Bone marrow transplantation for sickle cell disease using posttransplantation cyclophosphamide and 400 cGy TBI

Reduced-intensity conditioning (RIC), haploidentical donors, and posttransplantation cyclophosphamide (PTCy) have overcome many barriers associated with bone marrow transplantation (BMT) for sickle cell disease (SCD). However, initial approaches had high graft failure rates. Our preliminary data suggested increasing the total body irradiation (TBI) dose from 200 to 400 cGy could improve engraftment. This study included patients with SCD aged 2 to 70 years undergoing BMT from November 2014 to January 2025. The regimen included antithymocyte globulin, fludarabine, cyclophosphamide, and single-fraction 400 cGy TBI. Graft-versus-host disease (GVHD) prophylaxis included PTCy, mycophenolate mofetil, and sirolimus. Outcomes measured were disease-free survival (DFS), graft failure, overall survival (OS), and GVHD incidence. A total of 43 patients (median age, 23 years) received a transplant; 34 (79%) had ≥2 indications for BMT, and all had ≥2 SCD comorbidities. Five-year OS probability was 95.5% (95% confidence interval [CI], 0.87-1.0) at a median follow-up of 2.43 years. DFS probability at 2 years was 94.5% (95% CI, 0.87-1.0), with only 2 (5%) graft failures. Two patients died late (2.5 and 6 years) after BMT. The cumulative incidence of grade 3/4 acute GVHD was 2.4% (95% CI, 0-0.07), and that of moderate-severe chronic GVHD was 7.3% (95% CI, 0-0.15). Median time to discontinuation of immunosuppression was 354 days. Of 27 female patients, 12 had return of menses and/or normalized gonadal function. RIC haploidentical BMT with 400 cGy maintained a low-toxicity profile, provides high rates of durable engraftment, and may preserve fertility. This regimen expands the availability of curative therapy for severe SCD. This trial was registered at www.ClinicalTrials.gov as NCT00489281.