title: Establishing a target exposure for once-daily intravenous busulfan given with fludarabine and thymoglobulin before allogeneic transplantation.
abstract: A combination of fludarabine (Flu) and daily i.v. busulfan (Bu) is well tolerated and effective in patients undergoing allogeneic hematopoietic stem cell transplantation. Although there is some evidence that Bu exposures exceeding 6000 μM.min [corrected] may lead to excessive toxicity, there is little information on the effect of exposures below this level on outcomes. We studied Bu exposure, as measured by area under the concentration-time curve (AUC), in 158 patients with various hematologic malignancies in an attempt to identify an optimal range for targeted therapy. The preparative chemotherapy regimen comprised Flu 50 mg/m(2) on days -6 to -2 and i.v. Bu 3.2 mg/kg on days -5 to -2 inclusive. Graft-versus-host disease (GVHD) prophylaxis included methotrexate, cyclosporin A, and antithymocyte globulin. Patients with Bu exposures below the median AUC of 4439 μM.min [corrected] were at increased risk for acute GVHD grade II-IV (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.19 to 4.49; P = .014). Those in the highest and lowest Bu exposure quartiles (daily AUC <3814 μM.min and >4993 μM.min) [corrected] had an increased risk of nonrelapse mortality (subdistribution HR, 3.32; 95% CI, 1.46 to 7.54; P = .004), as well as worse disease-free survival (HR, 1.81; 95% CI, 1.09 to 2.99; P = .021) and overall survival (HR, 1.94; 95% CI, 1.12 to 3.37; P = .018). Bu exposures between 4440 and 4993 μM/min were accompanied by the lowest risk of both nonrelapse mortality and acute GVHD.
authors.affiliation: Departments of Medicine and Oncology, Foothills Hospital and Tom Baker Cancer Centre, Calgary, Alberta, Canada. jjamesrus@shaw.ca
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
authors.forename: Shahbal B
authors.initials: SB
authors.lastname: Kangarloo
authors.forename: Tyler
authors.initials: T
authors.lastname: Williamson
authors.forename: M Ahsan
authors.initials: MA
authors.lastname: Chaudhry
authors.forename: Mary Lynn
authors.initials: ML
authors.lastname: Savoie
authors.forename: A Robert
authors.initials: AR
authors.lastname: Turner
authors.forename: Loree
authors.initials: L
authors.lastname: Larratt
authors.forename: Jan
authors.initials: J
authors.lastname: Storek
authors.forename: Nizar J
authors.initials: NJ
authors.lastname: Bahlis
authors.forename: Mona
authors.initials: M
authors.lastname: Shafey
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Brown
authors.forename: Maggie
authors.initials: M
authors.lastname: Yang
authors.forename: Michelle
authors.initials: M
authors.lastname: Geddes
authors.forename: Nancy
authors.initials: N
authors.lastname: Zacarias
authors.forename: Ping
authors.initials: P
authors.lastname: Yue
authors.forename: Peter
authors.initials: P
authors.lastname: Duggan
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Stewart
authors.forename: Andrew
authors.initials: A
authors.lastname: Daly
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000961:Antilymphocyte Serum / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000961:Antilymphocyte Serum; C512542:thymoglobulin; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine
keywords: Busulfan; Exposure; Pharmacokinetics