Personalized dosing of cyclophosphamide in the total body irradiation-cyclophosphamide conditioning regimen: a phase II trial in patients with hematologic malignancy.

Publication Type:

Journal Article

Source:

Clinical pharmacology and therapeutics, Volume 85, Issue 6, p.615-22 (2009)

Keywords:

2009, Acute Disease, Adolescent, Adult, Age Factors, Antineoplastic Agents, Alkylating, Bayes Theorem, Bilirubin, Center-Authored Paper, Clinical Research Division, Combined Modality Therapy, Cyclophosphamide, Cytokine Analysis Core Facility, Dose-Response Relationship, Drug, Drug-Induced Liver Injury, Female, Flow Cytometry Core Facility, Hematologic Neoplasms, hematopoietic stem cell transplantation, Humans, Kidney Diseases, Male, Middle Aged, RECURRENCE, Research Trials Office Core Facility - Biostatistics Service, Shared Resources, Specimen Processing Core Facility, Transplantation Conditioning, Whole-Body Irradiation, Young Adult

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.