Background Conditioning regimens are crucial in allogeneic hematopoietic stem cell transplantation (allo-HSCT), especially for older patients (≥7 years) with transfusion-dependent thalassemia (TDT) recieving haplo indentical transplantation (HID). The development of low-toxicity conditioning yet myeloablative regimens is essential to address the dual challenges of high graft rejection rates and transplant-related mortality.

Objective This study aimed to evaluate the efficacy and safety of the F-BMT conditionig regimen in improving allo-HSCT outcomes for TDT patients, especially for older patients with HID transplantation .

Methods This prospective, multicenter clinical trial was conducted at 923rd Hospital of the Joint Logistics Support Force, the First Affiliated Hospital of Guilin Medical University, and the Eighth Affiliated Hospital of Southern Medical University.Patients with TDT aged 3–25 years were enrolled. The F-BMT regimen included fludarabine 30 mg/m² (days –7 to –2), busulfan 130 mg/m² (day –7), thiotepa 250 mg/m² (day –5), melphalan 100 mg/m² (day –3). For graft versus host disease (GVHD) prentation, porcine anti-human lymphocyte immunoglobulin (p-ALG) (25 mg/kg) or antithymocyte globulin (r-ATG) (2.5 mg/kg ) on days –1, cyclophosphamide 25 mg/kg (days +3 and +4)，methotrexate 5 mg/m² (day +5), cyclosporine (initiated on day +5, continued for 12 months). For HID donors, additional agents were administered: p-ALG (25 mg/kg ) or r-ATG (2 mg/kg) on day day +5, ruxolitinib (days +5 to +28). The primary endpoint was 1-year thalassemia-free survival (TFS). (ChiCTR2300077054)

Results From June 2023 to May 2025, 91 patients were enrolled. The median age was 10.0 years (range: 4-19 years), among them 76 patients aged ≥7y, and 63 patients with HID donors. With a median follow-up duration of 12 months (range: 3-25 months). 1-year TFS was 94.24%, 1-year overall survival (OS) was 96.44%.Two patients (2.2%) died from severe pneumonia or sepsis. The remaining 89 patients achieved both neutrophil and platelet engraftment within 28 days post-transplantation, with full donor chimerism. One patient experienced secondary graft failure due to infection, and one patient had primary graft failure. Both of these patients underwent secondary transplantation with successful engraftment.The engraftment rate by day +28 post-transplantation was 97.78%. The mean time to neutrophil engraftment was 13.7 ± 1.5 days, and the mean time to platelet engraftment was 13.1 ± 3.9 days.

By day +100 post-transplantation, the cumulative incidence of grade II-IV aGVHD was 7.1%, with only 4.4% (n=4) of patients developing grade III-IV aGVHD. Grade 1-2 hemorrhagic cystitis (HC) occurred in 3.3% (n=3) of patients. Viral reactivation was observed in 26% (n=24) of patients, including Cytomegalovirus (CMV) reactivation in 18 patients and Epstein-Barr virus (EBV) reactivation in 8 patients; 2 of these patients had concurrent CMV and EBV reactivation.Infections occurred in 12% (n=11) of patients within the first 3 months post-transplantation, including bacteremia in 11% (n=10). One patient developed posterior reversible encephalopathy syndrome (PRES), one had an invasive fungal infection, and two patients developed veno-occlusive disease (VOD). Post-transplant lymphoproliferative disorder (PTLD) was diagnosed in one patient and was cured after Rituximab injection.. Chronic graft-versus-host disease (cGVHD) occurred in 8.9% (6 cases) of evaluable patients, involving the pulmonary and hepatic systems, with all cases rated as moderate; all cases were cured with appropriate therapy. No cases of thrombotic microangiopathy (TMA) were observed.

Conclusion This study demonstrates that the F-BMT conditioning regimen followed by HSCT represents a low-toxicity protocol with significant efficacy and safety in TDT patients, even in older patients with HID donors.

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2025
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