Busulfan concentration and graft rejection in pediatric patients undergoing hematopoietic stem cell transplantation.
We retrospectively analyzed the relationship between busulfan average steady-state plasma concentration (C(SS)) and graft rejection in 53 children receiving busulfan/cyclophosphamide (BU/CY) preparative regimens prior to hematopoietic stem cell transplantation (HSCT). Patients received a total oral busulfan dose of 11 to 28 mg/kg followed by a total cyclophosphamide dose of 120 to 335 mg/kg in preparation for allogeneic grafts (HLA-matched or HLA partially matched sibling, parent or unrelated donor). Graft rejection occurred in eight (15%) patients. Busulfan C(SS) (P = 0.0024) was the only statistically significant predictor of rejection on univariate logistic regression analysis, with the risk of rejection decreasing with an increase in busulfan C(SS). Severe (grade 3 or 4) regimen-related toxicity (RRT) occurred in four patients. Ten patients (19%) had a busulfan C(SS) higher than 900 ng/ml, one of whom had severe RRT. Higher and variable doses of cyclophosphamide may explain the lack of a relationship between busulfan C(SS) and RRT in children. It may be possible to improve the outcome of HSCT in pediatric patients receiving the BU/CY regimen through optimization of busulfan C(SS) and better definition of the contribution of activated cyclophosphamide metabolites to toxicity.
Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
J S
JS
McCune
T
T
Gooley
J P
JP
Gibbs
J E
JE
Sanders
E W
EW
Petersdorf
F R
FR
Appelbaum
C
C
Anasetti
L
L
Risler
D
D
Sultan
J T
JT
Slattery
D000293:Adolescent; D000704:Analysis of Variance; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000633:toxicity; D002066:Busulfan / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage; D016903:Drug Monitoring; D005260:Female; D006084:Graft Rejection / Q000175:diagnosis*; D006402:Hematologic Diseases / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006648:Histocompatibility; D006801:Humans; D007223:Infant; D008297:Male; D011336:Probability; D011379:Prognosis; D012189:Retrospective Studies; D014184:Transplantation, Homologous / Q000009:adverse effects; D016896:Treatment Outcome
D003520:Cyclophosphamide; D002066:Busulfan