Autologous gene therapy versus allogeneic transplantation for sickle cell disease and transfusion-dependent β-thalassemia: Choosing between 2 definitive therapies.

Autologous hematopoietic stem and progenitor cell (HSPC) gene therapy and allogeneic hematopoietic cell transplantation (allo-HCT) can both provide durable hematologic and clinical correction for sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT). Allo-HCT has decades of follow-up and established rescue pathways, but outcomes depend on donor type, HLA matching, graft source, conditioning, and graft-versus-host disease (GVHD) prophylaxis. Gene therapy removes donor dependence, alloreactive graft rejection, and GVHD, but requires adequate HSPC collection, successful manufacturing and product release, myeloablative conditioning, and long-term genomic surveillance. In SCD, 29/30 efficacy-evaluable exagamglogene autotemcel recipients were free of severe vaso-occlusive crises for at least 12 consecutive months, and 28/32 efficacy-evaluable lovotibeglogene autotemcel recipients were free of vaso-occlusive events during months 6-18. In TDT, transfusion independence occurred in 32/35 efficacy-evaluable exagamglogene autotemcel recipients and 32/36 efficacy-evaluable betibeglogene autotemcel recipients. These percentages are conditional on reaching infusion and the prespecified assessment window. Among 1000 HLA-identical sibling HCT recipients with SCD, 5-year event-free survival was 91.4% and overall survival was 92.9%. In 823 prospectively studied patients with TDT, 2-year event-free survival was 97.2%, 92.9%, and 94.7% after matched-sibling, matched-unrelated, and haploidentical HCT. No randomized trial directly compares these platforms. Treatment selection should therefore compare the specific gene-therapy product with the available donor-graft-regimen option, accounting for disease urgency, organ reserve, conditioning exposure, time to treatment, fertility preservation, failure and rescue pathways, center-specific outcomes, and patient priorities.