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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-06-1860. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-06-1860v1 101/5/2043    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by McDonald, G. B. Articles by Gooley, T. Search for Related Content PubMed PubMed Citation Articles by McDonald, G. B. Articles by Gooley, T. Related Collections Transplantation Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 March 2003, Vol. 101, No. 5, pp. 2043-2048 TRANSPLANTATION Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation George B. McDonald, John T. Slattery, Michelle E. Bouvier, Song Ren, Ami L. Batchelder, Thomas F. Kalhorn, H. Gary Schoch, Claudio Anasetti, and Ted Gooley From the Clinical Research Division, Fred Hutchinson Cancer Research Center, and the Departments of Medicine and Pharmaceutics, University of Washington Schools of Medicine and Pharmacy, Seattle, WA. 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. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G B McDonald and D Frieze A problem-oriented approach to liver disease in oncology patients Gut, July 1, 2008; 57(7): 987 - 1003. [Full Text] [PDF] P. Afsharian, Y. Terelius, Z. Hassan, C. Nilsson, S. Lundgren, and M. Hassan The Effect of Repeated Administration of Cyclophosphamide on Cytochrome P450 2B in Rats Clin. Cancer Res., July 15, 2007; 13(14): 4218 - 4224. [Abstract] [Full Text] [PDF] D. H. Salinger, J. S. McCune, A. G. Ren, D. D. Shen, J. T. Slattery, B. Phillips, G. B. McDonald, and P. Vicini Real-time Dose Adjustment of Cyclophosphamide in a Preparative Regimen for Hematopoietic Cell Transplant: A Bayesian Pharmacokinetic Approach. Clin. Cancer Res., August 15, 2006; 12(16): 4888 - 4898. [Abstract] [Full Text] [PDF] E. A. Copelan Hematopoietic stem-cell transplantation. N. Engl. J. Med., April 27, 2006; 354(17): 1813 - 1826. [Full Text] [PDF] B. L. Scott and B. M. 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