Li Wenshu, Zhang Sitian, Wu Ruoyun, Li Ying, Wei Shifeng, Fu Lin, Sun Xuefei, Liu Yuanbo, Zhao Zhigang, Mei Shenghui
Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing, China.
Front Pharmacol. 2025 Aug 4;16:1561818. doi: 10.3389/fphar.2025.1561818. eCollection 2025.
High-dose methotrexate (HDMTX) is the cornerstone of the treatment for primary central nervous system lymphoma (PCNSL). The prevention of drug-induced toxicities is critical. This study aims to identify key factors associated with HDMTX-induced toxicities (hematotoxicity, hepatotoxicity and nephrotoxicit) in 713 Chinese PCNSL patients undergoing 3021 HDMTX treatment courses. Demographic data, administration information, laboratory tests, area under the curve, co-medications, and 30 single nucleotide polymorphisms were collected to analyze the association of HDMTX-related toxicities using PLINK and SPSS. Higher ALB level, female, ABCB1 rs1045642, MTHFR rs1801131, and MTHFD1 rs2236225 were associated with lower risk of anemia, while the combination of furosemide, torasemide, bumetanide, and levetiracetam associating with higher risk. Co-use of torasemide had higher incidence of neutropenia. Higher level of ALB was correlated with less leukopenia; torasemide and rs2236225 were related to more leukopenia. Female, furosemide, rs1801133, ABCG2 rs2231142, ABCC2 rs717620 were related to more thrombocytopenia, while rs1045642 and high ALB were related to less. Rs1801131 and female were correlated with more hepatotoxicity, whereas furosemide was correlated with less. In nephrotoxicity, female and rs1801394 were correlated with less, MTHFR rs1801131 and rs1801133 were correlated with more. In conclusion, higher ALB levels had a lower risk of HDMTX toxicities; loop diuretics and levetiracetam generally accelerated the occurrence of toxicities. Rs1801133 GG, rs1128503 GG + AG, rs2231142 AA+ AC, rs717620 TT + GT were associated with increased risk of toxicity; rs1045642 TT and rs1801394 GG + AG were less likely to develop toxicity.
大剂量甲氨蝶呤（HDMTX）是原发性中枢神经系统淋巴瘤（PCNSL）治疗的基石。预防药物诱导的毒性至关重要。本研究旨在确定713例接受3021个HDMTX治疗疗程的中国PCNSL患者中与HDMTX诱导的毒性（血液毒性、肝毒性和肾毒性）相关的关键因素。收集人口统计学数据、用药信息、实验室检查、曲线下面积、联合用药以及30个单核苷酸多态性，使用PLINK和SPSS分析HDMTX相关毒性的相关性。较高的白蛋白（ALB）水平、女性、ABCB1基因rs1045642、亚甲基四氢叶酸还原酶（MTHFR）基因rs1801131和亚甲基四氢叶酸脱氢酶1（MTHFD1）基因rs2236225与贫血风险较低相关，而呋塞米、托拉塞米、布美他尼和左乙拉西坦联合使用则与较高风险相关。联合使用托拉塞米时中性粒细胞减少的发生率较高。较高的ALB水平与白细胞减少较少相关；托拉塞米和rs2236225与白细胞减少较多相关。女性、呋塞米、rs1801133、ABCG2基因rs2231142、ABCC2基因rs717620与血小板减少较多相关，而rs1045642和高ALB水平与血小板减少较少相关。rs1801131和女性与肝毒性较多相关，而呋塞米与肝毒性较少相关。在肾毒性方面，女性和rs1801394与肾毒性较少相关，MTHFR基因rs1801131和rs1801133与肾毒性较多相关。总之，较高的ALB水平HDMTX毒性风险较低；袢利尿剂和左乙拉西坦通常会加速毒性的发生。rs1801133 GG、rs1128503 GG + AG、rs2231142 AA + AC、rs717620 TT + GT与毒性风险增加相关；rs1045642 TT和rs1801394 GG + AG发生毒性的可能性较小。
