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Refining busulfan exposure enhances pediatric ALL HSCT outcomes: insights from the International FORUM study
Khalil Ben Hassine1, Yvonne Sylvia Gloor2, Isabelle Dupanloup2
1Division of Pediatric Oncology and Hematology, Department of Women, Child and Adolescent, Geneva University Hospitals, Geneva, Switzerland.
Insights
Defining the optimal busulfan exposure window is crucial for pediatric acute lymphoblastic leukemia patients undergoing stem cell transplantation. This study identified a target busulfan exposure range (73.3-98.0 mg·h/L) to improve event-free and graft-versus-host disease-free relapse-free survival.
Area of Science:
- Hematology
- Pediatric Oncology
- Pharmacology
Background:
- Optimal busulfan exposure for pediatric acute lymphoblastic leukemia (ALL) patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) is not well-defined.
- Busulfan is a key component of conditioning regimens, and its exposure levels significantly impact treatment outcomes.
Purpose of the Study:
- To identify the optimal busulfan exposure window in pediatric patients with ALL receiving fludarabine-busulfan-thiotepa conditioning during HSCT.
- To evaluate the impact of busulfan exposure on event-free survival (EFS) and graft-versus-host disease-free relapse-free survival (GRFS).
Main Methods:
- Analysis of data from 145 pediatric patients in the ALLSCTped 2012 FORUM trial (NCT01949129).
- Busulfan exposure was estimated using a validated pediatric population pharmacokinetic model.
- Primary outcomes (EFS and GRFS) were analyzed in relation to busulfan area under the curve (cAUC).
Main Results:
- The optimal busulfan exposure window was determined to be cAUC 73.3-98.0 mg·h/L.
- Non-optimal busulfan exposure was associated with significantly lower EFS (HR 1.93) and GRFS (HR 2.01).
- Underexposure correlated with higher relapse rates, while overexposure increased toxicity and GvHD risk.
Conclusions:
- This study establishes a favorable busulfan exposure window for pediatric ALL patients undergoing HSCT.
- Therapeutic drug monitoring for personalized busulfan dosing can optimize HSCT outcomes.
- Optimized busulfan dosing may serve as an alternative to total-body irradiation in HSCT.
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.
