Hematopoietic stem cell transplantation with reduced toxicity myeloablative conditioning regimen for children and adults with sickle cell disease: A brazilian single center experience.

Abstract Background: Sickle cell disease (SCD), characterized by vaso-occlusive crises, hemolysis, endothelial damage, and chronic inflammation, is the most common inherited monogenic disorder worldwide. The mortality rate among patients with SCD in Brazil remains high, despite improvements in treatment over the past decades. Allogeneic hematopoietic stem cell transplantation (HSCT) remains, to date, the only curative therapy available for both children and adults in Brazil. The best outcomes, with overall survival (OS) and event-free survival (EFS) rates of 90%-100%, are mainly achieved in children, using HLA-identical sibling donors and a myeloablative conditioning regimen. In adults and in patients with comorbidities, reduced intensity and non-myeloablative conditioning regimens have been used to minimize both early and late HSCT-related toxicity. This study aims to assess the clinical outcomes of HLA-identical sibling HSCT using a reduced toxicity myeloablative (RTM) conditioning regimen in children and adults with sickle cell disease. Methods: This is a single center, observational and retrospective analysis of 60 patients (30 children and 30 adults), who underwent HLA-identical sibling HSCT for SCD after a RTM conditioning regimen, between 2008 and 2025. The conditioning regimen consisted of fludarabine (120-150mg/m2, busulfan (9.6-12.8mg/kg) and ATG (4.5-10.0mg/kg). Methotrexate and cyclosporin were used as graft-versus-host disease (GVHD) prophylaxis. Data was collected from medical records. The primary endpoint was 2-year overall survival (OS). Secondary endpoints included 2-year EFS, defined as survival without death or graft failure, and graft-versus-host disease-free, relapse-free survival (GRFS), defined as survival without grade III-IV acute and chronic GVHD requiring immunosuppressive therapy, relapse, or death. Cumulative incidence (CI) of relapse and grade III-IV acute or chronic GVHD requiring immunosuppression were also analyzed, with death considered a competing event. Continuous variables were summarized as median (range), and categorical variables as percentages. OS, EFS, and GRFS probabilities were estimated using the Kaplan–Meier method and comparisons were performed using the log-rank test. Risk factors were studied using Cox regression models. Multivariate analyses were not performed due to the low number of events. The analysis was performed using R statistical software (version 4.4.1). P values were considered statistically significant. Results: The median age at HSCT was 15 years (range, 7-35 years); 53% were male; 80% had sickle cell anemia (HbSS); cerebrovascular disease was present in 58% of patients (77% in children) and 22% had a previous history of erythrocyte alloimmunization. Prior to HSCT, 36% of patients were receiving hydroxyurea and chronic transfusion therapy. Bone marrow was the progenitor stem cell source in 97% of the patients (the others received peripheral blood). The mean (DP) dose of total nucleated cells was 3.88 x 108/kg (±1.48); 60% of HSCT were isogroups in the ABO system and 65% of donors had sickle cell trait. Median (IIQ) follow-up of survivors was 73 (30-122) months. All patients engrafted, except one who died due to multiple organ failure resulting from complications associated with transfusion refractoriness (severe alloimmunization) at day+15, before the expected period of engraftment. At day+30 and 1 year post-HSCT, mixed chimera was observed in 84% and 79%, respectively. Two-year OS, EFS and GRFS were 93% (95% CI 86-100); 80% (95% CI 70-91); and 72% (95% CI 85-61), respectively, and were not different between children and adults. Patients with prior erythrocyte alloimmunization had worse OS than those without alloimmunization (p=0.01). Cumulative incidence of secondary graft failure, grade III-IV acute GVHD and chronic GVHD requiring immunosuppressive therapy at 2 years post-HSCT were 10%, 5% and 5%, respectively. Variables associated with inferior overall survival was erythrocyte alloimmunization, age of patient and donor at HSCT (hazard ratio HR, 9.39, p=0.007; HR, 1.10, p=0.045; HR, 1.07, p=0.046, respectively). Conclusion: HSCT with RTM conditioning regimen resulted in similar outcomes in both adult and pediatric populations and is a viable and safe treatment option for SCD treatment in adults and children.