Harris Rachel D, Taylor Olga A, Gramatges M Monica, Hughes Amy E, Zobeck Mark, Pruitt Sandi, Bernhardt M Brooke, Chavana Ashley, Huynh Van, Ludwig Kathleen, Klesse Laura, Heym Kenneth, Griffin Timothy, Erana Rodrigo, Bernini Juan Carlos, Choi Ashley, Ohno Yuu, Richard Melissa A, Morrison Alanna C, Chen Han, Yu Bing, Lupo Philip J, Rabin Karen, Scheurer Michael E, Brown Austin L
Texas Children's Cancer and Hematology Centers, Houston, Texas, USA.
Division of Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
Pharmacotherapy. 2025 Jan;45(1):4-11. doi: 10.1002/phar.4638. Epub 2024 Dec 29.
Methotrexate is an important component of curative therapy in childhood acute lymphoblastic leukemia (ALL), but the role of genetic variation influencing methotrexate clearance and transport in toxicity susceptibility in children with ALL is not well established. Therefore, we evaluated the association between suspected methotrexate pharmacogenomic variants and methotrexate-related neurotoxicity.
This study included children (aged 2-20 years) diagnosed with ALL (2005-2019) at six treatment centers in the southwest United States. Clinical information was abstracted from medical records. Suspected neurotoxic events occurring within 21 days of intravenous and/or intrathecal methotrexate delivered between the end of induction and start of maintenance therapy were independently reviewed by at least two pediatric oncologists. Germline DNA was genotyped and 97 methotrexate pharmacogenomic variants of interest with at least grade 3 evidence were identified using the Pharmacogenomics Knowledge Base. Associations between variants and neurotoxicity were assessed by logistic regression. Data were randomly split (80/20) and random forest was constructed to estimate the ability of the variants to correctly classify neurotoxicity.
Of the 763 patients included in the study, 8.2% (n = 63) developed methotrexate-associated neurotoxicity. In logistic models, none of the 97 available pharmacogenomic variants reached adjusted statistical significance. However, two variants, rs17222723 (odds ratio [OR] = 2.83 [ref. = T allele], 95% confidence interval [CI]: 1.20-6.15) in ABCC2 and rs1045642 (OR = 0.66 [ref. = minor A allele], 95% CI: 0.44-0.98) in ABCB1, were nominally associated (p-value < 0.05) with neurotoxicity susceptibility. The addition of pharmacogenomic variants did not improve the predictive performance of random forest model (AUC = 0.73) compared to clinical information alone (AUC = 0.74).
Overall, our results suggest that associations between neurotoxicity susceptibility and methotrexate pharmacogenomic variants are generally modest and these variants do not significantly improve neurotoxicity risk stratification among children with ALL.
甲氨蝶呤是儿童急性淋巴细胞白血病（ALL）治愈性治疗的重要组成部分，但基因变异在ALL患儿甲氨蝶呤清除及转运中对毒性易感性的影响作用尚未明确。因此，我们评估了疑似甲氨蝶呤药物基因组变异与甲氨蝶呤相关神经毒性之间的关联。
本研究纳入了美国西南部六个治疗中心2005年至2019年诊断为ALL的2至20岁儿童。临床信息从病历中提取。至少两名儿科肿瘤学家独立审查诱导期结束至维持治疗开始期间静脉注射和/或鞘内注射甲氨蝶呤后21天内发生的疑似神经毒性事件。对种系DNA进行基因分型，并使用药物基因组知识库鉴定97个具有至少3级证据的感兴趣的甲氨蝶呤药物基因组变异。通过逻辑回归评估变异与神经毒性之间的关联。数据随机分割（80/20），构建随机森林以估计变异正确分类神经毒性的能力。
研究纳入的763例患者中，8.2%（n = 63）发生了甲氨蝶呤相关神经毒性。在逻辑模型中，97个可用的药物基因组变异均未达到校正后的统计学显著性。然而，ABCC2中的两个变异rs17222723（比值比[OR]=2.83[参照=T等位基因]，95%置信区间[CI]：1.20 - 6.15）和ABCB1中的rs1045642（OR = 0.66[参照=次要A等位基因]，95%CI：0.44 - 0.98）与神经毒性易感性存在名义上的关联（p值<0.05）。与仅使用临床信息相比（AUC = 0.74），添加药物基因组变异并未改善随机森林模型的预测性能（AUC = 0.73）。
总体而言，我们的结果表明神经毒性易感性与甲氨蝶呤药物基因组变异之间的关联通常较弱，且这些变异并未显著改善ALL患儿的神经毒性风险分层。
