, binds several TGF-β superfamily ligands to diminish Smad2/3 signaling and enhance late-stage erythropoiesis.

Aims
To explore the association between β-globin genotype and response to luspatercept in adult pts with β-thalassemia in the BELIEVE trial.

Methods
BELIEVE is a phase 3, double-blind, randomized, placebo (PBO)-controlled study evaluating the efficacy and safety of luspatercept in regularly transfused, adult pts with β-thalassemia (NCT02604433). Eligible pts were aged ≥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 transfusions of 6–20 RBC units in the 24 weeks prior to randomization, with no transfusion-free period >35 days. All pts provided informed written consent. Pts were randomized 2:1 to luspatercept 1.0 mg/kg (up to 1.25 mg/kg allowed) or PBO administered subcutaneously every 3 weeks for ≥48 weeks. Pts in both treatment arms continued RBC transfusions to maintain target pretransfusion Hb levels, as well as iron chelation therapy.

Results
Of the 336 pts randomized as part of the BELIEVE trial, 103 had genotype β00, 87 had genotype β0+, 84 had genotype β++, 9 had ≥1 unmutated β (includes β/β, β+/β, β0/β), and 52 had HbE/β-thalassemia.

The primary endpoint (≥33% reduction in RBC transfusion burden in Weeks 13–24, with a reduction of ≥2 units) was achieved with luspatercept vs PBO treatment by 9/68 (13.2%) vs 2/35 (5.7%; P=0.271) β00 pts, 15/59 (25.4%) vs 1/28 (3.6%; P=0.015) β0+ pts, 16/58 (27.6%) vs 0/26 (P=0.004) β++ pts, and 6/31 (19.4%) vs 2/21 (9.5%; P=0.341) HbE/β-thalassemia pts.

In the luspatercept arm, ≥33% reduction in transfusion burden during any 24 weeks was achieved by 26/68 (38.2%) β00 pts (vs 1/35 [2.9%] PBO; P<0.0001), 23/59 (39.0%) β0+ pts (vs 0/28 PBO; P=0.0001), 27/58 (46.6%) β++ pts (vs 0/26 PBO; P<0.0001), and 12/31 (38.7%) HbE/β-thalassemia pts (vs 1/21 PBO [4.8%]; P=0.007) (May 11, 2018 cutoff). With luspatercept treatment, 7/68 (10.3%) β00 pts (vs 1/35 [2.9%] PBO; P=0.193), 9/59 (15.3%) β0+ pts (vs 0/28 PBO; P=0.031), 10/58 (17.2%) β++ pts (vs 0/26 PBO; P=0.028), and 8/31 (25.8%) HbE/β‑thalassemia pts (vs 0/21 PBO; P=0.013) achieved ≥50% reduction in transfusion burden during any 24 weeks.

Least squares mean change (standard error) in RBC units transfused from baseline in Weeks 13–24 in luspatercept vs PBO arms, respectively, were −0.48 (0.205) vs 0.85 (0.288) for β00, −0.72 (0.273) vs 0.74 (0.395) for β0+, −0.90 (0.253) vs 0.71 (0.354) for β++, and −0.69 (0.416) vs 0.26 (0.469) for HbE/β-thalassemia pts.

Grade ≥3 treatment-emergent adverse events (TEAEs; ≥1) were reported in 18/68 (26.5%), 17/58 (29.3%), 14/58 (24.1%), and 14/31 (45.2%) luspatercept-treated β00, β0+, β++, and HbE/β-thalassemia pts, respectively. The incidence of specific adverse events was consistent with the overall population.

Conclusion
Although response rates were lower in pts with the most severe disease (β00), clinically meaningful reductions in transfusion burden were observed across genotypes.

Session topic: 27. Thalassemias

Keyword(s): Beta thalassemia, Clinical trial

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