Abstract Background: Allogeneic hematopoietic stem-cell transplantation has curative potential for sickle cell disease (SCD). Event-free survival (EFS) in children with SCD is 90% after a bone marrow transplant (BMT) from a matched sibling donor (MSD) using myeloablative conditioning, however 15% of patients with SCD have a MSD. We tested a novel reduced intensity conditioning regimen, post-BMT cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis, and haplo-identical BMT in adults and children with severe SCD in a multi-center single-arm, phase-II, prospective clinical trial (NCT03263559 or Blood 39 (95%) proceeded to BMT. The participants had Hb SS genotype (83%), were male (56.4%) and primarily Black (92.3%), with a median age that was 12.5 years at enrollment and transplanted from donors with 4/8 HLA-mismatches (82%). Five were lost to follow-up. Patients could satisfy more than one eligibility criterion: neurological criteria (n=37) were most common overt stroke (18), silent stroke (10), TCD elevation (9), followed by recurrent vaso-occlusive pain episodes (10) and acute chest syndrome (10). The 2-year EFS after BMT was 79.3% (95% CI: 62.8%, 89.1%) and 2-year OS post-BMT was 94.5% (95% CI: 79.7%, 98.6%). All qualifying events occurred within 15 months after BMT. The median time to neutrophil and platelet engraftment was 22 and 31 days, respectively. Graft failure occurred in 6 patients (15.4%) and was primary in 2 patients, and secondary in 4 patients; SCD recurred in these patients. The 2-year disease recurrence was 15.4% (95% CI 6.2% - 28.5%). Day-100 grade II-IV acute GVHD was 15.5% (95% CI: 6.2%, 28.7%), and grade III-IV ,was 5.2% (95% CI: 0.9%, 15.5%). The 2-year cGVHD incidence was 30.6% (CI: 16.3%, 46.1%); 6/31 patients were receiving immunosuppressive treatment 2 years after BMT. There were two deaths; one from adenovirus at 6 months post-BMT and the other from mucormycosis at 14 months post-BMT. Both infections occurred during treatment for cGVHD. A total of 62 severe infections were recorded among 23 (59.0%) participants; most infections were bacterial (n=25) or viral (n=33). Approximately half of infections (29 of 62) developed within 100 days of BMT.Conclusion: The results of this multi-center phase-II trial of a reduced intensity haploidentical-BMT for severe SCD show durable donor engraftment in most patients and mortality was low. Graft failure trended higher in children compared with adults with severe SCD treated by a similar approach (NEJM Evid. 2025 Mar;4(3):EVIDoa2400192). These data lend support for reduced intensity haploidentical BMT in the absence of an MSD. However, graft failure and GVHD negatively impacted EFS and novel strategies to address these risks should be developed.
Mendizabal et al. (Mon,) studied this question.