IMPROVEMENT IN ERYTHROPOIESIS IN PATIENTS WITH TRANSFUSION-DEPENDENT B-THALASSEMIA FOLLOWING TREATMENT WITH BETIBEGLOGENE AUTOTEMCEL (LENTIGLOBIN FOR B-THALASSEMIA) IN THE PHASE 3 HGB-207 STUDY
Author(s): ,
John B. Porter
Affiliations:
Haematology Department,University College London Hospitals,London,United Kingdom
,
Alexis A. Thompson
Affiliations:
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
,
Mark C. Walters
Affiliations:
Division of Hematology/Oncology,UCSF Benioff Children's Hospital,Oakland,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
,
Suradej Hongeng
Affiliations:
Mahidol University, Ramathibodi Hospital,Bangkok,Thailand
,
Martin G. Sauer
Affiliations:
Pediatric Hematology and Oncology,Medizinische Hochschule Hannover,Hannover,Germany
,
Adrian J. Thrasher
Affiliations:
UCL Great Ormond Street Institute of Child Health,London,United Kingdom
,
Isabelle Thuret
Affiliations:
Pediatric Hematology,Hôpital de la Timone,Marseille,France
,
Ge Tao
Affiliations:
bluebird bio, Inc.,Cambridge,United States
,
Richard A. Colvin
Affiliations:
bluebird bio, Inc.,Cambridge,United States
Franco Locatelli
Affiliations:
Department of Hematology/Oncology and Cell and Gene Therapy,IRCCS Bambino Gesù Children's Hospital,Rome,Italy
EHA Library. B. Porter J. 06/12/20; 295115; S296
John B. Porter
John B. Porter
Contributions
Abstract

Abstract: S296

Type: Oral Presentation

Presentation during EHA25: All oral abstract 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.

Session title: New therapeutic approaches for thalassemia

Background
Transfusion-dependent β-thalassemia (TDT) is a severe genetic disease requiring lifelong red blood cell (RBC) transfusions and regular iron chelation. Transfusions temporarily relieve anemia, but do not restore normal erythropoiesis. The goal of betibeglogene autotemcel (beti-cel; LentiGlobin for β-thalassemia; autologous CD34+ cells encoding βA-T87Q-globin gene) is to correct ineffective erythropoiesis and enable lifelong production of functional adult hemoglobin (Hb), thereby enabling patients to achieve transfusion independence.

Aims
To assess the change in ineffective erythropoiesis following treatment with beti-cel in the ongoing phase 3 HGB-207 study (Northstar-2; NCT02906202) in patients with TDT and non-β00 genotypes.

Methods
Patients received G-CSF and plerixafor to mobilize CD34+ cells which are collected via apheresis. Cells are then transduced with BB305 lentiviral vector and infused into patients following single-agent, pharmacokinetic-adjusted, busulfan myeloablation. The primary endpoint is transfusion independence (TI; weighted average Hb ≥9 g/dL without RBC transfusions for ≥12 months). Improvement of ineffective erythropoiesis was also evaluated. Patients are followed for 2 years and offered participation in a long-term follow-up study. Data are presented as median (min-max).

Results
As of 12 June 2019, 21 patients were treated and followed for 11.6 (0.9-26.3) months. The median age at enrollment was 15 (8-34) years; 6 patients were <12 years old. All patients engrafted. Ten patients with sufficient follow-up were evaluable for TI and 9 of these patients achieved transfusion independence for an ongoing duration of 15.2 (12.1-21.3) months. The weighted average Hb during TI was 12.2 (11.4-12.8) g/dL.

At Month 12, the 9 patients who achieved transfusion independence had improved bone marrow cellularity compared to baseline (44% vs 11% normocellular) and improved myeloid:erythroid ratios (baseline: 1:7.3-1:1.4; Month 12: 1:1.6-1.9:1). Seven of 9 patients had reticulocyte counts within normal range vs 44% (4/9) at baseline. Soluble transferrin receptor levels decreased from 171.8 (66-235) nmol/L at baseline to 49.4 (34-68) nmol/L with 78% (7/9) of patients within normal range at last follow-up (vs 44% [4/9] at baseline). Erythropoietin levels in patients achieving TI decreased 61.4% from 33.2 (10.8-73.4) U/L at baseline (n=9) to 12.8 (4.9-21.8) U/L at Month 12 (n=7). Finally, the hepcidin:ferritin ratio improved from 0.01 (0.00-0.06) at baseline (n=9) to 0.03 (0.01-0.4) at Month 12 (n=9).

