Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia
Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia
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DOI：
10.1200/jco.2013.53.0808
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发表时间：
2014-03-20
影响因子：
45.3
通讯作者：
Relling, Mary V.
中科院分区：
文献类型：
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作者：
Bhojwani, Deepa;Sabin, Noah D.;Relling, Mary V.
目的甲氨蝶呤（MTX）可引起严重的临床神经毒性和无症状性白质脑病.我们试图确定临床，药代动力学，儿童急性淋巴细胞白血病（ALL）治疗期间这些MTX相关毒性的遗传风险因素，并提供鞘内和高剂量MTX治疗的安全性数据。患者和方法前瞻性脑磁共振成像在四个时间点进行了369例儿童急性淋巴细胞白血病治疗在当代的研究，包括五个疗程的MTX再激发。高剂量MTX和13至25剂三联鞘内治疗。Logistic回归模型被用来评估临床和药代动力学因素，并进行全基因组关联研究（GWAS），以确定生殖细胞多态性与神经toxics.Results相关的MTX相关的临床神经毒性14例（3.8%）。在13例鞘内和/或高剂量MTX再激发的患者中，12例未发生神经毒性复发。在355例无症状患者和所有有症状患者中发现73例（20.6%）白质脑病，在治疗结束时，74%的无症状患者和58%的有症状患者持续存在白质脑病。在多变量分析中，高的42小时血浆MTX与甲酰四氢叶酸比值（MTX暴露的测量）与白质脑病的风险增加相关（P = 0.038）。GWAS揭示了基因多态性丰富的神经发育途径与合理的机制作用，在neurotoxication.Conclusion MTX相关的临床神经毒性是短暂的，大多数患者可以接受后续的MTX没有复发的急性或亚急性症状。所有有症状的患者和五分之一的无症状患者都会发生白质脑病，并可持续至治疗结束。神经发生相关基因的多态性可能导致MTX相关神经毒性的易感性。
Purpose Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity.Patients and Methods Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities.Results Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity.Conclusion MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.