Frangoul, H. and Locatelli, F. and Sharma, A. and Bhatia, M. and Mapara, M. and Molinari, L. and Wall, D. and Liem, R. I. and Telfer, P. and Shah, A. J. and Cavazzana, M. and Corbacioglu, Selim and Rondelli, D. and Meisel, R. and Dedeken, L. and Lobitz, S. and de Montalembert, M. and Steinberg, M. H. and Walters, M. C. and Eckrich, M. J. and Imren, S. and Bower, L. and Simard, C. and Zhou, W. and Xuan, F. and Morrow, P. K. and Hobbs, W. E. and Grupp, S. A. (2024) Exagamglogene Autotemcel for Severe Sickle Cell Disease. NEW ENGLAND JOURNAL OF MEDICINE, 390 (18). pp. 1649-1662. ISSN 0028-4793, 1533-4406
Full text not available from this repository. (Request a copy)Abstract
BACKGROUND Exagamglogene 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. METHODS We 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. RESULTS A 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. CONCLUSIONS Treatment with exa-cel eliminated vaso-occlusive crises in 97% of patients with sickle cell disease for a period of 12 months or more.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MARROW-TRANSPLANTATION; CHILDREN; BCL11A; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Pädiatrische Hämatologie, Onkologie und Stammzelltransplantation |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 18 Aug 2025 08:38 |
| Last Modified: | 18 Aug 2025 08:38 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65619 |
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