急性淋巴细胞白血病患儿化疗相关中枢神经系统损伤的研究进展

王蕾; 沈南平; 石思瑶; 杜苗; 严佳清; 蒋颖

doi:10.7499/j.issn.1008-8830.2507052

PDF(601 KB)

HTML

中国当代儿科杂志 ›› 2026, Vol. 28 ›› Issue (9) : 1163-1169. DOI: 10.7499/j.issn.1008-8830.2507052

综述

急性淋巴细胞白血病患儿化疗相关中枢神经系统损伤的研究进展

王蕾 ¹^,² ,
沈南平 ³ ,
石思瑶 ¹^,² ,
杜苗 ² ,
严佳清 ¹^,² (综述) ,
蒋颖 ² (审校)

作者信息 +

Chemotherapy-related central nervous system injury in children with acute lymphoblastic leukemia: research progress

Lei WANG ¹^,² ,
Nan-Ping SHEN ³ ,
Si-Yao SHI ¹^,² ,
Miao DU ² ,
Jia-Qing YAN ¹^,² ,
Ying JIANG ²

Author information +

文章历史 +

摘要

急性淋巴细胞白血病是最常见的儿童恶性肿瘤。随着医疗技术水平的提升，虽然患儿的生存率得以显著提高，但化疗相关中枢神经系统损伤问题日益凸显，严重影响患儿的神经功能预后和生活质量。该文综述了急性淋巴细胞白血病患儿化疗相关中枢神经系统损伤的临床表现、影像学与生物标志物诊断、药物毒性机制，并探讨了当前的治疗干预策略与存在的管理挑战。目前缺乏系统化的干预方案与分阶段管理路径，未来需结合治疗阶段及化疗方案制定更精准的中枢神经系统损伤预防管理策略。该综述旨在为临床医护人员深入理解急性淋巴细胞白血病患儿化疗相关中枢神经系统损伤的机制、识别与长期管理提供参考。

Abstract

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Although therapeutic advances have markedly improved survival, chemotherapy-related central nervous system (CNS) injury is increasingly recognized as a major determinant of neurofunctional outcomes and quality of life. This review summarizes the clinical manifestations, imaging characteristics, and biomarker-based approaches to diagnosing chemotherapy-related CNS injury in children with ALL; outlines drug-induced neurotoxic mechanisms; and discusses current therapeutic and supportive interventions alongside persistent management challenges. There is no standardized, stage-specific care pathway or integrated intervention program at present. Future strategies should align prevention and management with treatment phase and chemotherapy regimen to achieve more precise CNS protection. This review aims to provide information for clinical healthcare professionals to deepen their understanding of the mechanisms, identification, and long-term management of chemotherapy-related CNS injury in children with ALL.

导出引用

王蕾, 沈南平, 石思瑶, 等. 急性淋巴细胞白血病患儿化疗相关中枢神经系统损伤的研究进展[J]. 中国当代儿科杂志. 2026, 28(9): 1163-1169 https://doi.org/10.7499/j.issn.1008-8830.2507052

Lei WANG, Nan-Ping SHEN, Si-Yao SHI, et al. Chemotherapy-related central nervous system injury in children with acute lymphoblastic leukemia: research progress[J]. Chinese Journal of Contemporary Pediatrics. 2026, 28(9): 1163-1169 https://doi.org/10.7499/j.issn.1008-8830.2507052

参考文献

列表( 原文顺序 | 文献年度倒序 | 文中引用次数倒序 ) 可视化分析

[1]	Inaba H, Pui CH. Advances in the diagnosis and treatment of pediatric acute lymphoblastic leukemia [J]. J Clin Med, 2021, 10(9): 1926. PMCID: PMC8124693. DOI: 10.3390/jcm10091926 . https://www.ncbi.nlm.nih.gov/pubmed/33946897 本文引用 [1]

[2]	Tang J, Yu J, Cai J, et al. Prognostic factors for CNS control in children with acute lymphoblastic leukemia treated without cranial irradiation[J]. Blood, 2021, 138(4): 331-343. PMCID: PMC8323972. DOI: 10.1182/blood.2020010438 . https://www.ncbi.nlm.nih.gov/pubmed/33684941 本文引用 [1]

