Informed shared decision-making or rigid eligibility and exclusion criteria for gene therapy for sickle cell disease?

Hematopoietic cell transplant (HCT) for sickle cell disease from human leukocyte antigen (HLA)-identical sibling and alternate donors is associated with excellent outcomes. HCT was implemented under restrictive eligibility and exclusion criteria because mortality was >10% in the early experience. These restrictive criteria were carried over to contemporary HCT and gene therapy (GT) clinical trials. Additionally, patients with chronic pain, stroke, psychiatric disorders, or adherence issues were excluded from GT trials. The United States Food and Drug Administration qualification of GT broadly identifies recurrent vaso-occlusive episodes (VOE) as the indication and stipulates no exclusion criteria, thus raising the question of which criteria to use in clinical GT. Excellent overall and event-free survival, improvement in health-related quality of life, amelioration of VOE, and stabilization of cerebral vasculopathy following HLA-identical sibling donor HCT and GT justify broad application of GT in patients with a history of severe VOE, with shared decision-making guided by patient preferences while acknowledging gaps in evidence.