Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation

被引:266
作者
McDonald, GB
Slattery, JT
Bouvier, ME
Ren, S
Batchelder, AL
Kalhorn, TF
Schoch, HG
Anasetti, C
Gooley, T
机构
[1] Fred Hutchinson Canc Res Ctr, Gastroenterol Hepatol Sect D2 190, Div Clin Res, Seattle, WA 98109 USA
[2] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA
[3] Univ Washington, Sch Pharm, Dept Med, Seattle, WA 98195 USA
[4] Univ Washington, Sch Med, Dept Pharmaceut, Seattle, WA 98195 USA
[5] Univ Washington, Sch Pharm, Dept Pharmaceut, Seattle, WA 98195 USA
关键词
D O I
10.1182/blood-2002-06-1860
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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页码:2043 / 2048
页数:6
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