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. Clinical Pharmacology & Therapeutics (2009); 85 , 6, 615–622 doi:10.1038/clpt.2009.27