Severe encephalopathy induced by the first but not the second course of high-dose methotrexate mirrored by plasma homocysteine elevations and preceded by extreme differences in pretreatment plasma folate

Abstract

Plasma homocysteine has recently been associated with the occurrence of methotrexate-related neurotoxicity. We observed extreme elevations of homocysteine in a 9-year-old boy presenting with leukemia treated with the ALL-BFM 95 protocol. Coma occurred at about the 71st hour from the first methotrexate administration, and lasted for 30 h but MRI and CT studies showed no intracranial pathology. The second course of high-dose methotrexate was administered with no complications. Homocysteine areas under the curve (AUC) were calculated as the sum of areas of rectangles during the 6-hour intervals from T(0) to T(72) hours (AUC(0--72)) and methotrexate AUCs were evaluated using MW/PHARM 3.3 software. The AUC of homocysteine during the first, toxic course was 5.2 times higher than AUC during the second administration, whereas AUC of methotrexate also differed by a factor of 5. Plasma concentrations of folate prior to the first and the second courses, respectively, were 4.4 versus 45 micromol/l making this difference the most striking discriminator between the two courses. Mutation analysis showed that the patient was heterozygous for the C 677 T mutation in the MTHFR gene. We suggest that plasma homocysteine, pretreatment plasma folate and possibly the presence of MTHFR mutations may be biomarkers of methotrexate toxicity and possibly its antifolate effect targeted towards the tumor as well.