Betibeglogene Autotemcel Gene Therapy for Transfusion-Dependent β-Thalassemia

Betibeglogene autotemcel (beti-cel) is an FDA-approved lentiviral vector-based gene therapy for transfusion-dependent β-thalassemia (TDT) that introduces functional copies of a modified β-globin gene into hematopoietic stem and progenitor cells (HSPC). A landmark study showed that beti-cel helped patients with nonsevere genotypes achieve transfusion independence (N Engl J Med 2018; 378:1479).

To determine the impact of beti-cel in patients with severe TDT genotypes, including β0/β0 or IVS-I-110 mutations, investigators enrolled 18 patients (median age, 12.5 years; range, 4 –33 years) in an industry-supported, multinational, phase 3 study. Patients underwent HSPC mobilization before CD34+ cells were collected via apheresis, transduced with BB305 lentiviral vector, and infused following myeloablative busulfan conditioning. The target dose was ≥5.0 × 106 CD34+ cells/kg, with higher vector copy numbers and transduced cell proportions compared to earlier studies.

At a median follow-up of 4 years, 16 patients (89%) maintained transfusion independence, defined as weighted average hemoglobin ≥9 g/dL without red cell transfusions for at least 12 consecutive months post infusion. All patients experienced at least one transplant-related grade 3 adverse event; there were no deaths or detection of vector-derived replication-competent lentivirus, insertional oncogenesis, or hematologic malignancy. Levels of markers of ineffective erythropoiesis and iron overload decreased post infusion for all patients. Of 11 patients who continued with chelation, 5 (45%) discontinued chelation at a median of 14 months (range, 7–20).