title: Personalized dosing of cyclophosphamide in the total body irradiation-cyclophosphamide conditioning regimen: a phase II trial in patients with hematologic malignancy.
abstract: This study investigates the efficacy and safety of personalized cyclophosphamide (CY) dosing in 50 patients receiving CY along with total body irradiation (TBI). Participants received CY 45 mg/kg with subsequent therapeutic drug monitoring using Bayesian parameter estimation to personalize the second CY dose to a target area under the curve (AUC) for carboxyethylphosphoramide mustard (CEPM) (a reporter molecule for CY-derived toxins) and for hydroxycyclophosphamide (to ensure engraftment). The mean second CY dose was 66 mg/kg; the total dose ranged from 45 to 145 mg/kg. After completion of this phase II study, we compared participants' clinical outcomes with those of concurrent controls (n = 100) who received TBI along with standard CY doses of 120 mg/kg. Patients receiving personalized CY dosing had significantly lower postconditioning peak total serum bilirubin (P = 0.03); a 38% reduction in the hazard of acute kidney injury (AKI) (P = 0.03); and nonrelapse and overall survival rates similar to those in the controls (P = 0.70 and 0.63, respectively) despite the lower doses of CY administered to most of the patients in the personalized dosage group.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. jmccune@u.washington.edu
authors.forename: J S
authors.initials: JS
authors.lastname: McCune
authors.forename: A
authors.initials: A
authors.lastname: Batchelder
authors.forename: K A
authors.initials: KA
authors.lastname: Guthrie
authors.forename: R
authors.initials: R
authors.lastname: Witherspoon
authors.forename: F R
authors.initials: FR
authors.lastname: Appelbaum
authors.forename: B
authors.initials: B
authors.lastname: Phillips
authors.forename: P
authors.initials: P
authors.lastname: Vicini
authors.forename: D H
authors.initials: DH
authors.lastname: Salinger
authors.forename: G B
authors.initials: GB
authors.lastname: McDonald
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001499:Bayes Theorem; D001663:Bilirubin / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D019172:Transplantation Conditioning; D014916:Whole-Body Irradiation; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide; D001663:Bilirubin