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-close and intrathecal methotrexane (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/m(2)) followed by calcium folinate rescue (3 x 15 mg/m(2)) 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 clays 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-adenosyl-homocysteine was determined in all samples of neurotoxic patients but was below the limit of qualification 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. (c) 2008 Wiley-Liss, Inc.