Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia
Franco Locatelli, Peter Lang, Donna A. Wall, Roland Meisel, Selim Corbacioglu, Amanda M. Li, Josu de la Fuente, Ami J. Shah, Ben Carpenter, Janet L. Kwiatkowski, Markus Y. Mapara, Robert I. Liem, Maria Domenica Cappellini, Mattia Algeri, Antonis Kattamis, Sujit Sheth, Stephan A. Grupp, Rupert Handgretinger, Puja Kohli, Daoyuan Shi, Leorah Ross, Yael Bobruff, C Simard, Lanju Zhang, Phuong K. Morrow, William E. Hobbs, Haydar Frangoul
Abstract
BACKGROUND: in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs). METHODS: -like genotype. CD34+ HSPCs were edited by means of CRISPR-Cas9 with a guide mRNA. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was transfusion independence, defined as a weighted average hemoglobin level of 9 g per deciliter or higher without red-cell transfusion for at least 12 consecutive months. Total and fetal hemoglobin concentrations and safety were also assessed. RESULTS: A total of 52 patients with transfusion-dependent β-thalassemia received exa-cel and were included in this prespecified interim analysis; the median follow-up was 20.4 months (range, 2.1 to 48.1). Neutrophils and platelets engrafted in each patient. Among the 35 patients with sufficient follow-up data for evaluation, transfusion independence occurred in 32 (91%; 95% confidence interval, 77 to 98; P<0.001 against the null hypothesis of a 50% response). During transfusion independence, the mean total hemoglobin level was 13.1 g per deciliter and the mean fetal hemoglobin level was 11.9 g per deciliter, and fetal hemoglobin had a pancellular distribution (≥94% of red cells). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No deaths or cancers occurred. CONCLUSIONS: Treatment with exa-cel, preceded by myeloablation, resulted in transfusion independence in 91% of patients with transfusion-dependent β-thalassemia. (Supported by Vertex Pharmaceuticals and CRISPR Therapeutics; CLIMB THAL-111 ClinicalTrials.gov number, NCT03655678.).