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 & Marrow BMT Clinical Trials Network BMT-CTN 1507). Previously, we reported 2-year EFS of 88% in adults. Here-in we report the results in the pediatric stratum.

Study Design and Methods:

Eligibility: Children aged 5.00 – 14.99 years with prior stroke (silent or overt), abnormal transcranial Doppler cerebral arterial velocity ≥ 200 cm/sec with intracranial vasculopathy, recurrent severe acute chest syndrome (ACS), vaso-occlusive pain including recurrent priapism despite adequate supportive care and pulmonary hypertension were eligible. Participants were required to have an HLA-haploidentical first-degree relative bone marrow donor with 2, 3, or 4/8 HLA mismatches. The primary objective was to estimate EFS at 2 years after haploidentical-BMT. Secondary objectives included determining the effect of haploidentical-BMT on clinical and laboratory manifestations of SCD by 2 years post-BMT and the incidence of other BMT-related outcomes. The protocol was open for enrollment from 10/5/2017 to 12/2022, and data are current as of 5/21/2025. Treatment Description: Patients were preconditioned with hydroxyurea (HU) 30mg/kg/day (Day-70 to Day-10) followed by a conditioning regimen of Thymoglobulin (rATG), Thiotepa, fludarabine, Cyclophosphamide, and TBI (200 cGy). GVHD prophylaxis was PTCy, sirolimus, and mycophenolate mofetil.

Results: A total of 41 eligible participants were enrolled from 18 sites; 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.

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2025
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