Refining busulfan exposure enhances pediatric ALL HSCT outcomes: insights from the International FORUM study

Clinical Snapshot

Key Findings

• P Value: EFS p=0.008, GRFS p=0.002, relapse HR p=0.019

• Effect Size: Non-optimal busulfan exposure: HR 1.93 for EFS, HR 2.01 for GRFS

• Primary Outcome: Event-free survival (EFS) and graft-versus-host disease-free relapse-free survival (GRFS)

• Nnt Or Sensitivity: Optimal busulfan exposure window: cAUC 73.3-98.0 mg.h/L

• Confidence Interval: Not provided in abstract

Clinical Application

Requires therapeutic drug monitoring capabilities and pharmacokinetic expertise, available at Australian tertiary pediatric centres Relevant to Australian practice through ANZCHOG network; busulfan is PBS-listed for conditioning; TGA-approved indication; aligns with RACGP referral pathways to specialist centres Australian children and adolescents with ALL requiring allogeneic HSCT from matched donors, particularly relevant for major pediatric transplant centres

Abstract

The optimal busulfan exposure window in pediatric patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT) remains to be defined. We identify this window for patients receiving busulfan within the prospective international, randomized controlled phase 3 ALLSCTped 2012 FORUM trial. We included 145 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). Patients were aged between 0.5 and 19.5 years, with a median follow-up of 5.0 years. The optimal busulfan exposure was defined as area under busulfan concentration curve (cAUC) of 73.3 to 98.0 mg.h/L based on EFS and GRFS. Patients with nonoptimal exposure had lower EFS (hazard ratio [HR], 1.93; p = 0.008) and GRFS (HR, 2.01; p = 0.002). Underexposure (cAUC <73.3 mg.h/L) was associated with higher relapse rates (HR, 1.93; p = 0.019), and overexposure (cAUC >98.0 mg.h/L) with an increased risk of treatment-related toxicities and graft-versus-host disease. Patients with optimal busulfan exposure showed no differences in EFS, GRFS, overall survival, or relapse with post hoc matched total-body irradiation (TBI) recipients (n = 51 in each group). This study identifies a favorable busulfan exposure window for pediatric patients with ALL 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. This trial was registered at EudraCT as 2012-003032-22 and on www.ClinicalTrials.gov as NCT01949129.

References

1. 1.Ben Hassine, K., Gloor, Y., Dupanloup, I., Uppugunduri, C. R. S., Mlakar, V., Gonzales, F., Güngör, T., Ifversen, M., Shaw, P. J., Buechner, J., Truong, T. H., Bittencourt, H., Teague, L., Toporski, J., Sedlacek, P., Poetschger, U., Krajinovic, M., Kałwak, K., Balduzzi, A., Algeri, M., Bader, P., Peters, C., Dalle, J.-H., & Ansari, M. (2026). Refining busulfan exposure enhances pediatric ALL HSCT outcomes: insights from the International FORUM study. *Blood Advances*. https://doi.org/10.1182/bloodadvances.2025019142