BETIBEGLOGENE AUTOTEMCEL (LENTIGLOBIN) IN PATIENTS WITH TRANSFUSION-DEPENDENT Β-THALASSEMIA AND Β0/Β0, B+IVS-I-110/B+IVS-I-110, OR Β0/B+IVS-I-110 GENOTYPES: UPDATED RESULTS FROM THE HGB-212 STUDY
Author(s): ,
Evangelia Yannaki
Affiliations:
Hematology Department & HCT Unit,G. Papanikolaou Hospital,Thessaloniki,Greece
,
Franco Locatelli
Affiliations:
Department of Hematology/Oncology and Cell and Gene Therapy,IRCCS Bambino Gesù Children's Hospital,Rome,Italy
,
Andreas E. Kulozik
Affiliations:
Molecular Medicine Partnership Unit (MMPU),European Molecular Biology Laboratory (EMBL),Heidelberg,Germany;Department of Pediatric Oncology, Hematology and Immunology,University of Heidelberg,Heidelberg,Germany
,
John B. Porter
Affiliations:
Haematology Department,University College London Hospitals,London,United Kingdom
,
Isabelle Thuret
Affiliations:
Pediatric Hematology,Hôpital de la Timone,Marseille,France
,
Martin G. Sauer
Affiliations:
Pediatric Hematology and Oncology,Medizinische Hochschule Hannover,Hannover,Germany
,
Ashutosh Lal
Affiliations:
UCSF Benioff Children's Hospital,Oakland,United States
,
Weijian Liu
Affiliations:
bluebird bio, Inc.,Cambridge,United States
,
Richard A. Colvin
Affiliations:
bluebird bio, Inc.,Cambridge,United States
,
Alexis A. Thompson
Affiliations:
Pediatric Hematology,Ann & Robert H. Lurie Children's Hospital of Chicago,Chicago,United States;Department of Pediatrics (Hematology, Oncology, and Stem Cell Transplantation),Northwestern University Feinberg School of Medicine,Chicago,United States
Janet L. Kwiatkowski
Affiliations:
Division of Hematology,Children's Hospital of Philadelphia,Philadelphia,United States;Department of Pediatrics,Perelman School of Medicine University of Pennsylvania,Philadelphia,United States
EHA Library. Yannaki E. 06/12/20; 293980; EP1494
Evangelia Yannaki
Evangelia Yannaki
Contributions
Abstract

Abstract: EP1494

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background
β-thalassemia is a genetic disease characterized by reduced or absent production of β-globin chains which are necessary to form adult hemoglobin (HbA). The clinical severity of β-thalassemia is determined by multiple factors, including the underlying β-globin mutations. Patients with transfusion-dependent β-thalassemia (TDT) who have certain β-globin mutations only produce minimal HbA (mutations such as β+IVS-I-110) or have no HbA production (β0 mutations). These patients have a severe phenotype and high transfusion requirements to ameliorate anemia.

Aims
Evaluate updated safety and efficacy of betibeglogene autotemel (beti-cel; LentiGlobin for β-thalassemia, autologous CD34+ cells encoding βA-T87Q-globin gene) in patients with TDT and β00, β+IVS-I-110+IVS-I-110, or β0+IVS-I-110 genotypes in the ongoing phase 3 HGB-212 study (Northstar-3, NCT03207009).

Methods
CD34+ cells were mobilized using G-CSF and plerixafor and collected via apheresis. Cells were transduced with BB305 lentiviral vector and infused into patients following single-agent, pharmacokinetic-adjusted, busulfan myeloablation. The primary endpoint is transfusion reduction (≥60% reduction in red blood cell [RBC] transfusion volume from Month 12-24). A key secondary endpoint is transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). Patients are followed for 2 years and offered participation in a long-term follow-up study. Data presented as median (min-max).

Results
As of 30 September 2019, 13 patients were treated (8 β00, 3 β+IVS-I-110/β+IVS-I-110, 2 β0+IVS-I-110 genotypes) and were followed for 8.8 (2.5-20.0) months. Median age at enrollment was 17 (7-33) years; 4 patients were younger than 12 years of age. Median cell dose infused was 9.6 (5.9-15.8) x106 CD34+ cells/kg. Nine of 11 patients followed for ≥6 months have discontinued transfusions for ≥3 months. Total unsupported Hb in these patients ranged from 8.3 to 14.2 g/dL at last visit, including 3 patients with total Hb >12.5 g/dL. Beti-cel-derived HbAT87Q in these 9 patients was 3.8-12.4 g/dL at last visit, contributing 38-92% to total Hb. Soluble transferrin receptor, a marker of ineffective erythropoiesis, improved in these 9 patients at Month 6 (51.8 [35.3-177.7] nmol/L) compared to baseline (109.4 [34.1-214.1] nmol/L). Only two patients had sufficient follow-up to be evaluable for TI and both achieved transfusion independence. The two patients with ≥6 months follow-up who continue to receive RBC transfusions had HbAT87Q levels of 4.6 g/dL and 0.0 g/dL at last visit (Month 9 and 6, respectively).

