• Haydar Frangoul, Franco Locatelli, Akshay Sharma, Monica Bhatia, Markus Mapara, Lyndsay Molinari, Donna Wall, Robert I Liem, Paul Telfer, Ami J Shah, Marina Cavazzana, Selim Corbacioglu, Damiano Rondelli, Roland Meisel, Laurence Dedeken, Stephan Lobitz, Mariane de Montalembert, Martin H Steinberg, Mark C Walters, Michael J Eckrich, Suzan Imren, Laura Bower, Christopher Simard, Weiyu Zhou, Fengjuan Xuan, Phuong Khanh Morrow, William E Hobbs, Stephan A Grupp, and CLIMB SCD-121 Study Group.
• From Sarah Cannon Research Institute at the Children's Hospital at TriStar Centennial (H.F.), Nashville, and Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis (A.S.) - both in Tennessee; IRCCS, Ospedale Pediatrico Bambino Gesù, Catholic University of the Sacred Heart, Rome (F.L.); the Department of Pediatrics, Columbia University Irving Medical Center, New York-Presbyterian-Morgan Stanley Children's Hospital (M.B.), and the Department of Medicine, Division of Hematology-Oncology, Columbia University (M. Mapara) - both in New York; Sarah Cannon Pediatric Transplant and Cellular Therapy Program at Methodist Children's Hospital, San Antonio, TX (L.M., M.J.E.); the Hospital for Sick Children and the University of Toronto, Toronto (D.W.); Ann and Robert H. Lurie Children's Hospital of Chicago (R.I.L.) and the University of Illinois at Chicago (D.R.) - both in Chicago; Royal London Hospital, Barts Health NHS Trust, London (P.T.); Stanford University, Palo Alto (A.J.S.), and University of California San Francisco Benioff Children's Hospital, Oakland (M.C.W.) - both in California; the Biotherapy Department and Biotherapy Clinical Investigation Center (M.C.), Necker-Enfants Malades Hospital, Assistance Publique-Hopitaux de Paris, Université Paris-Cité (M. de Montalembert), Paris; the University of Regensburg, Regensburg (S.C.), the Division of Pediatric Stem Cell Therapy, Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich Heine University, Duesseldorf (R.M.), and Gemeinschaftsklinikum Mittelrhein, Koblenz (S.L.) - all in Germany; Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels (L.D.); Boston University Chobanian and Avedisian School of Medicine (M.H.S.) and Vertex Pharmaceuticals (S.I., L.B., C.S., W.Z., F.X., W.E.H.), Boston, and CRISPR Therapeutics, Cambridge (P.K.M.) - all in Massachusetts; and the Division of Oncology, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (S.A.G.).
• N. Engl. J. Med. 2024 May 9; 390 (18): 164916621649-1662.

BackgroundExagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis by means of ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region of BCL11A.MethodsWe conducted a phase 3, single-group, open-label study of exa-cel in patients 12 to 35 years of age with sickle cell disease who had had at least two severe vaso-occlusive crises in each of the 2 years before screening. CD34+ HSPCs were edited with the use of CRISPR-Cas9. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was freedom from severe vaso-occlusive crises for at least 12 consecutive months. A key secondary end point was freedom from inpatient hospitalization for severe vaso-occlusive crises for at least 12 consecutive months. The safety of exa-cel was also assessed.ResultsA total of 44 patients received exa-cel, and the median follow-up was 19.3 months (range, 0.8 to 48.1). Neutrophils and platelets engrafted in each patient. Of the 30 patients who had sufficient follow-up to be evaluated, 29 (97%; 95% confidence interval [CI], 83 to 100) were free from vaso-occlusive crises for at least 12 consecutive months, and all 30 (100%; 95% CI, 88 to 100) were free from hospitalizations for vaso-occlusive crises for at least 12 consecutive months (P<0.001 for both comparisons against the null hypothesis of a 50% response). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No cancers occurred.ConclusionsTreatment with exa-cel eliminated vaso-occlusive crises in 97% of patients with sickle cell disease for a period of 12 months or more. (CLIMB SCD-121; ClinicalTrials.gov number, NCT03745287.).Copyright © 2024 Massachusetts Medical Society.

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