Risk-Stratified Pretransplant Immunosuppressive Strategy Improves Outcomes of Unrelated Cord Blood Transplantation in Pediatric β-Thalassemia Major.

Unrelated umbilical cord blood transplantation (UD-UCBT) is a curative option for children with β-thalassemia major (β-TM) who lack HLA-matched sibling donors. However, challenges such as low CD34+ cell dose, pre-existing immune activation, and iron overload contribute to poor engraftment and high transplant-related mortality (TRM) in high-risk patients. To evaluate the safety and efficacy of a novel 5-factor risk-stratified pretransplant immunosuppressive strategy, combined with a myeloablative conditioning regimen featuring "early" reduced-dose anti-thymocyte globulin (ATG), in improving transplant outcomes and immune reconstitution in pediatric patients undergoing UD-UCBT for β-TM. In this single-center retrospective study, 30 pediatric patients with β-thalassemia major underwent single-unit unrelated umbilical cord blood transplantation (UD-UCBT) between September 2019 and December 2024. Patients were stratified into low-, intermediate-, and high-risk groups using a novel 5-factor scoring system incorporating age, serum ferritin, liver size, spleen size, and planned CD34+ cell dose. Intermediate- and high-risk patients received one or 2 cycles of pretransplant immunosuppressive therapy (PTIS; fludarabine and dexamethasone), followed by a myeloablative conditioning regimen with upfront low-dose ATG. Outcomes between PTIS and non-PTIS groups were compared using Fisher's exact tests, Mann-Whitney U tests, Kaplan-Meier survival analysis with log-rank tests, and linear mixed-effects models for immune reconstitution. All patients achieved engraftment without primary and secondary graft failure. The 3-yr overall survival (OS) and thalassemia-free survival (TFS) were both 94.4%, with 100% OS in the PTIS group. The cumulative incidence of grade II-IV acute GVHD by d 100 was 31.2%, and grade III-IV acute GVHD was 8.4%. Chronic GVHD occurred in 23.3% of patients, all limited type. Pulmonary infections were significantly lower in the PTIS group (27.8% versus 83.3%, P = .008). PTIS-treated patients demonstrated superior CD3+CD8+ T-cell and CD19+ B-cell recovery at 6 to 12 months post-transplant. This risk-stratified approach combining PTIS with a "early" reduced-dose ATG conditioning was safe, well-tolerated, and associated with excellent survival, engraftment, and immune reconstitution outcomes. It offers a promising strategy to improve the prognosis of high-risk pediatric β-TM patients undergoing UD-UCBT.