Busulfan exposure and allo-HSCT outcomes in pediatric ALL

An analysis evaluating the optimal busulfan exposure window in pediatric patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT; N = 145) was published in Blood Advances by Ben Hassine et al. Busulfan-treated patients with high-risk or relapsed ALL enrolled in the phase III FORUM trial (NCT01949129) and its pharmacogenetic add-on study (NCT02670564) were included. Patients received fludarabine + busulfan + thiotepa conditioning. The primary outcomes were event-free survival (EFS) and graft-versus-host disease-free relapse-free survival (GRFS). 

Key data: With a median follow-up of 5 years, based on EFS and GRFS data, the optimal busulfan exposure window was defined as a cumulative area under the concentration curve (cAUC) of 73.3–98.0 mg.h/L. Patients who received non-optimal busulfan exposure (<73.3 or >98.0 mg.h/L) had a lower EFS (hazard ratio [HR], 1.93; 95% confidence interval [CI], 1.19–3.14; p = 0.008) and GRFS (HR, 2.01; 95% CI, 1.29–3.13; p = 0.002) vs those who had optimal exposure. Underexposure was associated with higher relapse rates (HR, 1.93; 95% CI, 1.11–3.35; p = 0.026), while overexposure was associated with increased cumulative treatment-related toxicities and extensive chronic graft-versus-host disease (cGvHD). In a post hoc matched analysis (n = 51 per group), outcomes were comparable between optimally exposed patients and those receiving total-body irradiation (TBI). 

Key learning: An optimal busulfan exposure window was identified and associated with improved post-allo-HSCT outcomes in pediatric patients with ALL, supporting exposure-guided conditioning and highlighting chemotherapy-based conditioning as a potential alternative to TBI for selected patients.