Association of Busulfan Exposure with Event-Free Survival in a Chinese Pediatric Cohort: A Multicenter, Prospective Cohort Study

Purpose: Therapeutic drug monitoring-based individualized busulfan (Bu) administration improves hematopoietic stem cell transplantation (HSCT) outcomes, but optimal Bu exposure in Chinese pediatric patients remains unclear; we aim to identify the optimal exposure level of Bu in such patients receiving Bu-based conditioning regimens of different intensities. Patients and Methods: Pediatric patients from 5 transplant centers in China who received Bu-based myeloablative conditioning regimens were included. Bu exposure, defined as the area under the concentration–time curve (AUC), was estimated using a population pharmacokinetic model, including the first-dose AUC and cumulative AUC (cAUC). The primary and secondary outcomes included event-free survival (EFS) and transplantation-related complications. Restricted cubic splines and Cox proportional hazards models were used to analyze the exposure‒response relationships between the Bu AUC and outcomes. Results: A total of 455 pediatric patients were enrolled, with 326 receiving a 3-day Bu-based (Bu3) regimen and 129 receiving a 4-day Bu-based (Bu4) regimen. Among all patients, a first-dose Bu AUC ≥ 4.5 mg×h/L was associated with a significantly higher 2-year EFS compared with AUC < 4.5 mg×h/L (84.6% vs 76.4%; P = 0.02). In the Bu3 cohort, a cAUC < 54 mg×h/L was associated with a lower 2-year EFS rate (77.7% vs 86.4%; P =0.04). In the Bu4 cohort, a cAUC of 70– 90 mg×h/L was associated with a greater 2-year EFS rate (88.9%) than an exposure < 70 mg×h/L (71.0%; P = 0.03) or > 90 mg×h/L (66.1%; P = 0.04). Conclusion: This study demonstrated an association between Bu exposure and EFS in Chinese pediatric HSCT patients, with optimal cumulative AUC values of ≥ 54 mg×h/L and 70– 90 mg×h/L identified for the Bu3 and Bu4 regimens, respectively. Additionally, a first-dose Bu AUC ≥ 4.5 mg×h/L was associated with a favorable 2-year EFS. Keywords: busulfan, hematopoietic stem cell transplantation, pediatric patients, population pharmacokinetics, area under the concentration–time curve, event-free survival