Beyond One-Size-Fits-All: Risk-Adapted Transplant Strategies for Children with Hemoglobinopathies

Hematopoietic cell transplantation (HCT) is the only curative treatment currently available for thalassemia major (TM). A risk-adaptive treatment approach using reduced-intensity conditioning (RIC) prior to HCT in high-risk TM patients results in fewer complications compared to myeloablative conditioning (MAC) regimens. Retrospective review of HCTs for hemoglobinopathies between Jan2003 and June 2024, which describes patients’ and HSCT characteristics and outcomes. Out of 1,246 HCTs, HCTs from HLA-identical related donors for hemoglobinopathies accounted for 19% (n=237). Of these, 196 (16%) patients received HCT for thalassemia major, and 14 (1%) for sickle cell disease (SCD), with a median follow-up of 7.39 months. The median age at HCT was 11 years (range: 1–31 years). Females comprised 52% (n=110) of the patients. Reduced-intensity HCTs (RICs) constituted 64% of the transplants (n=125 for thalassemia major and n=10 for SCD). High-risk thalassemia major accounted for the majority of RIC transplants (63%, n=124), with 45% (n=69) classified as Pesaro class II and 35% (n=55) as class III. The RIC regimen included busulfan, fludarabine, TLI (500 cGy), and ATG, followed by PBSCTs. GVHD prophylaxis consisted of MMF and CSA. The median infused CD34+ cell dose was 7.7 × 10⁶/kg. All patients achieved neutrophil and platelet engraftment, with a median time of 15 days (range: 13–18 days) for neutrophils and 19 days (range: 16–28 days) for platelets. Persistent mixed donor and full donor chimerism were observed in 50% of HCTs each. Immune-suppressive therapy for GVHD treatment was required in 21% of patients. Sinusoidal occlusive syndrome occurred in 12% (n=24) of HCTs, with all cases recovering completely. Secondary graft failure was observed in 16% (n=32) of HCTs. The 5-year overall survival rate was 98%, while the 5-year probability of disease-free survival was 82%. Employing risk adaptive approach using RIC conditioning regimens HCT for high risk hemoglobinopathies demonstrates safety and efficacy and are associated with excellent engraftment and sustained donor chimerism; and leads to excellent disease- free and overall survival rates.