Optimizing outcomes and accessibility of matched sibling donor transplantation for severe hemoglobinopathies in low-resource settings

Abstract Allogenic HSCT remains the only curative approach for thalassemia major. We describe results of a cost-conscious and highly effective matched sibling transplantation strategy for thalassemia major and sickle cell disease. We retrospectively analyzed 113 patients who underwent matched sibling donor hematopoietic stem cell transplantation (HSCT) between February 2022 and June 2025 at two centers in India. The conditioning regimen included an initial course of fludarabine (Flu) 200 mg/m² and dexamethasone 125 mg/m² administered over 5 days. After a 3-week interval, patients received fludarabine 180 mg/m² over 6 days, oral busulfan (Bu) 14 mg/kg over 4 days, and intravenous cyclophosphamide (Cy) 200 mg/kg over 4 days. This was followed by infusion of granulocyte colony-stimulating factor (G-CSF)–primed bone marrow. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate (MTX). Out of 113 patients, the male to female ratio was approximately 2:1, with 74 and 39 males and 39 females, respectively. The median age at transplantation was 8.1 years (IQR 6–11; range, 2–16.5 years). The median time to neutrophil engraftment was 18 days (IQR 16–21), and for platelet engraftment, 20 days (IQR, 18–24). At a median follow-up of 12.2 months (IQR, 6–19), overall survival (OS) was 95.6%, thalassemia-free survival (TFS) was 93.9%, and graft-versus-host disease (GVHD)-free survival was 93.1%. Graft failure occurred in 2 patients (1.7%), and mixed chimerism was observed in 21 patients (18.5%). Acute GVHD grade ≥3 occurred in four patients (3.5%), while no patients developed moderate or severe chronic GVHD. 20 patients (17.6%) had Subclinical cytomegalovirus (CMV) reactivation, and CMV disease in 1 patient (0.8%). Veno-occlusive disease (VOD) developed in nine children (8%), all were managed with supportive care. Transplant-related mortality (TRM) was 4.4% (5 patients), with four deaths prior to engraftment: one due to intracranial hemorrhage and three due to septic shock and one death post-engraftment due to acute liver failure. The average total cost of this transplantation approach was approximately USD 9,600 per patient. Early results from our study demonstrate that very high GVHD-free and thalassemia/sickle cell disease-free survivals can be achieved in matched sibling transplantation with a cost-contained approach utilizing widely available drugs.