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

Area of Science:

• Immunology
• Hematology
• Pediatric Medicine

Background:

• Reduced intensity conditioning (RIC) is used for pediatric patients with inborn errors of immunity (IEI) undergoing allogeneic stem cell transplant (HCT).
• Optimizing RIC regimens to minimize toxicity and enhance immune reconstitution (IR) is crucial for improved patient outcomes.
• RIC regimens with strong immune ablation and low-dose alkylating agents may reduce conditioning-related toxicity and promote durable IR.

Purpose of the Study:

• To evaluate overall survival, event-free survival, toxicity rates, and immune reconstitution outcomes.
• To assess the efficacy of a specific RIC regimen (Bu2/Flu/rATG) in pediatric IEI patients.

Main Methods:

• Retrospective review of 73 pediatric IEI patients who received RIC HCT with busulfan, fludarabine, and rATG (Bu2/Flu/rATG) between 2000-2023.
• Comparison of outcomes between two cohorts based on busulfan target AUC (32mg/L*h vs. 40mg/L*h) and addition of thiotepa in cohort 2 for UCB transplants.
• Analysis of survival, toxicity (GVHD), graft failure, chimerism, and CD4+ immune reconstitution.

Main Results:

• 5-year overall survival was 80% for all IEI patients, with 83% for SCID and 77% for other IEI.
• 5-year event-free survival was significantly higher in cohort 2 (77%) compared to cohort 1 (44%).
• Graft failure occurred in 15% of patients; ≥grade 2 acute GVHD in 12%. At 1-year post-HCT, 87% achieved full T-cell chimerism and 89% showed CD4+ IR by day +100.

Conclusions:

• The busulfan (cumulative 40mg*h/L)/fludarabine/rATG RIC regimen demonstrates excellent overall and graft-failure-free survival in pediatric IEI patients.
• This regimen achieves high rates of early immune reconstitution and sustained donor chimerism.
• Low rates of GVHD and conditioning-related toxicity were observed, supporting its use in both SCID and non-SCID IEI populations.