title: Association between busulfan exposure and outcome in children receiving intravenous busulfan before hematologic stem cell transplantation.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacy of University Medical Center Utrecht, Utrecht, The Netherlands. i.bartelink@umcutrecht.nl
authors.forename: Imke H
authors.initials: IH
authors.lastname: Bartelink
authors.forename: Robert G M
authors.initials: RG
authors.lastname: Bredius
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Belitser
authors.forename: Marit M
authors.initials: MM
authors.lastname: Suttorp
authors.forename: Marc
authors.initials: M
authors.lastname: Bierings
authors.forename: Catherijne A J
authors.initials: CA
authors.lastname: Knibbe
authors.forename: Maarten
authors.initials: M
authors.lastname: Egeler
authors.forename: Arjan C
authors.initials: AC
authors.lastname: Lankester
authors.forename: Atoine C G
authors.initials: AC
authors.lastname: Egberts
authors.forename: Juliette
authors.initials: J
authors.lastname: Zwaveling
authors.forename: Jaap Jan
authors.initials: JJ
authors.lastname: Boelens
mesh_terms: D000293:Adolescent; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage / Q000633:toxicity*; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D006086:Graft vs Host Disease / Q000139:chemically induced; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods / Q000401:mortality*; D006801:Humans; D015994:Incidence; D007223:Infant; D008558:Melphalan / Q000633:toxicity; D052016:Mucositis / Q000139:chemically induced; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D002066:Busulfan; D008558:Melphalan