Refining Busulfan Exposure Enhances Pediatric ALL HSCT Outcomes: Insights from the International FORUM Study

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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Journal
Blood Advances
Published
2026-03-04
DOI
https://doi.org/10.1182/bloodadvances.2025019142
Primary Topic
Acute Lymphoblastic Leukemia research
Type
article
Field-Weighted Citation Impact
0.00

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article

Refining Busulfan Exposure Enhances Pediatric ALL HSCT Outcomes: Insights from the International FORUM Study

Jean‐Hugues Dalle, Lochie Teague, Tony H. Truong, Maja Krajinović et al.
Blood Advances
Acute Lymphoblastic Leukemia research
article

Refining Busulfan Exposure Enhances Pediatric ALL HSCT Outcomes: Insights from the International FORUM Study

Jean‐Hugues Dalle, Lochie Teague, Tony H. Truong, Maja Krajinović, Khalil Ben Hassine, Jochen Buechner, Fanny Gonzales, Vid Mlakar, Jacek Toporski, Chakradhara Rao Uppugunduri Satyanarayana, Marianne Ifversen, Adriana Balduzzi, T Güngör, Isabelle Dupanloup, Petr Sedláček, Ulrike Pöetschger, Marc Ansari, Krzysztof Kalwak, Yvonne Sylvia Gloor, Christina Peters, Peter Bader, Henrique Bittencourt, Peter J. Shaw, Mattia Algeri
article en

Abstract

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.

Blood Advances
Goethe University Frankfurt (DE), University of Geneva (CH), Oslo University Hospital (NO), Karolinska University Hospital (SE), Alberta Children's Hospital (CA), Centre Hospitalier Universitaire Sainte-Justine (CA), Children's Hospital at Westmead (AU), Copenhagen University Hospital (DK), Rigshospitalet (DK), Magna Graecia University (IT), Wroclaw Medical University (PL), Hôpital Beau-Séjour (CH), University Hospital in Motol (CZ), University Hospital of Geneva (CH), Bambino Gesù Children's Hospital (IT), St Anna Children's Hospital (AT), Hôpital Robert-Debré (FR), University Children's Hospital Zurich (CH), Starship Children's Health (NZ), Jawaharlal Institute of Post Graduate Medical Education and Research (IN), University of Milano-Bicocca (IT)
National Science Foundation, Cancer Research Institute, Amgen, Pfizer, Sanofi, Teva Pharmaceutical Industries, Jazz Pharmaceuticals, Les Laboratories Pierre Fabre, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Novo Nordisk, Medac
Partnerships for the goals
Openalex Percentile: Top 38%
Acute Lymphoblastic Leukemia research
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