Excellent Long-Term Survival and Immune Recovery With Reduced-Intensity Conditioning HCT in Inborn Errors of Immunity

Reduced intensity conditioning (RIC) for pediatric patients with inborn errors of immunity (IEI) receiving allogeneic stem cell transplant (HCT) has improved outcomes, though the ideal regimen to minimize toxicity and optimize immune reconstitution (IR) remains unclear. RIC regimens with strong immune-ablation and low-dose alkylating agents offer an alternative that may reduce conditioning-related toxicity and lead to durable immune reconstitution. We aimed to determine the outcomes including overall survival, event free survival, rates of toxicity, and IR outcomes for patients with IEI receiving RIC HCT at our institution. We reviewed survival, toxicity, and IR outcomes for patients with IEI receiving RIC HCT with targeted busulfan (2 days), fludarabine 180mg/m2, and rATG 8mg/kg (Bu2/Flu/rATG). Prior to 2007, busulfan target cumulative AUC was 32mg/L*h (cohort 1). Given high observed rates of graft failure, busulfan target was increased to 40mg/L*h and thiotepa was added in cord blood (UCB) transplants from 2008 to 2023 (cohort 2). Between 2000 and 2023, 73 patients received Bu2/Flu/rATG conditioning. Five-year OS was 80%, 83% for SCID, and 77% for other IEI. For SCID, 5-year OS was lower for UCB recipients compared to PBSC - 58% vs 96% (P = .002). Patients in cohort 1 experienced lower 5-year EFS - 44% vs 77% in cohort 2 (P = .02). Graft failure was seen in 11 patients (15%). Incidence of ≥grade 2 acute GVHD was 12%. At 1-year post-HCT, 87% of patients with evaluable data maintained full T-cell chimerism, with 80% demonstrating myeloid chimerism >50%. CD4⁺ IR by day +100 was seen in 89% of patients. We demonstrate excellent overall and graft-failure free survival in patients with IEI receiving a busulfan (cumulative 40mg*h/L)/fludarabine/rATG RIC regimen with high rates of early IR and sustained donor chimerism in both SCID and non-SCID IEI populations while maintaining low rates of GVHD and conditioning-related toxicity.