Betibeglogene Autotemcel Gene Therapy for Non-β 0 /β 0 Genotype β-Thalassemia

• Published in: The New England journal of medicine Vol. 386; no. 5; pp. 415 - 427
• Main Authors: Locatelli, Franco, Thompson, Alexis A, Kwiatkowski, Janet L, Porter, John B, Thrasher, Adrian J, Hongeng, Suradej, Sauer, Martin G, Thuret, Isabelle, Lal, Ashutosh, Algeri, Mattia, Schneiderman, Jennifer, Olson, Timothy S, Carpenter, Ben, Amrolia, Persis J, Anurathapan, Usanarat, Schambach, Axel, Chabannon, Christian, Schmidt, Manfred, Labik, Ivan, Elliot, Heidi, Guo, Ruiting, Asmal, Mohammed, Colvin, Richard A, Walters, Mark C
• Format: Journal Article
• Language: English
• Published: United States 03.02.2022
• Subjects: Adolescent; Adult; beta-Globins - genetics; beta-Thalassemia - blood; beta-Thalassemia - genetics; beta-Thalassemia - therapy; Biological Products - adverse effects; Biological Products - therapeutic use; Busulfan - therapeutic use; Child; Erythrocyte Transfusion - adverse effects; Erythropoiesis; Female; Genetic Therapy - methods; Genetic Vectors; Genotype; Hemoglobins - analysis; Humans; Iron Overload - prevention & control; Lentivirus - genetics; Male; Middle Aged; Myeloablative Agonists - therapeutic use
• ISSN: 0028-4793; 1533-4406
• DOI: 10.1056/NEJMoa2113206

Betibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent β-thalassemia contains autologous CD34+ hematopoietic stem cells and progenitor cells transduced with the BB305 lentiviral vector encoding the β-globin (β ) gene. In this open-label, phase 3 study, we evaluated the efficacy and safety of beti-cel in adult and pediatric patients with transfusion-dependent β-thalassemia and a non-β /β genotype. Patients underwent myeloablation with busulfan (with doses adjusted on the basis of pharmacokinetic analysis) and received beti-cel intravenously. The primary end point was transfusion independence (i.e., a weighted average hemoglobin level of ≥9 g per deciliter without red-cell transfusions for ≥12 months). A total of 23 patients were enrolled and received treatment, with a median follow-up of 29.5 months (range, 13.0 to 48.2). Transfusion independence occurred in 20 of 22 patients who could be evaluated (91%), including 6 of 7 patients (86%) who were younger than 12 years of age. The average hemoglobin level during transfusion independence was 11.7 g per deciliter (range, 9.5 to 12.8). Twelve months after beti-cel infusion, the median level of gene therapy-derived adult hemoglobin (HbA) with a T87Q amino acid substitution (HbA ) was 8.7 g per deciliter (range, 5.2 to 10.6) in patients who had transfusion independence. The safety profile of beti-cel was consistent with that of busulfan-based myeloablation. Four patients had at least one adverse event that was considered by the investigators to be related or possibly related to beti-cel; all events were nonserious except for thrombocytopenia (in 1 patient). No cases of cancer were observed. Treatment with beti-cel resulted in a sustained HbA level and a total hemoglobin level that was high enough to enable transfusion independence in most patients with a non-β /β genotype, including those younger than 12 years of age. (Funded by Bluebird Bio; HGB-207 ClinicalTrials.gov number, NCT02906202.).