Post-infusion non-hematologic grade ≥3 treatment-emergent adverse events (AEs) reported in ≥3 patients included stomatitis (n=12), febrile neutropenia (n=7), epistaxis (n=3), pyrexia (n=3), and veno-occlusive liver disease (n=3). Adverse events considered related to beti-cel by the investigator included thrombocytopenia (n=2, one event was serious), abdominal pain (n=1), and pain in extremity (n=1). There were no deaths and no evidence of insertional oncogenesis or clonal dominance. Updated results with outcomes from all 23 patients treated in the HGB-207 study will be presented.

Conclusion
Following treatment with betibeglogene autotemcel (beti-cel; LentiGlobin for β-thalassemia) gene therapy, 9/10 patients with TDT and non-β00 genotypes achieved transfusion independence. These patients showed improvements in erythropoiesis, suggesting that the the bone marrow is in process of normalizing. The treatment regimen comprised of conditioning and beti-cel infusion had a tolerability profile consistent with the known effects of busulfan myeloablation.

Session topic: 27. Thalassemias

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

Abstract: S296

Type: Oral Presentation

Presentation during EHA25: All oral abstract 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.

Session title: New therapeutic approaches for thalassemia

Background
Transfusion-dependent β-thalassemia (TDT) is a severe genetic disease requiring lifelong red blood cell (RBC) transfusions and regular iron chelation. Transfusions temporarily relieve anemia, but do not restore normal erythropoiesis. The goal of betibeglogene autotemcel (beti-cel; LentiGlobin for β-thalassemia; autologous CD34+ cells encoding βA-T87Q-globin gene) is to correct ineffective erythropoiesis and enable lifelong production of functional adult hemoglobin (Hb), thereby enabling patients to achieve transfusion independence.

Aims
To assess the change in ineffective erythropoiesis following treatment with beti-cel in the ongoing phase 3 HGB-207 study (Northstar-2; NCT02906202) in patients with TDT and non-β00 genotypes.

Methods
Patients received G-CSF and plerixafor to mobilize CD34+ cells which are collected via apheresis. Cells are then transduced with BB305 lentiviral vector and infused into patients following single-agent, pharmacokinetic-adjusted, busulfan myeloablation. The primary endpoint is transfusion independence (TI; weighted average Hb ≥9 g/dL without RBC transfusions for ≥12 months). Improvement of ineffective erythropoiesis was also evaluated. Patients are followed for 2 years and offered participation in a long-term follow-up study. Data are presented as median (min-max).

Results
As of 12 June 2019, 21 patients were treated and followed for 11.6 (0.9-26.3) months. The median age at enrollment was 15 (8-34) years; 6 patients were <12 years old. All patients engrafted. Ten patients with sufficient follow-up were evaluable for TI and 9 of these patients achieved transfusion independence for an ongoing duration of 15.2 (12.1-21.3) months. The weighted average Hb during TI was 12.2 (11.4-12.8) g/dL.

At Month 12, the 9 patients who achieved transfusion independence had improved bone marrow cellularity compared to baseline (44% vs 11% normocellular) and improved myeloid:erythroid ratios (baseline: 1:7.3-1:1.4; Month 12: 1:1.6-1.9:1). Seven of 9 patients had reticulocyte counts within normal range vs 44% (4/9) at baseline. Soluble transferrin receptor levels decreased from 171.8 (66-235) nmol/L at baseline to 49.4 (34-68) nmol/L with 78% (7/9) of patients within normal range at last follow-up (vs 44% [4/9] at baseline). Erythropoietin levels in patients achieving TI decreased 61.4% from 33.2 (10.8-73.4) U/L at baseline (n=9) to 12.8 (4.9-21.8) U/L at Month 12 (n=7). Finally, the hepcidin:ferritin ratio improved from 0.01 (0.00-0.06) at baseline (n=9) to 0.03 (0.01-0.4) at Month 12 (n=9).

Post-infusion non-hematologic grade ≥3 treatment-emergent adverse events (AEs) reported in ≥3 patients included stomatitis (n=12), febrile neutropenia (n=7), epistaxis (n=3), pyrexia (n=3), and veno-occlusive liver disease (n=3). Adverse events considered related to beti-cel by the investigator included thrombocytopenia (n=2, one event was serious), abdominal pain (n=1), and pain in extremity (n=1). There were no deaths and no evidence of insertional oncogenesis or clonal dominance. Updated results with outcomes from all 23 patients treated in the HGB-207 study will be presented.

Conclusion
Following treatment with betibeglogene autotemcel (beti-cel; LentiGlobin for β-thalassemia) gene therapy, 9/10 patients with TDT and non-β00 genotypes achieved transfusion independence. These patients showed improvements in erythropoiesis, suggesting that the the bone marrow is in process of normalizing. The treatment regimen comprised of conditioning and beti-cel infusion had a tolerability profile consistent with the known effects of busulfan myeloablation.

Session topic: 27. Thalassemias

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

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