The optimal busulfan exposure window in pediatric patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation remains to be defined. We identify this window for patients receiving busulfan within the prospective international, randomized controlled phase III ALLSCTped 2012 FORUM trial (NCT01949129). We included prospectively recruited participants receiving fludarabine-busulfan-thiotepa conditioning, with available busulfan plasma levels. Busulfan exposure was estimated using a validated pediatric population pharmacokinetic model. Primary outcomes were event-free survival (EFS) and graft-versus-host disease-free relapse-free survival (GRFS). Data from 145 patients aged between 0.5 and 19.5 years (treated from 2014 to 2022), with a median follow-up of 5.0 years (IQR 4.8-5.4) were analyzed. The optimal busulfan exposure was defined as cAUC 73.3-98.0 mg·h/L based on EFS and GRFS. Patients with non-optimal exposure had lower EFS (hazard ratio of event [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). Underexposure (cAUC <73.3 mg.h/L) was associated with higher relapse rates (HR 1.93, 95%CI 1.11-3.35, p=0.026), and overexposure (cAUC >98.0 mg.h/L) with an increased risk of treatment-related toxicities and GvHD. Patients with optimal busulfan exposure showed no differences in EFS, GRFS, overall survival or relapse with post-hoc matched total-body irradiation recipients (N=51 in each group). This study identifies a favorable busulfan exposure window for pediatric ALL patients undergoing HSCT from an HLA-matched donor. Therapeutic drug monitoring for optimized personalized busulfan dosing improves HSCT outcomes and might be validated for use as an alternative to irradiation.
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