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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-06-1860.
Submitted June 24, 2002
Accepted October 5, 2002
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
Department of Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
Department of Pharmaceutics, University of Washington School of Pharmacy, Seattle, WA, USA
* Corresponding author; email: gmcdonal{at}fhcrc.org.
Rationale: 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. Objectives: Cyclophosphamide was infused at 60 mg/kg over 1 to 2 hours on each of two consecutive days, followed by total body irradiation. Plasma was analyzed for cyclophosphamide and its major metabolites. Liver toxicity was scored by development of Sinusoidal Obstruction Syndrome (veno-occlusive disease) and by total serum bilirubin levels. The hazards of liver toxicity, non-relapse mortality, tumor relapse, and survival were calculated using regression analysis that included exposure to cyclophosphamide metabolites (as the area under the curve). Findings: Of 147 patients, 23 (16%) developed moderate or severe Sinusoidal Obstruction Syndrome. The median peak serum bilirubin level through day +20 was 2.6 (range 0.5 to 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, non-relapse 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 of non-relapse mortality, compared to patients in the lowest quartile. Engraftment and tumor relapse were not statistically significantly related to cyclophosphamide metabolite exposure. Conclusions: Increased exposure to toxic metabolites of cyclophosphamide leads to increased liver toxicity and non-relapse mortality and lower overall survival after hematopoietic cell transplant.
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