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Toxicity following concurrent intrathecal and moderate-dose intravenous methotrexate
J Blatt1, D L Howrie, M R Wollman
1Department of Pediatrics, Children's Hospital of Pittsburgh 15213-2583.
Abstract:
To evaluate factors predisposing children with non-Hodgkin's lymphoma to toxicity from moderate dose methotrexate (MTX) (300 mg/m2 per 4 hours), we reviewed the medical records of 15 patients treated at our institution according to two similar protocols. Five patients experienced hyperemesis and/or severe mucositis. In two of these patients, pharmacokinetic analysis demonstrated delayed terminal excretion of methotrexate with a half-life of 3-3.5 days, compared to a previously reported t1/2 of 8-15 hours in subjects with normal clearance. All affected patients were large (body surface area 1.6-1.9 m2), and MTX toxicity was seen only during courses where intravenous MTX was given concurrently with intrathecal MTX. Four patients also received simultaneous prophylactic doses of oral trimethoprim-sulfamethoxazole (trimethoprim 5 mg/kg per day). We recommend that, in protocol design, consideration be given to avoiding concurrent use of intravenous and intrathecal MTX, and possibly trimethoprim-sulfamethoxazole. Where high doses of MTX are given based on large body surface area, urine alkalinization may be indicated.
Insights
Children with non-Hodgkin's lymphoma receiving moderate-dose methotrexate (MTX) may experience toxicity, especially when given intravenously and intrathecally concurrently. Larger patients and concurrent trimethoprim-sulfamethoxazole use are also risk factors.
Area of Science:
- Pediatric Oncology
- Pharmacology
- Clinical Toxicology
Background:
- Moderate-dose methotrexate (MTX) is used in treating childhood non-Hodgkin's lymphoma (NHL).
- Identifying factors that predispose patients to MTX toxicity is crucial for optimizing treatment protocols.
Purpose of the Study:
- To evaluate factors associated with toxicity in pediatric patients with non-Hodgkin's lymphoma receiving moderate-dose methotrexate.
- To identify potential risk factors for methotrexate-related adverse events.
Main Methods:
- Retrospective review of medical records for 15 pediatric patients with non-Hodgkin's lymphoma treated with moderate-dose MTX.
- Analysis of patient characteristics, treatment protocols, and adverse events, including pharmacokinetic assessments in affected patients.
Main Results:
- Five of 15 patients experienced significant toxicity, including hyperemesis and severe mucositis.
- Pharmacokinetic analysis in two patients revealed delayed MTX excretion (half-life 3-3.5 days).
- Toxicity was observed in larger patients (BSA 1.6-1.9 m2) and specifically during courses with concurrent intravenous and intrathecal MTX administration; four patients also received trimethoprim-sulfamethoxazole.
Conclusions:
- Concurrent administration of intravenous and intrathecal methotrexate may increase toxicity risk in pediatric non-Hodgkin's lymphoma patients.
- Consideration should be given to avoiding this concurrent MTX administration and potentially trimethoprim-sulfamethoxazole in protocol design.
- Urine alkalinization may be beneficial for high-dose MTX regimens in large patients.