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 T₀ to T₇₂ hours (AUC_0–72) and methotrexate AUCs were evaluated using MW/PHARM3.3 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 µmol/l making this difference the most striking discriminator between the two courses. Mutation analysis showed that the patient was heterozygous for the C677T 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.

Pretreatment Plasma Folate Modulates the Pharmacodynamic Effect of High-Dose Methotrexate in Children with Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma: “Folate Overrescue” Concept Revisited

“…Because differences in relapse rates in their study did not reach statistical significance, it remained largely unnoticed by the medical community. Nevertheless, since then, published reports from various medical fields, including dermatology (37 ), gynecology (38 ), and oncology (26 ), have collectively indicated that increased endogenous folate concentrations may indeed a priori neutralize the antimetabolic effect of MTX. These reports, although indicating the existence of a potentially detrimental consequence, have not yet led to a systematic study of the timing of leucovorin/MTX administration, although the clinical effectiveness of MTX-containing regimens different from the original 5 g/m 2 over 24 h specified by BFM 95 is well known both within and outside the BFM group.…”

“…In our in-house pilot study carried out during 1999 and 2000, we gathered data suggesting that a strong correlation may exist between MTX exposure and time-dependent changes in homocysteine whole-body accumulation, implying that homocysteine may behave as a marker of the in vivo antifolate effect of MTX at the individual patient level. Observing a case with severe toxicity after the first but not the second course of HDMTX administration within the duration of this study (26 ) further stimulated us to investigate the relationship between homocysteine accumulation and MTX exposure to elucidate the sequence in antifolate/folate whole-body pharmacodynamics. To accomplish this we defined an in vivo functional model induced by treatment with MTX characterized as a timedependent, multiparametric in situ system in which (a) input variables were plasma pretreatment (t 0 ) folate, vitamin B 12 , and homocysteine, and (b) output variables were plasma total MTX area under the curve (AUC 0 h-ϱ ) and plasma homocysteine AUC 0 -66 h obtained for every HDMTX course of administration.…”

Homocysteine and Polyamines: Metabolic Relationship and Its Clinical Significance in Folate Inhibitors Chemotherapy

“…рис. 1), поэтому накопление гомоцистеина при введении высокодозной MТХ является биохими-ческой основой отражения степени подавления синтеза фолатов [80]. Таким образом, уменьшение обратного превращения гомоцистеина в метионин на фоне действия метотрексата не может не оказы-вать влияния на полиаминовый обмен, поскольку ожидаемо приводит к уменьшению образования их предшественника SАМ.…”

Pharmacogenetics of the neurodevelopmental impact of anticancer chemotherapy

“…Plasma folate concentration at the start of each cycle (originating from the folinic acid rescue administered during previous therapeutic cycles) was the principal determinant of the extent of whole-body Hcy accumulation in response to MTX administration . Hcy accumulation has been associated in some case studies with severe neurotoxic effects [Kishi et al, 2003;Quinn et al, 2004;Valik et al, 2005].…”