[3]	Birenboim SB, Rabinowicz R. Acute therapy-related toxicities in pediatric acute lymphoblastic leukemia[J]. Haematologica, 2025, 110(9): 1923-1933. PMCID: PMC12399958. DOI: 10.3324/haematol.2024.285702 . https://www.ncbi.nlm.nih.gov/pubmed/40045890 本文引用 [1]

[4]

Anastasopoulou

, Nielsen

, Als-Nielsen

, et al. Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia: phenotypes, risk factors and genotypes[J]. Haematologica, 2022, 107(10): 2318-2328. PMCID: PMC9521239. DOI: 10.3324/haematol.2021.280016 .

https://www.ncbi.nlm.nih.gov/pubmed/35354251

本文引用 [1]

[5]

Kranjčec

, Rajačić

, Janjić

, et al. Acute neurotoxicity in children treated for acute lymphoblastic leukemia and lymphoblastic lymphoma: a 10-year single-centre experience[J]. Children (Basel), 2025, 12(1): 31. PMCID: PMC11763474. DOI: 10.3390/children12010031 .

https://www.ncbi.nlm.nih.gov/pubmed/39857862

本文引用 [1]

[6]	Rahiman EA, Rajendran A, Sankhyan N, et al. Acute neurological complications during acute lymphoblastic leukemia therapy: a single-center experience over 10 years[J]. Indian J Cancer, 2021, 58(4): 545-552. DOI: 10.4103/ijc.IJC_422_19 . https://www.ncbi.nlm.nih.gov/pubmed/34380827 本文引用 [2]

[7]	Roganovic J, Haupt R, Bárdi E, et al. Late adverse effects after treatment for childhood acute leukemia[J]. Acta Med Acad, 2024, 53(1): 59-80. PMCID: PMC11237916. DOI: 10.5644/ama2006-124.438 . https://www.ncbi.nlm.nih.gov/pubmed/38984700 本文引用 [1]

[8]

Keleş Gülnerman

, Çam

, Elbasan

, et al. The contribution of neurocognitive situation, physical capacity and daily life activities to quality of life in childhood acute lymphoblastic leukemia survivors[J]. Turk J Med Sci, 2021, 51(5): 2510-2515. PMCID: PMC8742482. DOI: 10.3906/sag-2010-299 .

https://www.ncbi.nlm.nih.gov/pubmed/34174789

本文引用 [1]

[9]	Ekici A, Ayan B, Kazancı EG, et al. Central nervous system complications during treatment in childhood acute leukemia[J]. Acta Neurol Belg, 2025, 125(1): 77-88. DOI: 10.1007/s13760-024-02602-0 . https://www.ncbi.nlm.nih.gov/pubmed/39192159 本文引用 [3]

[10]	Thastrup M, Duguid A, Mirian C, et al. Central nervous system involvement in childhood acute lymphoblastic leukemia: challenges and solutions[J]. Leukemia, 2022, 36(12): 2751-2768. PMCID: PMC9712093. DOI: 10.1038/s41375-022-01714-x . https://www.ncbi.nlm.nih.gov/pubmed/36266325 本文引用 [2]

[11]	Mavrea K, Efthymiou V, Katsibardi K, et al. Cognitive function of children and adolescent survivors of acute lymphoblastic leukemia: a meta-analysis[J]. Oncol Lett, 2021, 21(4): 262. PMCID: PMC7882890. DOI: 10.3892/ol.2021.12523 . https://www.ncbi.nlm.nih.gov/pubmed/33664825 本文引用 [1]

[12]

Hamoda

, Bedair

, Semary

, et al. Patterns and outcomes of acute central nervous system complications during treatment of childhood acute lymphoblastic leukemia: a single-center experience[J]. J Pediatr Hematol Oncol, 2024, 46(2): 72-79. DOI: 10.1097/MPH.0000000000002797 .

https://www.ncbi.nlm.nih.gov/pubmed/38132573

本文引用 [2]

[13]

