Busulfan, combined with therapeutic drug monitoring-guided dosing, is associated with higher event-free survival (EFS) rates due to fewer graft failures/relapses and lower toxicity. The optimal target area under the curve (AUC) and dosing schedule of intravenous
busulfan in children undergoing
hematopoietic stem cell transplantation (HSCT) remain unclear, however. We conducted a retrospective analysis of the association between
busulfan exposure and clinical outcome in 102 children age 0.2 to 21 years who received
busulfan 1 or 4 times daily before undergoing HSCT (46 malignant and 56 nonmalignant indications). EFS and overall survival after a median of 2 years of follow-up were 68% and 72%, respectively. EFS was optimal when the exposure of
busulfan (AUC) was 78 mg x h/L (95% confidence interval=74 to 82 mg x h/L). Acute
graft-versus-host disease (aGVHD) grade II-IV occurred more frequently with greater
busulfan exposure. The addition of
melphalan was an independent risk factor;
melphalan use combined with high
busulfan exposure (AUC >74 mg x h/L) was associated with high incidences of aGVHD (58%), veno-occlusive disease (66%), and
mucositis grade III-IV (26%). Dosing frequency (1 or 4 times daily) was not related to any outcome. In conclusion, dose targeting of
busulfan to a narrow therapeutic range was found to increase EFS in children. Adding
melphalan to optimal
busulfan exposure is associated with a high incidence of toxicity.