Betibeglogene autotemcel gene therapy effective for β-thalassemia

1. Betibeglogene autotemcel (beti-cel) gene therapy resulted in sustained hemoglobin A with a T87Q amino acid substitution (HbA^T87Q) in non-β⁰/β⁰ genotype patients.

2. The gene therapy resulted in a total hemoglobin level sufficient for transfusion independence in these patients.

Evidence Rating Level: 1 (Excellent)

Study Rundown: β-thalassemia is caused by β-globin gene mutations, leading to reduced (β⁺) or absent (β⁰) functional β-globin. The disbalance between β-globin and α-globin hinders red blood cell development, chronic anemia and hemolysis. Patients with severe anemia require life-long red-cell transfusions and have impaired quality of life. While allogeneic hematopoietic stem-cell transplantation is curative for β-thalassemia, its feasibility is impacted by lack of donors and transplantation-related complications. Beti-cel gene therapy utilizes a lentiviral vector to introduce a modified β-globin^A-T78Q gene into hematopoietic stem cells and is a sustainable and potentially curative alternative. This study evaluated the efficacy of beti-cel gene therapy in treating transfusion-dependent β-thalassemia patients with non-β⁰/β⁰ genotypes. In the 22 patients who were treated and assessed, transfusion independence was achieved in the 20 of them. This was attributed to sustained production of functional HbA^T87Q, formed with the transduced β-globin^T87Q, and total hemoglobin level. Despite the small study size and limited follow-up period, this study provided evidence to support the efficacy of beti-cel gene therapy in treating β-thalassemia patients with non-β⁰/β⁰ genotypes and achieving transfusion dependence.

Click here to read the study in NEJM

Relevant Reading: Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia

In-Depth [prospective cohort study]: This was a single-group, open-label, single-dose, phase 3 efficacy and safety study of beti-cel gene therapy in patients with transfusion-dependent β-thalassemia. 23 patients were enrolled, among whom 15 were 12 to 50 years of age and 8 were younger than 12. Patients 50 years of age or younger with transfusion-dependent β-thalassemia, who received transfusions of ≥100mL per kilogram bodyweight of pack red cells per year, were included. However, patients with β⁰/β⁰, β⁰/β^+IVS-I-110 or β^+IVS-I-110/β^+IVS-I-110 genotypes were excluded. Hematopoietic stem cells were collected from periphery blood and CD34+ progenitor cells were isolated. These cells were activated and transduced with BB305 lentiviral vector carrying the modified β-globin gene. Patients underwent myeloablation with busulfan prior to receiving the modified progenitor cell infusion. The primary outcome was transfusion independence, defined as weighted average hemoglobin level ≥9g per deciliter for at least 12 months without red-cell transfusions. Secondary outcomes include characteristics of transfusion independence. The median duration of follow-up was 29.5 months (range, 13.0 to 48.2). Successful engraftment was observed in neutrophils, platelets, and lymphocytes. Vector genome was detected in all treated patients and stable over time. 22 patients were evaluated, 20 (91%) of whom had transfusion independence. The median time to last transfusion was 0.9 months (range, 05 to 2.4) after the treatment infusion. Transfusion independence was also sustained for the median of 20.4 months (range, 15.7 to 21.6). The average hemoglobin level during transfusion was 11.7g per deciliter (range, 9.5 to 12.8) and the median HbA^T87Q level was 8.7g per deciliter (range, 5.2 to 10.6). The two patients who did not have transfusion independence saw a reduction in transfusion volume. All patients had at least one adverse event during the study and the safety profile was consistent with busulfan-based myeloablation. Two patients developed thrombocytopenia that was deemed to be related to beti-cel. Overall, these findings showed that beti-cel gene therapy led to functional modified HbA^T78Q and normalized hemoglobin levels, contributing to transfusion independence in patients. Despite the small sample size and short follow-up, this study provided strong evidence to support the use of beti-cel therapy for transfusion-dependent β-thalassemia patients and forming the basis for larger, longer-term trials.

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