Ramanathan

, Subramani

, Kembhavi

, et al. Clinical features, predictors and outcome of posterior reversible encephalopathy syndrome (PRES) in children with hematolymphoid malignancies[J]. Childs Nerv Syst, 2022, 38(9): 1689-1698. DOI: 10.1007/s00381-022-05557-w .

https://www.ncbi.nlm.nih.gov/pubmed/35614149

本文引用 [1]

[14]	Harris RD, Taylor OA, Raghubar KP, et al. Episodes of acute methotrexate-related neurotoxicity linked to compromised long-term neurocognitive function[J]. Pediatr Blood Cancer, 2024, 71(9): e31169. PMCID: PMC11514057. DOI: 10.1002/pbc.31169 . https://www.ncbi.nlm.nih.gov/pubmed/38961583 本文引用 [1]

[15]	覃李娇, 麦惠容. 急性淋巴细胞白血病儿童认知功能损害的临床研究进展[J]. 中国当代儿科杂志, 2023, 25(3): 315-320. PMCID: PMC10032075. DOI: 10.7499/j.issn.1008-8830.2210063 . https://www.ncbi.nlm.nih.gov/pubmed/36946169 本文引用 [1]

[16]	褚思嘉, 汤继宏, 张兵兵, 等. 儿童急性淋巴细胞白血病化疗伴发白质脑病的临床特点及远期随访[J]. 中国小儿血液与肿瘤杂志, 2024, 29(5): 332-336, 343. DOI: 10.3969/j.issn.1673-5323.2024.05.006 . 本文引用 [1]

[17]	Schroyen G, Meylaers M, Deprez S, et al. Prevalence of leukoencephalopathy and its potential cognitive sequelae in cancer patients[J]. J Chemother, 2020, 32(7): 327-343. DOI: 10.1080/1120009X.2020.1805239 . https://www.ncbi.nlm.nih.gov/pubmed/32799637 本文引用 [1]

[18]	Peng L, Yang LS, Yam P, et al. Neurocognitive and behavioral outcomes of Chinese survivors of childhood lymphoblastic leukemia[J]. Front Oncol, 2021, 11: 655669. PMCID: PMC8093634. DOI: 10.3389/fonc.2021.655669 . https://www.ncbi.nlm.nih.gov/pubmed/33959507 本文引用 [1]

[19]	Phillips NS, Duke ES, Schofield HT, et al. Neurotoxic effects of childhood cancer therapy and its potential neurocognitive impact[J]. J Clin Oncol, 2021, 39(16): 1752-1765. PMCID: PMC8260913. DOI: 10.1200/JCO.20.02533 . https://www.ncbi.nlm.nih.gov/pubmed/33886374 本文引用 [1]

[20]

Latoch

, Zubowska

, Młynarski

, et al. Late effects of childhood cancer treatment in long-term survivors diagnosed before the age of 3 years: a multicenter, nationwide study[J]. Cancer Epidemiol, 2022, 80: 102209. DOI: 10.1016/j.canep.2022.102209 .

https://www.ncbi.nlm.nih.gov/pubmed/35868173

本文引用 [1]

[21]

Laniel

, Sultan

, Sinnett

, et al. Cumulative dosage of intrathecal chemotherapy agents predicts white matter integrity in long-term survivors of acute lymphoblastic leukemia: a PETALE study[J]. Cancers (Basel), 2024, 16(6): 1208. PMCID: PMC10969288. DOI: 10.3390/cancers16061208 .

https://www.ncbi.nlm.nih.gov/pubmed/38539543

本文引用 [1]

[22]

Joo

, Yang

, Koh

. Molecular and mechanistic divergence of seizures in pediatric acute lymphoblastic leukemia: CNS infiltration versus chemotherapy-induced neurotoxicity[J]. Int J Mol Sci, 2026, 27(7): 3307. PMCID: PMC13073153. DOI: 10.3390/ijms27073307 .

https://www.ncbi.nlm.nih.gov/pubmed/41977486

本文引用 [1]