Neutrophil and platelet engraftment occurred at 26 (14-38) days and 41 (21-64) days, respectively. Post-infusion non-hematologic grade ≥3 adverse events (AEs) in ≥3 patients included febrile neutropenia (n=7) and stomatitis (n=5). AEs considered possibly related to beti-cel included abdominal pain (n=2), thrombocytopenia (n=1), leukopenia (n=1) and neutropenia (n=1). There were no deaths, graft failure, or cases of insertional oncogenesis. Updated results from all treated patients will be presented.

Conclusion
In HGB-212, 9/11 patients treated with betibeglogene autotemcel (beti-cel) gene therapy with ≥6 months follow-up produce sufficient beti-cel-derived HbAT87Q to become free of RBC transfusions. The treatment regimen comprised of conditioning and beti-cel infusion had a tolerability profile consistent with busulfan myeloablation. Longer follow-up will further establish the efficacy and safety of beti-cel in patients with TDT and β00, β+IVS-I-110+IVS-I-110, or β0+IVS-I-110 genotypes.

Session topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical

Keyword(s): Autologous hematopoietic stem cell transplantation, Beta thalassemia, Gene therapy, Lentiviral vector

Abstract: EP1494

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background
β-thalassemia is a genetic disease characterized by reduced or absent production of β-globin chains which are necessary to form adult hemoglobin (HbA). The clinical severity of β-thalassemia is determined by multiple factors, including the underlying β-globin mutations. Patients with transfusion-dependent β-thalassemia (TDT) who have certain β-globin mutations only produce minimal HbA (mutations such as β+IVS-I-110) or have no HbA production (β0 mutations). These patients have a severe phenotype and high transfusion requirements to ameliorate anemia.

Aims
Evaluate updated safety and efficacy of betibeglogene autotemel (beti-cel; LentiGlobin for β-thalassemia, autologous CD34+ cells encoding βA-T87Q-globin gene) in patients with TDT and β00, β+IVS-I-110+IVS-I-110, or β0+IVS-I-110 genotypes in the ongoing phase 3 HGB-212 study (Northstar-3, NCT03207009).

Methods
CD34+ cells were mobilized using G-CSF and plerixafor and collected via apheresis. Cells were transduced with BB305 lentiviral vector and infused into patients following single-agent, pharmacokinetic-adjusted, busulfan myeloablation. The primary endpoint is transfusion reduction (≥60% reduction in red blood cell [RBC] transfusion volume from Month 12-24). A key secondary endpoint is transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). Patients are followed for 2 years and offered participation in a long-term follow-up study. Data presented as median (min-max).

Results
As of 30 September 2019, 13 patients were treated (8 β00, 3 β+IVS-I-110/β+IVS-I-110, 2 β0+IVS-I-110 genotypes) and were followed for 8.8 (2.5-20.0) months. Median age at enrollment was 17 (7-33) years; 4 patients were younger than 12 years of age. Median cell dose infused was 9.6 (5.9-15.8) x106 CD34+ cells/kg. Nine of 11 patients followed for ≥6 months have discontinued transfusions for ≥3 months. Total unsupported Hb in these patients ranged from 8.3 to 14.2 g/dL at last visit, including 3 patients with total Hb >12.5 g/dL. Beti-cel-derived HbAT87Q in these 9 patients was 3.8-12.4 g/dL at last visit, contributing 38-92% to total Hb. Soluble transferrin receptor, a marker of ineffective erythropoiesis, improved in these 9 patients at Month 6 (51.8 [35.3-177.7] nmol/L) compared to baseline (109.4 [34.1-214.1] nmol/L). Only two patients had sufficient follow-up to be evaluable for TI and both achieved transfusion independence. The two patients with ≥6 months follow-up who continue to receive RBC transfusions had HbAT87Q levels of 4.6 g/dL and 0.0 g/dL at last visit (Month 9 and 6, respectively).

Neutrophil and platelet engraftment occurred at 26 (14-38) days and 41 (21-64) days, respectively. Post-infusion non-hematologic grade ≥3 adverse events (AEs) in ≥3 patients included febrile neutropenia (n=7) and stomatitis (n=5). AEs considered possibly related to beti-cel included abdominal pain (n=2), thrombocytopenia (n=1), leukopenia (n=1) and neutropenia (n=1). There were no deaths, graft failure, or cases of insertional oncogenesis. Updated results from all treated patients will be presented.

Conclusion
In HGB-212, 9/11 patients treated with betibeglogene autotemcel (beti-cel) gene therapy with ≥6 months follow-up produce sufficient beti-cel-derived HbAT87Q to become free of RBC transfusions. The treatment regimen comprised of conditioning and beti-cel infusion had a tolerability profile consistent with busulfan myeloablation. Longer follow-up will further establish the efficacy and safety of beti-cel in patients with TDT and β00, β+IVS-I-110+IVS-I-110, or β0+IVS-I-110 genotypes.

Session topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical

Keyword(s): Autologous hematopoietic stem cell transplantation, Beta thalassemia, Gene therapy, Lentiviral vector

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