MTHFR polymorphisms and neurotoxicity and overall survival after methotrexate-based therapy in primary CNS lymphoma

2079 Background: The folate-antagonist methotrexate (HD-MTX) is an integral to induction chemotherapy for primary CNS lymphoma (PCNSL); however, it can be associated with toxicities, including injury to cerebral white matter known as leukoencephalopathy. Methylenetetrahydrofolate Reductase (MTHFR) is involved in intracellular folate metabolism, and MTHFR polymorphisms may affect CNS-specific side effects of HD-MTX. Here, we evaluated the possible association of MTHFR polymorphisms an HD-MTX related CNS toxicity. Methods: We retrospectively searched our institutional database at the Massachusetts General Hospital for newly diagnosed PCNSL patients treated with HD-MTX (without use of radiotherapy or intrathecal chemotherapy). MTHFR polymorphisms were correlated with evolution of leukoencephalopathy over a time period of five years and patient outcomes. ROC curves were generated to estimate the diagnostic ability of specific MTHFR genotypes. Survival was calculated using Kaplan-Meier survival analysis and log-rank test. The significance level was set at p ≤ 0.05. Results: Among 68 PCNSL patients, MTHFR polymorphisms were found in 60 individuals (88.2%; 677C>T: 29 patients, 1298A>C: 18 patients, combined 677C>T & 1298A>C: 13 patients). Neither MTX clearance nor disease response to HD-MTX was affected by specific genotypes, and complete response was achieved in 72.1% of patients by induction with HD-MTX-based therapy. However, the 1298A>C genotype was associated with increased frequency and severity of leukoencephalopathy over time (χ 2 = 7.43). Such genotype predicted treatment-induced leukoencephalopathy with a sensitivity of 71.0%% and a specificity of 62.2% (ROC: p = 0.019). While progression-free survival did not differ in genotype-based subgroups, overall survival was significantly lower when the 1298A>C genotype was present. Conclusions: The MTHFR 1298A>C genotype may serve to identify PCNSL patients at elevated risk for HD-MTX-induced leukoencephalopathy. This was associated with reduced overall survival, potentially due to decreased functional status in patients less suitable for aggressive subsequent therapies.