[23]	Apiraksattayakul N, Jitprapaikulsan J, Sanpakit K, et al. Potential neurotoxicity associated with methotrexate[J]. Sci Rep, 2024, 14(1): 18548. PMCID: PMC11315891. DOI: 10.1038/s41598-024-69263-0 . https://www.ncbi.nlm.nih.gov/pubmed/39122917 本文引用 [1]

[24]	Inaba H, Mullighan CG. Pediatric acute lymphoblastic leukemia[J]. Haematologica, 2020, 105(11): 2524-2539. PMCID: PMC7604619. DOI: 10.3324/haematol.2020.247031 . https://www.ncbi.nlm.nih.gov/pubmed/33054110 本文引用 [1]

[25]

Mateos

, Marshall

, Barbaro

, et al. Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia[J]. Haematologica, 2022, 107(3): 635-643. PMCID: PMC8883571. DOI: 10.3324/haematol.2020.268565 .

https://www.ncbi.nlm.nih.gov/pubmed/33567813

本文引用 [2]

[26]	Śliwa-Tytko P, Kaczmarska A, Lejman M, et al. Neurotoxicity associated with treatment of acute lymphoblastic leukemia chemotherapy and immunotherapy[J]. Int J Mol Sci, 2022, 23(10): 5515. PMCID: PMC9146746. DOI: 10.3390/ijms23105515 . https://www.ncbi.nlm.nih.gov/pubmed/35628334 本文引用 [1]

[27]	Bhojwani D, Sabin ND, Pei D, et al. Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia[J]. J Clin Oncol, 2014, 32(9): 949-959. PMCID: PMC3948096. DOI: 10.1200/JCO.2013.53.0808 . https://www.ncbi.nlm.nih.gov/pubmed/24550419 本文引用 [1]

[28]

Pryweller

, Glass

, Sabin

, et al. Characterization of leukoencephalopathy and association with later neurocognitive performance in pediatric acute lymphoblastic leukemia[J]. Invest Radiol, 2021, 56(2): 117-126. PMCID: PMC8059361. DOI: 10.1097/RLI.0000000000000715 .

https://www.ncbi.nlm.nih.gov/pubmed/32769417

本文引用 [1]

[29]	Dabagh S, David H, Young S, et al. Severe, fatal methotrexate-related neurotoxicity in 2 adolescent patients with ALL[J]. J Pediatr Hematol Oncol, 2020, 42(8): e839-e844. PMCID: PMC7469921. DOI: 10.1097/MPH.0000000000001706 . https://www.ncbi.nlm.nih.gov/pubmed/31876782 本文引用 [1]

[30]

Di Francia

, Crisci

, De Monaco

, et al. Response and toxicity to cytarabine therapy in leukemia and lymphoma: from dose puzzle to pharmacogenomic biomarkers[J]. Cancers (Basel), 2021, 13(5): 966. PMCID: PMC7956511. DOI: 10.3390/cancers13050966 .

https://www.ncbi.nlm.nih.gov/pubmed/33669053

本文引用 [1]

[31]	Kamińska K, Cudnoch-Jędrzejewska A. A review on the neurotoxic effects of doxorubicin[J]. Neurotox Res, 2023, 41(5): 383-397. PMCID: PMC10499694. DOI: 10.1007/s12640-023-00652-5 . https://www.ncbi.nlm.nih.gov/pubmed/37351828 本文引用 [1]

[32]

Anastasopoulou

, Swann

, Andres-Jensen

, et al. Severe steroid-related neuropsychiatric symptoms during paediatric acute lymphoblastic leukaemia therapy: an observational Ponte di Legno Toxicity Working Group Study [J]. Br J Haematol, 2024, 205(4): 1450-1459. DOI: 10.1111/bjh.19610 .

https://www.ncbi.nlm.nih.gov/pubmed/38924051

本文引用 [1]

[33]

van Hulst

, Grootenhuis

, Verwaaijen

, et al. Unraveling dexamethasone-induced neurobehavioral and sleep problems in children with ALL: which determinants are important?[J]. JCO Precis Oncol, 2023, 7: e2200678. PMCID: PMC10309531. DOI: 10.1200/PO.22.00678 .

https://www.ncbi.nlm.nih.gov/pubmed/37343203

本文引用 [1]

