title: Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation.
abstract: Liver toxicity caused by high-dose myeloablative therapy leads to significant morbidity after hematopoietic cell transplantation. We examined the hypothesis that liver toxicity after cyclophosphamide and total body irradiation is related to cyclophosphamide through its metabolism to toxins. Cyclophosphamide was infused at 60 mg/kg over 1 to 2 hours on each of 2 consecutive days, followed by total body irradiation. Plasma was analyzed for cyclophosphamide and its major metabolites. Liver toxicity was scored by the development of sinusoidal obstruction syndrome (veno-occlusive disease) and by total serum bilirubin levels. The hazards of liver toxicity, nonrelapse mortality, tumor relapse, and survival were calculated using regression analysis that included exposure to cyclophosphamide metabolites (as the area under the curve). Of 147 patients, 23 (16%) developed moderate or severe sinusoidal obstruction syndrome. The median peak serum bilirubin level through day 20 was 2.6 mg/dL (range, 0.5-41.1 mg/dL). Metabolism of cyclophosphamide was highly variable, particularly for the metabolite o-carboxyethyl-phosphoramide mustard, whose area under the curve varied 16-fold. Exposure to this metabolite was statistically significantly related to sinusoidal obstruction syndrome, bilirubin elevation, nonrelapse mortality, and survival, after adjusting for age and irradiation dose. Patients in the highest quartile of o-carboxyethyl-phosphoramide mustard exposure had a 5.9-fold higher risk for nonrelapse mortality than did patients in the lowest quartile. Engraftment and tumor relapse were not statistically significantly related to cyclophosphamide metabolite exposure. Increased exposure to toxic metabolites of cyclophosphamide leads to increased liver toxicity and nonrelapse mortality and lower overall survival after hematopoietic cell transplantation.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, and the Department of Medicine, University of Washington Schools of Medicine and Pharmacy, Seattle, WA 98109-1024, USA.
authors.forename: George B
authors.initials: GB
authors.lastname: McDonald
authors.forename: John T
authors.initials: JT
authors.lastname: Slattery
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Bouvier
authors.forename: Song
authors.initials: S
authors.lastname: Ren
authors.forename: Ami L
authors.initials: AL
authors.lastname: Batchelder
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Kalhorn
authors.forename: H Gary
authors.initials: HG
authors.lastname: Schoch
authors.forename: Claudio
authors.initials: C
authors.lastname: Anasetti
authors.forename: Ted
authors.initials: T
authors.lastname: Gooley
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000209:etiology*; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D019337:Hematologic Neoplasms / Q000628:therapy*; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced* / Q000453:epidemiology; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced / Q000453:epidemiology; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils; D036102:Peripheral Blood Stem Cell Transplantation / Q000401:mortality*; D010752:Phosphoramide Mustards / Q000009:adverse effects / Q000097:blood; D010976:Platelet Count; D011446:Prospective Studies; D012008:Recurrence; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000401:mortality*; D014916:Whole-Body Irradiation
chemical_list: D010752:Phosphoramide Mustards; C445000:carboxyethylphosphoramide mustard; D003520:Cyclophosphamide