Steroid Pre-Busulfan Based Reduced-Intensity Conditioning in Matched Related Hematopoietic Stem Cell Transplantation: Outcomes in Young and Adult Sickle Cell Disease Patients

Background: Sickle cell disease (SCD) is a complex genetic disorder causing significant morbidity and reduced life expectancy. Hematopoietic stem cell transplantation (HSCT) remains the only widely available curative option for SCD. However, its efficacy and safety in adult patients is still under-explored, as most studies focus on pediatric populations.

Methods: We retrospectively analyzed 115 consecutive SCD patients who underwent HLA-identical sibling HSCT between 2013 and 2023 at King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.

Procedures: Patients underwent 4 weeks pre-transplant conditioning regimen comprising alternate-day prednisone (0.5 mg/kg/day). This glucocorticoid therapy served dual purposes: attenuation of inflammatory processes via cytokine suppression and endothelial stabilization, coupled with mitigation of intravascular hemolysis. These preparatory measures aimed to optimize the recipient's status prior to HSCT.

All patients underwent a uniform reduced intensity conditioning (RIC) regimen comprising fludarabine, antithymocyte globulin and intravenous busulfan (Flu/r-ATG/IV-Bu). The protocol consisted of Flu (40 mg/m²/day, days -8 to -5), r-ATG (Thymoglobulin®, 2 mg/kg/day, days -7 to -5), and IV-Bu (0.8 mg/kg q6h, days -4 to -1; 14 doses total). Graft-versus-host disease (GVHD) prophylaxis utilized either Cyclosporine A/Methotrexate (57.4%, n=66) or Tacrolimus/Methotrexate (42.6%, n=49). Bone marrow served as the exclusive stem cell source for all transplantations.

Results: The majority 76.5% (n=88) were adults (≥18 years), with a median age of 23 years (range 14-43). This age distribution provides valuable data on HSCT outcomes across both adolescent and adult SCD populations, addressing a critical gap in the literature.

With a median follow-up of 12.5 months (range 0.7-60), we observed a remarkably high overall survival rate of 96.5% (111 out of 115 patients alive at last follow-up). Engraftment was robust across the cohort. The median time to neutrophil recovery (>500 × 10^9/L) was 16 days (range 9-30), and platelet recovery (>50 × 10^9/L) occurred at a median of 20 days (range 13-30).

The incidence of acute graft-versus-host disease (aGVHD) was 19.1% (n=22), while chronic GVHD (cGVHD) occurred in 10.4% (n=12). These rates are within acceptable ranges for allogeneic HSCT. The distribution of aGVHD grades was: Grade 1 in 6% (n=7), Grade 2 in 9.5% (n=11), Grade 3 in 1.7% (n=2), and Grade 4 in 1.7% (n=2).

Regimen-related toxicities were observed, with mucositis being the most common, affecting 74.8% of patients (n=86). Serious complications were relatively infrequent. Hemorrhagic cystitis and veno-occlusive disease were rare, each affecting only 0.9% of the cohort (1 patient each). Renal toxicity, as evidenced by elevated creatinine levels, was observed in 12.2% of patients (14 individuals).

Infection rates were notable, with CMV reactivation occurring in 63.5% of patients (n=73). Fungal infections were less common, affecting 3.5% of the cohort (n=4).

Conclusion: This large cohort study demonstrates remarkably high survival rates and acceptable toxicity profiles for HLA-identical sibling HSCT in SCD, particularly in adult patients using RIC. The overall survival rate of 96.5% at a median follow-up of 12.5 months surpasses many previously reported survival rates in SCD transplantation.

The favorable outcomes may be attributed, in part, to our pre-transplant conditioning regimen, which included a 4-week course of alternate-day prednisone. The use of bone marrow as the sole stem cell source aligns with current best practices in SCD transplantation and may have contributed to the relatively low incidence of chronic GVHD observed in our cohort.

While overall complication rates were low, the high incidence of CMV reactivation 63.5% (n=73) underscores the need for rigorous viral monitoring and pre-emptive therapy protocols in the post-transplant period. The recent approval of Letermovir for CMV prophylaxis is likely to decrease the risk of post-transplant CMV viremia.

These findings may significantly impact treatment paradigms for young and adult SCD patients, offering hope for a curative option to a broader patient population.