大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病对碱性磷酸酶的影响

doi:10.12092/j.issn.1009-2501.2025.08.011

摘要/Abstract

摘要： 目的：探讨大剂量甲氨蝶呤（MTX）对碱性磷酸酶（ALP）的影响、ALP的变化对骨骼代谢、骨髓粒系功能、肝功能及排泄的影响。方法：对某儿童医院血液肿瘤科2022年1月至2024年3月收治的急性淋巴细胞白血病（acute lymphoblastic leukemia,ALL）患儿巩固化疗前后生化、电解质、血常规指标及甲氨蝶呤C_48h血液浓度进行回顾性分析,以天门冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、白蛋白（ALB）为肝功指标,血清钙（Ca）、磷（P）为骨代谢指标,中性粒细胞（ANC）、白细胞计数（WBC）为骨髓粒系功能观测指标,以甲氨蝶呤C_48h浓度≥1 μmol/L为排泄延迟;对首次化疗、再次化疗前后ALP水平进行单因素方差分析,按ALP水平将再次化疗患儿分成正常组及低下组,对化疗前后7项指标进行定量及定性分析,并对再次化疗患儿甲氨蝶呤C_48h浓度与上述指标进行单因素及多因素Logistic回归分析。结果：首次化疗、再次化疗后,ALP明显降低[（204.0±83.6）U/L vs. （172.8±67.3）U/L,（179.4±59.3）U/L vs. （169.6±57.1）U/L,P均<0.05],ALP低下患儿再次化疗后,血清Ca、P、ANC、WBC、ALB均明显降低（P<0.05）,AST、ALT升高（P<0.05）;ALT是排泄延迟独立危险因素（OR=1.049,95%CI 1.023~1.077,P<0.001）,ALB为排泄延迟独立保护因素（OR=0.551,95%CI 0.460~0.660,P<0.001）,ALP不甲氨蝶呤排泄延迟的显著影响因素。结论：大剂量甲氨蝶呤导致ALP显著下降,伴随整个巩固化疗过程,ALP不是一个良好的肝功及骨髓粒系功能的预测指标,ALP连同血清钙磷水平可以构成骨代谢障碍的一个预警指标,ALL患儿接受甲氨蝶呤巩固化疗期间,可适量补充钙剂。

关键词: 大剂量甲氨蝶呤, 急性淋巴细胞白血病, 碱性磷酸酶, 骨代谢, 排泄延迟

Abstract: AIM: To investigate the effects of high-dose methotrexate (MTX) on alkaline phosphatase (ALP) and the effects of ALP changes on bone metabolism, bone marrow granulogram function, liver function and excretion. METHODS: Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and albumin (ALB) were used as liver function indicators, serum calcium (Ca) and phosphorus (P) were used as bone metabolism indicators, neutrophil (ANC) and white blood cell count (WBC) were used as bone marrow granuloline function indicators, and methotrexate C_48h concentration ≥1 μmol/L was used as the excretion delay. One-way ANOVA analysis was performed on the ALP levels before and after the first chemotherapy and the second chemotherapy, and the children were divided into normal group and low group according to the ALP level, and the seven indexes before and after chemotherapy were quantitatively and qualitatively analyzed, and univariate and multivariate Logistic regression analysis was performed on the concentration of methotrexate C_48h and the above indexes in the children treated with the second chemotherapy. RESULTS: After the first chemotherapy and the second chemotherapy, ALP was significantly decreased [(204.0±83.6) U/L vs.(172.8±67.3) U/L, (179.4±59.3) U/L vs. (169.6±57.1) U/L, all P<0.05], and the serum Ca, P, ANC, WBC, and ALB were significantly decreased (P<0.05), and AST and ALT were increased (P<0.05), and ALT was an independent risk factor for delayed excretion (OR=1.049, 95%CI 1.023-1.077, P<0.001), ALB was an independent protective factor for delayed excretion (OR=0.551, 95% CI 0.460-0.660, P<0.001), and ALP was not a significant contributor to MTX excretion delay. CONCLUSION: ALP is not a good predictor of liver function and bone marrow granulopathy function due to a significant decrease in ALP caused by high-dose MTX, and ALP together with serum calcium and phosphorus levels can constitute an early warning indicator of bone metabolism disorders.

