• Franco Locatelli, Peter Lang, Donna Wall, Roland Meisel, Selim Corbacioglu, Amanda M Li, Josu de la Fuente, Ami J Shah, Ben Carpenter, Janet L Kwiatkowski, Markus Mapara, Robert I Liem, Maria Domenica Cappellini, Mattia Algeri, Antonis Kattamis, Sujit Sheth, Stephan Grupp, Rupert Handgretinger, Puja Kohli, Daoyuan Shi, Leorah Ross, Yael Bobruff, Christopher Simard, Lanju Zhang, Phuong Khanh Morrow, William E Hobbs, Haydar Frangoul, and CLIMB THAL-111 Study Group.
• From IRCCS Ospedale Pediatrico Bambino Gesù (F.L., M.A.) and Catholic University of the Sacred Heart (F.L.), Rome, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (M.D.C.), and the Department of Health Sciences, Magna Graecia University, Catanzaro (M.A.) - all in Italy; University Children's Hospital Tübingen (R.H.), and the Cluster of Excellence iFIT (EXC 2180) "Image-guided and Functionally Instructed Tumor Therapies" and the German Cancer Consortium, Partner Site Tübingen, University of Tübingen (P.L.), Tübingen, the Division of Pediatric Stem Cell Therapy, Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf (R.M.), and the University of Regensburg, Regensburg (S.C.) - all in Germany; the Hospital for Sick Children and University of Toronto, Toronto (D.W.), and BC Children's Hospital, University of British Columbia, Vancouver (A.M.L.) - all in Canada; Imperial College Healthcare NHS Trust, St. Mary's Hospital (J.F.), and University College London Hospitals NHS Foundation Trust (B.C.) - both in London; Stanford University, Palo Alto, CA (A.J.S.); Children's Hospital of Philadelphia and Perlman School of Medicine, University of Pennsylvania, Philadelphia (J.L.K., S.G.); Herbert Irving Comprehensive Cancer Center, Columbia University (M.M.), and Joan and Sanford I. Weill Medical College of Cornell University (S.S.) - both in New York; Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago (R.I.L.); National and Kapodistrian University of Athens, Athens (A.K.); Vertex Pharmaceuticals, Boston (P.K., D.S., L.R., Y.B., C.S., L.Z., W.E.H.), and CRISPR Therapeutics, Cambridge (P.K.M.) - both in Massachusetts; and Sarah Cannon Research Institute at the Children's Hospital at TriStar Centennial, Nashville (H.F.).
• N. Engl. J. Med. 2024 May 9; 390 (18): 166316761663-1676.

BackgroundExagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis through ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of the erythroid-specific enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs).MethodsWe conducted an open-label, single-group, phase 3 study of exa-cel in patients 12 to 35 years of age with transfusion-dependent β-thalassemia and a β0/β0, β0/β0-like, or non-β0/β0-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.ResultsA 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.ConclusionsTreatment 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.).Copyright © 2024 Massachusetts Medical Society.

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