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Published on: June 16, 2017
Association of MTHFR Polymorphisms With Leukoencephalopathy Risk in Patients With Primary CNS Lymphoma Treated With
Philipp Karschnia1, Sylvia C Kurz2, Priscilla K Brastianos2
1From the Division of Neuro-Oncology (P.K., P.K.B., S.F.W., A.G., S.J., M.P., N.N., S.R.P., J.D.), Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston; Department of Neurosurgery (P.K., J.-C.T.), Ludwig-Maximilians-University Munich; German Cancer Consortium (DKTK) (P.K.), Partner Site Munich; Section for Neuro-Oncology (S.C.K.), Department of Neurology, University of Tuebingen, Germany; and Department of Neurology (T.T.B.), Brigham and Woman's Hospital, Harvard Medical School, Boston, MA. p.karschnia@med.uni-muenchen.de.
Objectives:
The folate antagonist high-dose 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 of 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 patients with PCNSL, 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% (area under the curve 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 patients with PCNSL at elevated risk of HD-MTX-induced leukoencephalopathy. This seems to translate into reduced survival, potentially due to decreased functional status.
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