Gene Therapies for Hemoglobinopathies: Efficacy, Cell Collection & Transfusion Support

Sickle cell disease (SCD) and transfusion dependent β-thalassemia (TDT) are complex disorders, often resulting in lifelong morbidity and reduced life expectancy. Allogeneic hematopoietic stem cell transplant (HSCT) is curative, with matched-related donor (MRD) transplant having the highest success. MRD availability is limited for both disorders, and HCT carries the risk of transplant-related complications, such as graft-versus-host disease (GHVD) and graft failure. Gene therapy (GT) offers an alternative curative option by modifying autologous hematopoietic stem and progenitor cells (HSPCs), making the treatment available to all, while eliminating the risk of GVHD. The U.S. Food and Drug Administration (FDA) has approved GTs for both SCD and TDT: lovotibeglogene autotemcel (Lyfgenia) and exagamglogene autotemcel (Casgevy) in 2023 for SCD and betibeglogene autotemcel (Zynteglo) in 2022 and exagamglogene autotemcel (Casgevy) in 2024 for TDT. This article appraises the studies the FDA approvals were based upon, with comments on transfusion and stem collection regimens. The latter aspects highlighting variability in practice and the need for additional studies to optimize pretransfusion regimens and the collection process for successful GT.