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

Reduced intensity conditioning (RIC), haploidentical donors, and post-transplantation 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 SCD patients aged 2-70 undergoing BMT from November 2014 - January 2025. The regimen included anti-thymocyte globulin, fludarabine, cyclophosphamide, and single fraction 400 cGy TBI. Graft-vs-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. Forty-three patients (median age 23) were transplanted. Thirty-four (79%) had 2 indications for BMT and all had 2 SCD comorbidities. Five-year OS probability was 95.5% (CI 0.87 - 1.0) at a median follow-up of 2.43 years. DFS probability at 2 years was 94.5% (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 grades 3-4 acute GVHD was 2.4% (CI 0 - 0.07) and moderate-severe chronic GVHD was 7.3% (CI 0 - 0.15). Median time to discontinuation of immunosuppression was 354 days. Of the 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. NCT00489281