Nonmyeloablative and reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation in sickle cell disease: a narrative review of safety, engraftment, and graft-versus-host-disease outcomes in adults and high-risk populations.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only widely available cure for sickle cell disease (SCD), yet its use in adults has historically been limited by transplant-related toxicity. Non-myeloablative (NMA) and reduced-intensity conditioning (RIC) regimens have addressed this by maintaining durable engraftment at considerably lower risk. The NIH NMA protocol, alemtuzumab plus 300 cGy total body irradiation, achieves overall survival (OS) above 90% in matched sibling transplants, with no chronic graft-versus-host disease (GVHD) and preserved fertility. Haploidentical transplantation has likewise matured; a thiotepa-based regimen with post-transplant cyclophosphamide (PTCy) yielded 2-year OS of 95% and graft failure of just 7% in a phase 2 multicenter trial, with mixed donor chimerism of at least 20% myeloid cells sufficient for phenotypic cure. Chronic GVHD incidence differs across platforms, from 0% with NMA conditioning, 13-22% with RIC, to 22% in the haploidentical plus PTCy setting, and non-relapse mortality follows a similar pattern at 0-5% and 5-10% across these groups. Survivors report meaningful improvements in quality of life, though infectious complications and secondary malignancies continue to warrant close follow-up. Taken together, the data support NMA and RIC transplantation as genuinely curative options carrying an acceptable risk profile for adults living with SCD, and advances in haploidentical conditioning have largely put to rest the graft failure rates that once made unrelated or mismatched transplantation prohibitive. How to best target chimerism levels, reduce late toxicity, and weigh transplant against the rapidly advancing field of gene therapy are questions the field has yet to fully resolve.