Key words: high-dose methotrexate, acute lymphoblastic leukemia, alkaline phosphatase, bone metabolism, delayed excretion

中图分类号:

李新贵, 徐达良, 于飚, 顾筠, 邓妍, 张诗海. 大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病对碱性磷酸酶的影响[J]. 中国临床药理学与治疗学, 2025, 30(8): 1099-1104.

LI Xingui¹, XU Daliang², YU Biao¹, GU Yun¹, DENG Yan¹, ZHANG Shihai³. Effect of high-dose methotrexate on alkaline phosphatase in children with acute lymphoblastic leukemia[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2025, 30(8): 1099-1104.

参考文献

[1] Polesie S, Gillstedt M, Paoli J, et al.Methotrexate exposure and risk of cutaneous malignant melanoma: Investigation of a possible dose-response relationship[J]. Acta DV, 2018, 98(9): 888-895.
[2] Chinese Society of Clinical Oncology. Expert consensus on high-dose methotrexate-calcium folate-rescue therapy for malignant tumors[J]. Chin Oncol Clin, 2019, 46(15): 761-767.
[3] 热比姑丽·伊斯拉木, 尤力都孜·买买提, 买合素提·卡德尔, 等. 甲氨蝶呤片对正常大鼠血液生化指标的影响[J]. 中国药业, 2015, 24(10): 17-19.
[4] 石倩倩, 赵相卓, 王颖, 等. 小剂量甲氨蝶呤治疗幼年型类风湿关节炎的疗效及其急性肝损伤作用[J]. 中南医学科学杂志, 2023, 51(6): 920-922.
[5] 王磊庆, 何咏霖, 廖智鹏, 等. 机械压应力对成骨细胞分化增殖和碱性磷酸酶的影响[J]. 兰州大学学报(医学版), 2022, 48(8): 71-75.
[6] 陈晨, 张媛, 吴彦霖, 等. 骨肽原液抗骨质疏松的药效学研究[J]. 中国药理学通报, 2020, 36(7): 1012-1018.
[7] Cao XX, Gao YQ, Zhang WH, et al.Cholestasis morbidity rate in frist-hospitalized patients with chronic liver disease in Shanghai[J]. Zhonghua Gan Zang Bing Za Zhi, 2015, 23(8): 569-573.
[8] 李春姬, 元顺女, 曲风珍. 急性淋巴细胞白血病与急性非淋巴细胞白血病骨髓细胞碱性磷酸酶活性的检测结果分析[J]. 中国当代医药, 2015, 22(36): 105-107.
[9] 高增杰, 覃裕, 宋红. 贵阳市1000例患者25-羟维生素D缺乏及临床特征[J]. 中国骨质疏松杂志, 2022, 28(8): 1192-1196.
[10] 国家卫生健康委员会. 关于印发儿童急性淋巴细胞白血病、儿童急性早幼粒细胞白血病治疗规范(2018)的通知: 国卫办医函[2018]868号[EB/OL]. http://www.nhc.gov.cn/yzygj/s7653/201810/aef82930claf4fc5bf325938e2fcb075.shtml.
[11] Sari1 NM, Rakhmilla LE, Bashari MH, et al. Monitoring of high-dose methotrexate (mtx)-related toxicity and mtx levels in children with acute lymphoblastic leukemia: a pilot-study in indonesia[J]. Asian Pac J Cancer Prev, 2021, 22(7): 2025-2031.
[12] 于丽婷, 杨秋实, 张顺国, 等. 高剂量甲氨蝶呤排泄延迟解救措施的病例系列报告[J]. 中国循证儿科杂志, 2023, 18(1): 71-74.