[34]	Wu SY, Short NJ, Nasr L, et al. Central nervous system prophylaxis and treatment in acute leukemias[J]. Curr Treat Options Oncol, 2022, 23(12): 1829-1844. PMCID: PMC9767998. DOI: 10.1007/s11864-022-01032-5 . https://www.ncbi.nlm.nih.gov/pubmed/36510037 本文引用 [1]

[35]	Maese L, Rau RE. Current use of asparaginase in acute lymphoblastic leukemia/lymphoblastic lymphoma[J]. Front Pediatr, 2022, 10: 902117. PMCID: PMC9279693. DOI: 10.3389/fped.2022.902117 . https://www.ncbi.nlm.nih.gov/pubmed/35844739 本文引用 [1]

[36]	原琴琴, 周玉敏, 顾兵, 等. 低剂量甲氨蝶呤的抗炎作用机制及其在脊髓损伤中应用[J]. 中国药理学通报, 2017, 33(3): 312-316. DOI: 10.3969/j.issn.1001-1978.2017.03.005 . 本文引用 [1]

[37]	Was H, Borkowska A, Bagues A, et al. Mechanisms of chemotherapy-induced neurotoxicity[J]. Front Pharmacol, 2022, 13: 750507. PMCID: PMC8996259. DOI: 10.3389/fphar.2022.750507 . https://www.ncbi.nlm.nih.gov/pubmed/35418856 本文引用 [2]

[38]	Shao Y, Tan B, Shi J, et al. Methotrexate induces astrocyte apoptosis by disrupting folate metabolism in the mouse juvenile central nervous system[J]. Toxicol Lett, 2019, 301: 146-156. DOI: 10.1016/j.toxlet.2018.11.016 . https://www.ncbi.nlm.nih.gov/pubmed/30502384 本文引用 [1]

[39]	Lee NW, Lee KH. Methotrexate-induced stroke-like leukoencephalopathy[J]. Ann Child Neurol, 2024, 32(3): 193-196. DOI: 10.26815/acn.2024.00507 . 本文引用 [1]

[40]

Alhowail

. Cisplatin induces hippocampal neurotoxicity and cognitive impairment in rats through neuroinflammation, oxidative stress, and overexpression of glutamatergic receptors mRNA[J]. Front Pharmacol, 2025, 16: 1592511. PMCID: PMC12163336. DOI: 10.3389/fphar.2025.1592511 .

https://www.ncbi.nlm.nih.gov/pubmed/40520187

本文引用 [1]

[41]	Almalki RS, Eweis H, Kamal F, et al. Methotrexate toxicity: molecular mechanisms and management[J]. J Pharm Res Int, 2021, 33(49B): 204-217. DOI: 10.9734/JPRI/2021/v33i49B33357 . 本文引用 [2]

[42]

Zou

, Su

, Xu

, et al. Structural brain alteration in survivors of acute lymphoblastic leukemia with chemotherapy treatment: a voxel-based morphometry and diffusion tensor imaging study[J]. Brain Res, 2017, 1658: 68-72. DOI: 10.1016/j.brainres.2017.01.017 .

https://www.ncbi.nlm.nih.gov/pubmed/28109978

[43]

Gandy

, Scoggins

, Jacola

, et al. Structural and functional brain imaging in long-term survivors of childhood acute lymphoblastic leukemia treated with chemotherapy: a systematic review[J]. JNCI Cancer Spectr, 2021, 5(5): pkab069. PMCID: PMC8421809. DOI: 10.1093/jncics/pkab069 .

https://www.ncbi.nlm.nih.gov/pubmed/34514328

本文引用 [1]

[44]	Bansal R, Bhojwani D, Sun BF, et al. Progression of brain injuries associated with methotrexate chemotherapy in childhood acute lymphoblastic leukemia[J]. Pediatr Res, 2025, 97(1): 348-359. PMCID: PMC11798858. DOI: 10.1038/s41390-024-03351-9 . https://www.ncbi.nlm.nih.gov/pubmed/38951657 本文引用 [1]

[45]

