To pursue gene therapy or not? Is it feasible after graft failure in allogeneic hematopoietic cell transplant recipients.

Two autologous hematopoietic stem cell (HSC)-based gene therapies (GTs) are now commercially available for severe sickle cell disease and transfusion-dependent β-thalassemia. However, the safety and efficacy of a subsequent autologous HSC-based GT after graft failure with a previous allogeneic hematopoietic cell transplant (HCT) remains unclear. Some individuals who have experienced a failed first attempt at a potentially curative therapy might seek a second opportunity for cure via GT. In this article, we discuss various factors related to patient and HSC health that may influence feasibility, and shared decision-making regarding whether an individual who has previously received an allogeneic HCT and experienced graft failure could consider an autologous GT. Exposure to chronic inflammatory stress and conditioning chemotherapy may compromise HSC fitness, reduce hematopoietic reserve, accelerate HSC aging, and promote the accumulation of deleterious genetic mutations, all of which may adversely affect the safety and efficacy of the GT.