叶酸拮抗剂甲氨蝶呤（HD-MTX）是初发中枢神经系统淋巴瘤（PCNSL）诱导化疗的重要组成部分；然而，它可能与白质脑病相关。甲基四氢叶酸还原酶（MTHFR）参与细胞内叶酸耗竭。我们评估了MTHFR多态性是否影响白质脑病的风险。我们在麻省总医院的数据库中对接受HD-MTX治疗（无放疗或脑脊液化疗）的新诊断PCNSL进行了回顾性搜索。在68例PCNSL患者中，60例（88.2%）患者存在MTHFR多态性，包括677C→T基因型、1298A→C基因型或联合677C→T/1298A→C基因型。特定基因型对MTX清除能力和诱导治疗的反应均无影响，HD-MTX诱导疗法使72.1%的患者达到完全缓解。然而，1298A→C基因型与白质脑病的频率和严重程度随时间增加有关（比值比：4.0，CI 1.5-11.4）。这种基因型以71.0%的敏感性和62.2%的特异性（AUC：0.67，CI 0.5-0.8；p=0.019）预测了治疗导致的白质脑病。虽然基于基因型的亚组在无进展生存上没有差异，但1298A→C基因型患者的总生存率较低。MTHFR 1298A→C基因型可能用于确定HD-MTX诱导的白质脑病风险增高的PCNSL患者。这可能导致生存减少，可能是由于功能状态降低。 © 2023美国神经学学会。

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.We retrospectively searched our database at the Massachusetts General Hospital for newly diagnosed PCNSL treated with HD-MTX (without radiotherapy nor intrathecal chemotherapy).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.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.© 2023 American Academy of Neurology.