From 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.
Neurology. 2023 Oct 24;101(17):e1741-e1746. doi: 10.1212/WNL.0000000000207670. Epub 2023 Aug 1.
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 polymorphisms affect the risk of 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 patients with PCNSL, 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; = 0.019). While progression-free survival did not differ in genotype-based subgroups, overall survival was lower for the 1298A→C genotype.
The 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.
叶酸拮抗剂大剂量甲氨蝶呤（HD-MTX）是原发性中枢神经系统淋巴瘤（PCNSL）诱导化疗的重要组成部分；然而，它可能与脑白质病有关。亚甲基四氢叶酸还原酶（MTHFR）参与细胞内叶酸耗竭。我们评估了多态性是否会影响脑白质病的风险。
我们回顾性地在马萨诸塞州总医院的数据库中搜索了新诊断为 PCNSL 并接受 HD-MTX 治疗（无放疗和鞘内化疗）的患者。
在 68 例 PCNSL 患者中，发现了 60 例个体（88.2%）存在 多态性，包括 677C→T 基因型、1298A→C 基因型或 677C→T/1298A→C 基因型的组合。MTX 清除率或对诱导治疗的反应不受特定基因型的影响，72.1%的患者通过基于 HD-MTX 的诱导治疗达到完全缓解。然而，1298A→C 基因型与脑白质病的频率和严重程度随时间增加有关（比值比 4.0，95%CI 1.5-11.4）。该基因型对治疗诱导的脑白质病具有 71.0%的敏感性和 62.2%的特异性（曲线下面积 0.67，95%CI 0.5-0.8； = 0.019）。虽然基因型亚组的无进展生存率没有差异，但总体生存率在 1298A→C 基因型中较低。
1298A→C 基因型可能有助于识别 PCNSL 患者发生 HD-MTX 诱导的脑白质病的风险增加。这似乎转化为生存能力降低，可能是由于功能状态下降。
