title: High busulfan exposure is associated with worse outcomes in a daily i.v. busulfan and fludarabine allogeneic transplant regimen.
abstract: Low plasma busulfan (Bu) area under the concentration-time curve (AUC) is associated with graft failure and relapsed leukemias, and high AUC with toxicities when Bu is used orally or i.v. 4 times daily combined with cyclophosphamide in myeloablative hematopoietic stem cell transplantation (SCT) conditioning regimens. We report Bu AUC and its association with clinical outcomes in 130 patients with hematologic malignancies given a once-daily i.v. Bu (3.2 mg/kg days -5 to -2) and fludarabine (Flu, 50 mg/m(2) days -6 to -2) regimen. Total-body irradiation (TBI) 200 cGy x 2 was added for 51 patients with acute leukemias. Plasma AUC varied 3.6-fold (2184-7794 microM.min, median 4699 microM.min). Patients with an AUC >6000 microM.min had lower overall survival (OS) than those with AUC < or =6000 microM.min at 12 months (38% versus 74%) and 36 months (23% versus 68%, P < .001). This effect was apparent in patients with standard-risk and high-risk disease, and persisted when potential confounders were considered (hazard ratio 3.2, 95% confidence interval 1.7-6.3). Nonrelapse mortality (NRM) at 100 days (6% versus 19%) and progression free survival (PFS; 58% versus 16%) at 3 years were better with AUC < or =6000 microM.min. These data support a role for therapeutic dose monitoring and dose adjustment with daily i.v. busulfan.
authors.affiliation: Division of Hematology and Hematologic Malignancy, University of Calgary, Calgary, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Geddes
authors.forename: S Bill
authors.initials: SB
authors.lastname: Kangarloo
authors.forename: Farrukh
authors.initials: F
authors.lastname: Naveed
authors.forename: Diana
authors.initials: D
authors.lastname: Quinlan
authors.forename: M Ahsan
authors.initials: MA
authors.lastname: Chaudhry
authors.forename: Douglas
authors.initials: D
authors.lastname: Stewart
authors.forename: M Lynn
authors.initials: ML
authors.lastname: Savoie
authors.forename: Nizar J
authors.initials: NJ
authors.lastname: Bahlis
authors.forename: Christopher
authors.initials: C
authors.lastname: Brown
authors.forename: Jan
authors.initials: J
authors.lastname: Storek
authors.forename: Borje S
authors.initials: BS
authors.lastname: Andersson
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D016903:Drug Monitoring / Q000379:methods; D006085:Graft Survival; D019337:Hematologic Neoplasms / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods* / Q000401:mortality; D006801:Humans; D008875:Middle Aged; D019172:Transplantation Conditioning / Q000379:methods* / Q000401:mortality; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014916:Whole-Body Irradiation
chemical_list: D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine