LUSPATERCEPT INCREASES FETAL HEMOGLOBIN (HBF) LEVELS IN ADULT Β-THALASSEMIA PATIENTS WHO REQUIRE RED BLOOD CELL (RBC) TRANSFUSIONS
Author(s): ,
Maria-Domenica Cappellini
Affiliations:
Fondazione IRCCS Ca’ Granda Policlinico Hospital,University of Milan,Milan,Italy
,
Martin Schwickart
Affiliations:
Celgene Corporation,San Francisco,United States
,
Olivier Hermine
Affiliations:
Necker Hospital,Paris,France;Imagine Institute,Paris,France
,
Antonio Piga
Affiliations:
Department of Clinical and Biological Sciences,University of Turin,Turin,Italy
,
Alberto Risueño
Affiliations:
Celgene Institute for Translational Research Europe,Seville,Spain
,
Melih Acar
Affiliations:
Celgene Corporation,San Francisco,United States
,
Tatiana Zinger
Affiliations:
Celgene International,Boudry,Switzerland
,
Abderrahmane Laadem
Affiliations:
Celgene Corporation,Summit,United States
,
Jeevan Shetty
Affiliations:
Celgene International,Boudry,Switzerland
,
Jessica Morison
Affiliations:
Celgene Corporation,Summit,United States
,
Dimana Miteva
Affiliations:
Celgene International,Boudry,Switzerland
,
Kyle MacBeth
Affiliations:
Celgene Corporation,San Francisco,United States
Ali Taher
Affiliations:
Department of Internal Medicine,American University of Beirut Medical Center,Beirut,Lebanon
EHA Library. Cappellini M. 06/14/19; 267344; S143
Maria-Domenica Cappellini
Maria-Domenica Cappellini
Contributions
Abstract

Abstract: S143

Type: Oral Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 12:15 - 12:30

Location: Hall E106

Background
The β-thalassemias are a group of inherited disorders characterized by absent or reduced production of the β-globin chains of hemoglobin (Hb), leading to ineffective erythropoiesis, chronic anemia, and multiple morbidities, and often require lifelong RBC transfusions. Increasing HbF is a therapeutic approach to rescuing the defect imposed by reduced/absent β-globin in β-thalassemias. Luspatercept is a first-in-class erythroid maturation agent that binds to select TGF-β superfamily ligands and enhances late-stage erythropoiesis by a mechanism that is still not fully understood. The phase 3, randomized, double-blind, placebo-controlled BELIEVE study evaluated the efficacy and safety of luspatercept in adult β-thalassemia patients requiring regular RBC transfusions. In the BELIEVE study, treatment with luspatercept resulted in significant reductions in RBC transfusion burden compared with placebo.

Aims
To explore the effects of luspatercept treatment on HbF levels in patients with RBC transfusion-dependent (TD) β-thalassemia, and to explore the relationship of HbF changes with transfusion burden reduction.

Methods
In the BELIEVE study, 336 adults with TD β-thalassemia were randomized to receive either luspatercept or placebo, administered subcutaneously every 21 days for 48 weeks, plus best supportive care. Hb variants were analyzed by HPLC and HbF was reported as a percentage of total Hb from whole blood samples collected at baseline and throughout the treatment period. P values were derived by 2-tailed t-test (parametric method) and Wilcoxon test (non-parametric method). Differences in HbF changes during treatment were compared between responders and non-responders (as defined by transfusion burden decrease of ≥33% over any 12 weeks), patients with baseline HbF<1% and HbF>1%, and luspatercept- and placebo-treated patients.

Results
HbF levels increased by a mean 1.2-fold in luspatercept-treated patients beginning at Dose2 Day1, increasing to 2.5-fold by the end of the evaluation period (Dose16 Day1). Mean change in HbF levels remained relatively unchanged in placebo-treated patients through Dose16 Day1, ranging from 0.9- to 1.2-fold of baseline levels.

Among luspatercept-treated patients starting at Dose5 until Dose16 Day1, HbF fold increase was greater in responders vs non-responders (Dose5 Day1: 2.1 vs 1.8 mean fold increase, P<0.024, Dose16 Day1: 2.7 vs 2.1 mean fold increase, P=0.012). To determine whether changes in HbF were secondary to RBC transfusion reduction or a direct effect of luspatercept, a subgroup analysis was performed in patients with normal HbF (HbF≤1%) at baseline. In luspatercept-treated patients with normal HbF at baseline, HbF increased by a mean 1.4-fold in responders and 1.5-fold in non-responders, beginning at Dose2 Day1, and continued to increase to 3.8-fold in responders and 2.9-fold in non-responders by Dose16 Day1, with no statistically significant difference between HbF changes in responders and non-responders (Figure). HbF levels were not modulated in placebo-treated patients. In luspatercept-treated patients with elevated (>1%) levels of HbF at baseline, HbF levels increased more in responders compared with non-responders (2.8 vs 2.0 mean fold increase, P=0.009).

