Demyelination and single-carbon transfer pathway metabolites during the treatment of acute lymphoblastic leukemia: CSF studies.
OBJECTIVE
To investigate the hypothesis that methotrexate causes demyelination due to a deficiency in S-adenosylmethionine (SAM) during the treatment of acute lymphoblastic leukemia (ALL).


METHODS
Twenty-four patients treated on the Medical Research Council United Kingdom ALL trial no. 11 (MRC UKALL XI) were studied. The trial randomized patients at the presymptomatic CNS treatment (PCNS) phase to receive (1) intrathecal methotrexate and cranial radiotherapy (CRTX); (2) high-dose intravenous methotrexate with folinic acid rescue and continuing intrathecal methotrexate (HDMTX); and (3) continuing intrathecal methotrexate alone (ITMTX). Serial CSF samples were collected throughout treatment and concentrations of 5-methyltetrahydrofolate (MTF), methionine (MET), SAM, and myelin basic protein (MBP) were measured. The results 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 and MBP concentrations. CSF MTF reached a nadir during the induction phase of treatment, while SAM and MET reached their nadir during the consolidation phase. CSF MBP mirrored SAM concentration and there was a significant inverse relationship between the two. MTF, SAM, and MBP returned to normal values by the end of treatment, while MET was increased significantly. The effect of treatment was decremental across the ITMTX, HDMTX, and CRTX groups.


CONCLUSIONS
Treatment of ALL causes marked abnormalities in the single-carbon transfer pathway and subclinical demyelination. Methotrexate is one cause of this. Whether these abnormalities contribute to the late cognitive deficits requires further study.
Surtees
R
R
Institute of Child Health, University College London Medical School, Department of Haematology and Oncology, Great Ormond Street Hospital for Children National Health Service Trust, United Kingdom. r.surtees@ich.ucl.ac.uk
Clelland
J
J
Hann
I
I
D000931:Antidotes / Q000008:administration & dosage; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D003711:Demyelinating Diseases / Q000139:chemically induced*; D004347:Drug Interactions; D006801:Humans; D007223:Infant; D002955:Leucovorin / Q000008:administration & dosage; D008715:Methionine / Q000134:cerebrospinal fluid; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects*; D004676:Myelin Basic Protein / Q000134:cerebrospinal fluid; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D012436:S-Adenosylmethionine / Q000134:cerebrospinal fluid / Q000172:deficiency*; D013763:Tetrahydrofolates / Q000134:cerebrospinal fluid
D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D004676:Myelin Basic Protein; D013763:Tetrahydrofolates; D012436:S-Adenosylmethionine; D008715:Methionine; D002955:Leucovorin; C005984:5-methyltetrahydrofolate; D008727:Methotrexate