Methotrexate‐associated alterations of the folate and methyl‐transfer pathway in the CSF of ALL patients with and without symptoms of neurotoxicity

Background

Severe neurotoxicity has been observed after systemic high‐dose and intrathecal methotrexate (MTX) treatment. The role of biochemical MTX‐induced alterations of the folate and methyl‐transfer pathway in the development of neurotoxic symptoms is not yet fully elucidated.

Procedure

MTX, 5‐methyltetrahydrofolate, calcium folinate, S‐adenosylmethionine, and S‐adenosylhomocysteine were measured in the cerebrospinal fluid (CSF) of 29 patients with acute lymphoblastic leukemia (ALL) who were treated with high‐dose MTX (5 g/m²) followed by calcium folinate rescue (3 × 15 mg/m²) and/or intrathecal (8–12 mg) MTX. Two patients developed subacute MTX‐associated neurotoxicity. CSF was obtained by lumbal puncture 1–3 weeks after administration of MTX and shortly after the occurrence of neurotoxicity. The analytes were measured using HPLC assays with UV and/or fluorescence detection.

Results

In non‐toxic patients, CSF concentrations of 5‐methyltetrahydrofolate and S‐adenosylmethionine were in the normal range 2 weeks after administration of high‐dose and intrathecal MTX followed by rescue. In contrast, when these patients received intrathecal MTX without rescue, 5‐methyltetrahydrofolate concentrations were significantly decreased 12 days after the first MTX administration. S‐adenosylmethionine concentrations were significantly decreased up to 45 days. The two patients suffering from neurotoxicity had decreased levels of 5‐methyltetrahydrofolate and S‐adenosylmethionine during or following toxicity. S‐adenosylhomocysteine was determined in all samples of neurotoxic patients but was below the limit of quantification in most samples of non‐toxic patients. Calcium folinate was not detected; MTX was present only in samples obtained during its infusion.

Conclusion

Intrathecal MTX without folinate rescue as well as MTX‐associated neurotoxicity are likely to be associated with specific alterations of the folate and methyl‐transfer pathway. Pediatr Blood Cancer 2009;52:26–32. © 2008 Wiley‐Liss, Inc.