Guo

, Han

, Li

, et al. Reduced brain microstructural asymmetry in patients with childhood leukemia treated with chemotherapy compared with healthy controls[J]. PLoS One, 2019, 14(5): e0216554. PMCID: PMC6508708. DOI: 10.1371/journal.pone.0216554 .

https://www.ncbi.nlm.nih.gov/pubmed/31071157

本文引用 [1]

[46]	褚思嘉, 汤继宏. 儿童急性淋巴细胞白血病及其治疗所伴发的中枢神经系统损伤研究进展[J]. 临床儿科杂志, 2024, 42(9): 811-816. DOI: 10.12372/jcp.2024.23e0892 . 本文引用 [1]

[47]	Deak D, Gorcea-Andronic N, Sas V, et al. A narrative review of central nervous system involvement in acute leukemias[J]. Ann Transl Med, 2021, 9(1): 68. PMCID: PMC7859772. DOI: 10.21037/atm-20-3140 . https://www.ncbi.nlm.nih.gov/pubmed/33553361 本文引用 [1]

[48]	Badr MA, Hassan TH, El-Gerby KM, et al. Magnetic resonance imaging of the brain in survivors of childhood acute lymphoblastic leukemia[J]. Oncol Lett, 2013, 5(2): 621-626. PMCID: PMC3573121. DOI: 10.3892/ol.2012.1072 . https://www.ncbi.nlm.nih.gov/pubmed/23420690 本文引用 [1]

[49]

Fellah

, Cheung

, Scoggins

, et al. Brain activity associated with attention deficits following chemotherapy for childhood acute lymphoblastic leukemia [J]. J Natl Cancer Inst, 2019, 111(2): 201-209. PMCID: PMC6376909. DOI: 10.1093/jnci/djy089 .

https://www.ncbi.nlm.nih.gov/pubmed/29790971

本文引用 [1]

[50]	Lisgaras CP, de la Prida LM, Bertram E, et al. The role of electroencephalography in epilepsy research: from seizures to interictal activity and comorbidities[J]. Epilepsia, 2025, 66(5): 1374-1393. PMCID: PMC12097480. DOI: 10.1111/epi.18282 . https://www.ncbi.nlm.nih.gov/pubmed/39913107 本文引用 [1]

[51]

Kroczka

, Stepien

, Witek-Motyl

, et al. Clinical utility of complex assessment with evoked potentials in acute lymphoblastic leukemia survivors: comparison of various treatment protocols[J]. BMC Cancer, 2021, 21(1): 150. PMCID: PMC7876796. DOI: 10.1186/s12885-021-07873-x .

https://www.ncbi.nlm.nih.gov/pubmed/33568096

本文引用 [1]

[52]

Cheung

, Khan

, Liu

, et al. Association of cerebrospinal fluid biomarkers of central nervous system injury with neurocognitive and brain imaging outcomes in children receiving chemotherapy for acute lymphoblastic leukemia[J]. JAMA Oncol, 2018, 4(7): e180089. PMCID: PMC5885182. DOI: 10.1001/jamaoncol.2018.0089 .

https://www.ncbi.nlm.nih.gov/pubmed/29596541

本文引用 [2]

[53]	Hooke MC, Mathiason MA, Kunin-Batson AS, et al. Biomarkers and cognitive function in children and adolescents during maintenance therapy for leukemia[J]. Oncol Nurs Forum, 2021, 48(6): 623-633. PMCID: PMC12817264. DOI: 10.1188/21.ONF.623-633 . https://www.ncbi.nlm.nih.gov/pubmed/34673759 本文引用 [1]

[54]	陈福宜, 吴婕翎, 马廉. 儿童急性淋巴细胞白血病长期生存的康复管理[J]. 肿瘤防治研究, 2022, 49(9): 893-898. DOI: 10.3971/j.issn.1000-8578.2022.22.0110 . 本文引用 [1]

[55]	孟岑, 徐刚. 儿童急性淋巴细胞白血病中ABCB1C3435T位点基因多态性对大剂量甲氨蝶呤血药浓度及不良反应的影响[J]. 实用药物与临床, 2021, 24(1): 43-47. DOI: 10.14053/j.cnki.ppcr.202101009 . 本文引用 [1]