Conditioning Intensity and Outcomes in Pediatric HLA-Identical Transplant for Sickle Cell Disease: Comparison of MAC,...

Children with sickle cell disease (SCD) increasingly undergo HLA-identical sibling donor hematopoietic cell transplant (HCT), yet the optimal conditioning intensity remains uncertain. Myeloablative conditioning (MAC) has been the conventional approach, but reduced-intensity conditioning (RIC) and nonmyeloablative conditioning (NMA) may achieve cure with less toxicity.

Among pediatric patients with SCD undergoing HLA-identical HCT, to compare outcomes by conditioning intensity.

We evaluated all patients who underwent HLA-identical HCT for SCD at a single pediatric center from 2012-2025. Data were retrospectively collected for MAC and RIC recipients and prospectively collected for NMA recipients enrolled on two clinical trials (NCT03587272, NCT06358638).

Among 91 patients studied, 50 received busulfan-based MAC, 10 received alemtuzumab/fludarabine/melphalan ± thiotepa RIC, and 31 received alemtuzumab/300 cGy total body total body irradiation (TBI) ± daratumumab NMA. Compared with MAC and RIC, NMA recipients required significantly less supportive care, including markedly less use of patient-controlled analgesia, total parenteral nutrition, transfusions, and hospitalization. No NMA recipients developed the combined graft-versus-host disease (GVHD) endpoint (acute grade 2-4 or chronic GVHD), compared with 20% of MAC and 30% of RIC recipients. Graft failure occurred in only one patient (NMA), although eight patients (4 RIC and 4 NMA) underwent successful low-toxicity second HCT for declining donor myeloid chimerism to avert secondary graft failure. All four deaths occurred in the MAC group (8%). The proportion of patients alive without SCD at last follow-up in each group was: MAC 46/50 (92%), RIC 10/10 (100%), NMA 30/31 (96.8%). Post-HCT cardiac and pulmonary function were similar across groups, while ovarian reserve measured by anti-Müllerian hormone was significantly higher after NMA.

NMA conditioning with alemtuzumab and low-dose TBI substantially reduces toxicity compared with MAC and RIC. Although some patients require second HCT to improve donor engraftment, overall outcomes support this NMA approach as an option for children and adolescents with SCD.