Conclusion
Luspatercept treatment was associated with increased HbF in patients with RBC TD β-thalassemia. This luspatercept treatment effect on increasing HbF levels was observed in both responders and non-responders. Luspatercept-mediated increases in HbF were observed early and maintained throughout the treatment period.

Session topic: 27. Thalassemias

Keyword(s): Beta thalassemia, Clinical trial

Abstract: S143

Type: Oral Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 12:15 - 12:30

Location: Hall E106

Background
The β-thalassemias are a group of inherited disorders characterized by absent or reduced production of the β-globin chains of hemoglobin (Hb), leading to ineffective erythropoiesis, chronic anemia, and multiple morbidities, and often require lifelong RBC transfusions. Increasing HbF is a therapeutic approach to rescuing the defect imposed by reduced/absent β-globin in β-thalassemias. Luspatercept is a first-in-class erythroid maturation agent that binds to select TGF-β superfamily ligands and enhances late-stage erythropoiesis by a mechanism that is still not fully understood. The phase 3, randomized, double-blind, placebo-controlled BELIEVE study evaluated the efficacy and safety of luspatercept in adult β-thalassemia patients requiring regular RBC transfusions. In the BELIEVE study, treatment with luspatercept resulted in significant reductions in RBC transfusion burden compared with placebo.

Aims
To explore the effects of luspatercept treatment on HbF levels in patients with RBC transfusion-dependent (TD) β-thalassemia, and to explore the relationship of HbF changes with transfusion burden reduction.

Methods
In the BELIEVE study, 336 adults with TD β-thalassemia were randomized to receive either luspatercept or placebo, administered subcutaneously every 21 days for 48 weeks, plus best supportive care. Hb variants were analyzed by HPLC and HbF was reported as a percentage of total Hb from whole blood samples collected at baseline and throughout the treatment period. P values were derived by 2-tailed t-test (parametric method) and Wilcoxon test (non-parametric method). Differences in HbF changes during treatment were compared between responders and non-responders (as defined by transfusion burden decrease of ≥33% over any 12 weeks), patients with baseline HbF<1% and HbF>1%, and luspatercept- and placebo-treated patients.

Results
HbF levels increased by a mean 1.2-fold in luspatercept-treated patients beginning at Dose2 Day1, increasing to 2.5-fold by the end of the evaluation period (Dose16 Day1). Mean change in HbF levels remained relatively unchanged in placebo-treated patients through Dose16 Day1, ranging from 0.9- to 1.2-fold of baseline levels.

Among luspatercept-treated patients starting at Dose5 until Dose16 Day1, HbF fold increase was greater in responders vs non-responders (Dose5 Day1: 2.1 vs 1.8 mean fold increase, P<0.024, Dose16 Day1: 2.7 vs 2.1 mean fold increase, P=0.012). To determine whether changes in HbF were secondary to RBC transfusion reduction or a direct effect of luspatercept, a subgroup analysis was performed in patients with normal HbF (HbF≤1%) at baseline. In luspatercept-treated patients with normal HbF at baseline, HbF increased by a mean 1.4-fold in responders and 1.5-fold in non-responders, beginning at Dose2 Day1, and continued to increase to 3.8-fold in responders and 2.9-fold in non-responders by Dose16 Day1, with no statistically significant difference between HbF changes in responders and non-responders (Figure). HbF levels were not modulated in placebo-treated patients. In luspatercept-treated patients with elevated (>1%) levels of HbF at baseline, HbF levels increased more in responders compared with non-responders (2.8 vs 2.0 mean fold increase, P=0.009).

Conclusion
Luspatercept treatment was associated with increased HbF in patients with RBC TD β-thalassemia. This luspatercept treatment effect on increasing HbF levels was observed in both responders and non-responders. Luspatercept-mediated increases in HbF were observed early and maintained throughout the treatment period.

Session topic: 27. Thalassemias

Keyword(s): Beta thalassemia, Clinical trial

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