Abstract
Objectives: The folate-antagonist methotrexate (HD-MTX) is integral to induction chemotherapy for primary CNS lymphoma (PCNSL); however, it can be associated with leukoencephalopathy. Methylenetetrahydrofolate-reductase (MTHFR) is involved in intracellular folate depletion. We assessed whether MTHFR polymorphisms affect the risk for leukoencephalopathy.
Methods: We retrospectively searched our database at the Massachusetts General Hospital for newly diagnosed PCNSL treated with HD-MTX (without radiotherapy nor intrathecal chemotherapy).
Results: Among 68 PCNSL patients, MTHFR polymorphisms were found in 60 individuals (88.2%) including a 677C→T genotype, a 1298A→C genotype, or a combined 677C→T/1298A→C genotype. Neither MTX clearance nor response to induction therapy was affected by specific genotypes, and complete response was achieved in 72.1% of patients by HD-MTX-based induction. However, the 1298A→C genotype was associated with increased frequency and severity of leukoencephalopathy over time (odds ratio: 4.0, CI 1.5-11.4). Such genotype predicted treatment-induced leukoencephalopathy with a sensitivity of 71.0% and a specificity of 62.2% (AUC: 0.67, CI 0.5-0.8; p=0.019). While progression-free survival did not differ in genotype-based subgroups, overall survival was lower for the 1298A→C genotype.
Discussion: The MTHFR 1298A→C genotype may serve to identify PCNSL patients at elevated risk for HD-MTX-induced leukoencephalopathy. This appears to translate into reduced survival, potentially due to decreased functional status.
- Received March 1, 2023.
- Accepted in final form July 12, 2023.
- © 2023 American Academy of Neurology
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