Association between busulfan exposure and outcome in children receiving intravenous busulfan before hematopoietic stem cell transplantation.
OBJECTIVE
Intravenous (IV) busulfan (Bu) combined with therapeutic drug monitoring-guided dosing is associated with better event-free survival (EFS), lower transplant-related mortality. But optimal target steady-state concentration (Css) of Bu in children undergoing hematopoietic stem cell transplantation (HSCT) remains unclear. This study aimed to evaluate the relation between Css of Bu and clinical outcomes in children receiving Bu before HSCT.


METHODS
This study includes 75 children receiving IV Bu in 16 doses, with first dose assigned based on age. Bu first-dose pharmacokinetic parameters were estimated from Bu plasma concentrations measured at 6 time points by high-performance liquid chromatography. Doses were adjusted at the fifth dose to a target Css of 600-900 ng/mL. Cumulative incidence of overall survival (OS), EFS, transplant-related mortality, acute graft-versus host disease (aGVHD), and other toxicities in relation to Css of Bu were analyzed using Kaplan-Meier curves in univariate and Cox's proportional hazards model in multivariate analysis.


RESULTS
After the first dose, median Css was 578 (325-1227) ng/mL. Forty-one patients had Bu IV dose increased by > 10%. Neutrophil and platelet recoveries, grade 2-4 aGVHD, and nonrelapse mortality (NRM) incidences were 90%, 91%, 12%, and 13%, respectively. Relapse incidence was 33%. Incidence of veno-occlusive disease, hemorrhagic cystitis, and lung toxicities were 13%, 24%, and 7%, respectively. OS and EFS were 70% and 58%. First-dose Bu Css >600 ng/mL was associated with a higher NRM (P < 0.001) and grade 2-4 aGVHD (P = 0.04), a lower EFS (P < 0.001), and OS (P = 0.001).


CONCLUSIONS
This study demonstrated a significant association between the first-dose pharmacokinetics of Bu and NRM, OS, and EFS. Bu therapeutic drug monitoring provides information that potentially influences outcomes of HSCT in pediatric patients.
*Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Canada; †Department of Pediatrics, Onco-Hematology Division, CHU Sainte-Justine, Montreal, Canada; ‡CANSEARCH Research Center, Faculty of Medicine, Geneva University, Geneva, Switzerland; §Clinical Pharmacology Unit, CHU Sainte-Justine Research Center, Montreal, Canada; ¶Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Canada; ‖Department of Pediatrics, Stem Cell Transplantation Unit, St Anna Children's Hospital, Vienna, Austria; **Department of Pediatrics Onco-Hematology Division, CHU Sainte-Justine Research Center, Montreal, Canada.
Marc
M
Ansari
Yves
Y
Théoret
Mohamed Aziz
MA
Rezgui
Christina
C
Peters
Samira
S
Mezziani
Catherine
C
Desjean
Marie-France
MF
Vachon
Martin A
MA
Champagne
Michel
M
Duval
Maja
M
Krajinovic
Henrique
H
Bittencourt
D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001800:Blood Specimen Collection; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D008297:Male; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D015996:Survival Rate; D013997:Time Factors; D019172:Transplantation Conditioning / Q000379:methods; D016896:Treatment Outcome; D055815:Young Adult
D018906:Antineoplastic Agents, Alkylating; D002066:Busulfan