Reduced-Intensity Haploidentical Bone Marrow Transplantation in Children with Severe Sickle Cell Disease: BMT CTN 1507

This is a multi-center, single-arm, phase-II, trial (NCT03263559) of haploidentical bone marrow transplant (BMT) for children with severe sickle cell disease (SCD). Eligible participants were children 5.00 - 14.99 years of age with stroke (silent or overt), abnormal transcranial Doppler cerebral arterial velocity > 200 cm/sec with intracranial vasculopathy, severe acute chest syndrome (ACS) or recurrent vaso-occlusive pain. The primary outcome was 2-year event-free survival (EFS; alive and disease-free). The transplant regimen included hydroxyurea 30mg/kg/day (Day-60 to Day-10), followed by thymoglobulin, thiotepa, fludarabine, cyclophosphamide, and total body irradiation (200 cGy). Graft-versus-host disease (GVHD) prophylaxis included post-transplant cyclophosphamide (PTCy), sirolimus and mycophenolate mofetil. Forty-one participants were enrolled from 18 sites and 95% (39/41) proceeded to BMT. The median age at enrollment was 12.5 years; 98% (38/39) had hemoglobin SS disease, and 82.1% (32/39) had donors mismatched at 4 HLA-loci. The most common indication for BMT was a qualifying neurological event in 69% (27/39), including 15 with overt stroke. Nine participants had recurrent vaso-occlusive pain and 5, severe ACS. The 2-year EFS and overall survival were 79.3% (95% CI: 62.8%, 89.1) and 94.5% (95% CI: 79.7%, 98.6%), respectively. FEV1% predicted increased from 79.5 to 95.7 at 2 years (p=0.014), and eGFR declined from 174 to 127 mL/min/1.73m2 (p<0.001), indicating resolved hyperfiltration. No new or progressive cerebral infacts were detected by serial brain MRI per central adjudication (n=22). While graft failure and GVHD negatively impacted EFS, reduced-intensity haploidentical BMT with PTCy is a promising therapy for children who lack a matched sibling donor.