DEMYELINATION AND SINGLE-CARBON TRANSFER PATHWAY METABOLITES DURING THE TREATMENT OF ACUTE LYMPHOBLASTIC-LEUKEMIA - CSF STUDIES

Purpose: To investigate the hypothesis that methotrexate causes demyel ination due to a deficiency in S-adenosylmethionine (SAM) during the t reatment of acute lymphoblastic leukemia (ALL). Patients and Methods: Twenty-four patients treated on the Medical Research Council United Ki ngdom ALL trial no. 11 (MRC UKALL XI) were studied. The trial randomis ed patients at the presymptomatic CNS treatment (PCNS) phase to receiv e (1) intrathecal methotrexate and cranial radiotherapy (CRTX); (2) hi gh-dose intravenous methotrexate with folinic acid rescue and continui ng intrathecal methotrexate (HDMTX); and (3) continuing intrathecal me thotrexate alone (ITMTX). Serial CSF samples were collected throughout treatment and concentrations of 5-methyltetrahydrofolate (MTF), methi onine (MET), SAM, and myelin basic protein (MBP) were measured. The re sults were grouped into treatment milestones and compared with an age- matched reference population, Results: There was a highly significant effect of both treatment milestones and trial arm on the metabolite an d MBP concentrations. CSF MTF reached a nadir during the induction pha se of treatment, while SAM and MET reached their nadir during the cons olidation phase, CSF MBP mirrored SAM concentration and there was a si gnificant inverse relationship between the two, MTF, SAM, and MBP retu rned to normal valves by the end of treatment, while MET was increased significantly The effect of treatment was decremental across the ITMT X, HDMTX, and CRTX groups. Conclusion: Treatment of ALL causes marked abnormalities in the single-carbon transfer pathway and subclinical de myelination. Methotrexate is one cause of this, Whether these abnormal ities contribute to the late cognitive deficits requires further study . (C) 1998 by American Society of Clinical Oncology.