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Cyclophosphamide Metabolism in Children with Non-Hodgkin’s Lymphoma

¹ Departments of Child Health, ² Pharmacological Sciences, and ³ Northern Institute for Cancer Research, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne; ⁴ Department of Haematology, Yorkhill National Health Service Trust, Glasgow; and ⁵ Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom

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/m² (range, 2.3–5.0 liter/h/m²), compared with 2.2 (range, 1.5–2.5 liter/h/m²) in those with disease recurrence. Likelihood of recurrence was higher in patients with low clearance (<3.5 liter/h/m²) 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.

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