Cyclophosphamide metabolism in children with non-Hodgkin's lymphoma.

PURPOSE: The purpose of our study was to determine whether variation in cyclophosphamide metabolism influences the incidence of recurrence among children receiving chemotherapy for B-cell non-Hodgkin's lymphoma. EXPERIMENTAL DESIGN: The pharmacokinetics and metabolism of cyclophosphamide were studied during a single course of treatment in 36 children receiving a uniform chemotherapy regimen for B-cell non-Hodgkin's lymphoma and were analyzed in terms of disease recurrence and hematological toxicity. RESULTS: At a median follow-up of 43 months (range, 17-98 months), six children had developed recurrent disease, giving an overall disease-free survival of 83%. The median clearance of cyclophosphamide in patients who remain free of B-cell non-Hodgkin's lymphoma was 3.7 liter/h/m(2) (range, 2.3-5.0 liter/h/m(2)), compared with 2.2 (range, 1.5-2.5 liter/h/m(2)) in those with disease recurrence. Likelihood of recurrence was higher in patients with low clearance (<3.5 liter/h/m(2)) of cyclophosphamide (P < 0.01) and positively related to detection of the inactive metabolites carboxyphosphamide and dechloroethylcyclophosphamide in plasma (P = 0.01). There was no correlation between cyclophosphamide metabolism and hematological toxicity. CONCLUSIONS: Inadequate clearance of cyclophosphamide to active metabolites is associated with increased risk of recurrence of B-cell non-Hodgkin's lymphoma in children. Modified chemotherapy strategies should be considered in patients who exhibit low rates of clearance of the parent drug and/or extensive production of inactive metabolites.