Refining busulfan exposure enhances pediatric ALL HSCT outcomes: insights from the International FORUM study
Year: 2026
Type: article
Abstract: 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.
Source: Blood Advances
Authors: Khalil Ben Hassine, Yvonne Gloor, Isabelle Dupanloup, Chakradhara Rao Satyanarayana Uppugunduri, Vid Mlakar, Fanny Gonzales, Tayfun Güngör, Marianne Ifversen, Peter J. Shaw, Jochen Buechner, Tony H. Truong, Henrique Bittencourt, Lochie Teague, Jacek Toporski, Petr Sedlacek, Ulrike Poetschger, Maja Krajinovic, Krzysztof Kałwak, Adriana Balduzzi, Mattia Algeri, Peter Bader, Christina Peters, Jean-Hugues Dalle, Marc Ansari
Institutions: University of Geneva, University Hospital of Geneva, Jawaharlal Institute of Post Graduate Medical Education and Research, University Children's Hospital Zurich, Copenhagen University Hospital, Rigshospitalet, Children's Hospital at Westmead, Oslo University Hospital, Alberta Children's Hospital, Centre Hospitalier Universitaire Sainte-Justine, Starship Children's Health, Karolinska University Hospital, University Hospital in Motol, St. Anna Children's Cancer Research Institute, Université de Montréal, University of Wrocław, Wroclaw Medical University, University of Milano-Bicocca, Bambino Gesù Children's Hospital, Goethe University Frankfurt, St Anna Children's Hospital, Université Paris Cité, Hôpital Robert-Debré
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
OpenAlex ID: W7133547147