[13] 陈益勤. 碱性磷酸酶和骨碱性磷酸酶检测在小儿缺钙筛查中的运用分析[J]. 现代诊断与治疗, 2023, 34(23): 3580-3582.
[14] 钱方方, 戴梅清, 赵丽, 等. 血清碱性磷酸酶与2型糖尿病合并非酒精性脂肪肝病的相关性分析[J]. 临床肝胆病杂志, 2023, 39(1): 83-88.
[15] 《中国骨质疏松杂志》骨代谢专家组. 骨代谢生化指标临床应用专家共识(2023修订版)[J]. 中国骨质疏松杂志, 2023, 29(4): 469-476.
[16] 宋倩. NAP-PCT-CRP联合检测对骨科术后感染的诊断价值[J]. 临床输血与检验, 2019, 21(2): 183-186.
[17] 黄凯. CRP与ESR在骨科内固定手术后的表达变化及意义[J]. 标记免疫分析与临床, 2016, 23(8): 874-877.
[18] 卢晶, 张雅敏, 李华, 等. 血清甲胎蛋白联合碱性磷酸酶评分对可切除肝细胞癌患者预后的预测价值[J].临床肝胆病杂志, 2023, 39(3): 599-605.
[19] 曹琳, 居博伟, 冉峥, 等. 肉苁蓉苯乙醇总苷对胆汁淤积型肝病小鼠的预防保护作用[J]. 中国药物警戒, 2023, 20(3): 286-291.
[20] Zaiwei S, Yang H, Shuang L, et al.Evidence-based practice guideline of medication therapy of high-dose methotrexate in china[J]. Br J Clin Pharmacol, 2022, 88(5): 2456-2472.
[21] 彭澎, 罗晓明, 王欣欣, 等. 大剂量甲氨蝶呤化疗致肝脏毒副作用的观察[J]. 浙江预防医学, 2003, 15(9): 56-57.
[22] Douvas MG, Riegler LL.Meeting challenges in the long-term care of children,adolescents, and young adults with acute lymphoblastic leukemia[J]. Curr Hematol Malig R, 2022, 17(1): 15-24.
[23] Cheung YT, Zhang H, Cai J, et al.Identifying priorities for harmonizing guidelines for the long-term surveillance of childhood cancer survivors in the chinese children cancer group (CCCG)[J]. JCO Glob Oncol, 2021, 7: 261-276.
[24] Van Atteveld JE, de Winter DT, Pieters R, et al. Recent perspectives on the association between osteonecrosis and bone mineral density decline in childhood acute lymphoblastic leukemia[J]. Fac Rev, 2021, 10: 57.
[25] 侯林, 王春晓, 谭江威, 等. 骨代谢标志物及其在骨质疏松诊断中的应用进展[J]. 中国医药导报, 2020, 17(28): 44-47.
[26] 唐秋灵, 马廉. 糖皮质激素对急性淋巴细胞白血病患儿骨骼的影响[J]. 北京医学, 2014, 36(4): 309-313.
[27] 钱卿, 胡楠, 陈荣, 等. 大剂量甲氨蝶呤治疗血液系统恶性肿瘤后排泄延迟的影响因素及其与不良反应的相关性研究[J]. 中国医院用药评价与分析, 2020, 20(1): 56-59.
[28] 宋再伟, 刘爽, 赵荣生, 等.《中国大剂量甲氨蝶呤循证用药指南》解读[J]. 中国药房, 2022, 33(16): 2032-2039.
[29] 中国临床肿瘤学会抗淋巴瘤联盟, 中国临床肿瘤学会抗白血病联盟, 中华医学会血液学分会, 等. 恶性血液病患者药物性肝损伤的预防和规范化治疗中国专家共识(2021年版)[J].中华血液学杂志, 2021, 42(3): 185-192.
[30] 朱露林, 张奇, 刘梦琴, 等. 中药及天然药物对甲氨蝶呤致肝损伤保护作用的研究进展[J]. 中国中药杂志, 2021, 46(7): 1727-1737.
[31] 赵嘉澍, 赵志刚, 王睿韬, 等. 大剂量甲氨蝶呤化疗后延迟排泄的影响因素和发生机制的研究进展[J]. 现代肿瘤医学, 2021, 29(17): 3104-4108.
[32] 赵嘉澍, 梅升辉, 王睿韬, 等. 大剂量甲氨蝶呤治疗儿童颅内生殖细胞瘤延迟排泄的影响因素[J]. 医学综述, 2022, 28(7): 1430-1434.