Nonmyeloablative HLA-identical sibling transplant for sickle cell disease in children: a multicenter prospective study

ABSTRACT: HLA-identical sibling donor hematopoietic cell transplant (HCT) is an established curative therapy for sickle cell disease (SCD). Although myeloablative HCT conditioning achieves a high event-free survival (EFS) in children, it carries substantial toxicity, including risks of graft-versus-host disease (GVHD), transplant-related mortality, and infertility. Nonmyeloablative conditioning with alemtuzumab, 300 cGy total body irradiation, and sirolimus has demonstrated tolerability as a curative approach in adults with SCD. We conducted a multicenter, prospective clinical trial to evaluate this regimen in children and adolescents with SCD. Thirty-eight patients (aged 2.9-21.9 years; median age, 13.5 years) underwent HCT. All achieved initial engraftment; however, 7 patients (18.4%) experienced secondary graft failure between day +39 and day +391 with autologous hematologic reconstitution. One additional patient received an unconditioned second HCT. At 2 years after HCT, overall survival was 100%, and EFS was 78.9%. Among patients with engraftment, 2-year median donor myeloid chimerism was 95%, and T-cell chimerism was 75%. No patients developed acute or chronic GVHD. The median number of platelet transfusions received was 0 (interquartile range, 0-3). Patient-reported health-related quality of life remained stable early after HCT and significantly improved at 1 year. After year 2, 3 additional patients received a reduced-intensity second HCT to avert secondary graft failure. Although regimen modifications are needed to reduce graft failure risk, this nonmyeloablative approach offers a relatively low-toxicity curative option for children with SCD who have an HLA-identical sibling donor. This trial was registered at www.clinicaltrials.gov as NCT03587272.