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

Lei WANG; Nan-Ping SHEN; Si-Yao SHI; Miao DU; Jia-Qing YAN; Ying JIANG

doi:10.7499/j.issn.1008-8830.2507052

PDF(601 KB)

Chinese Journal of Contemporary Pediatrics ›› 2026, Vol. 28 ›› Issue (9) : 1163-1169. DOI: 10.7499/j.issn.1008-8830.2507052

REVIEW

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 +

History +

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.

Key words

Acute lymphoblastic leukemia / Central nervous system / Chemotherapy / Neurotoxicity / Child

Cite this article

EndNote

Ris (Procite)

Bibtex

Download Citations

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

References

List( Publishing order | Descend order by publishing year | Descend order by cited within ) Chart analysis

[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 Cited in this article [1]

[2]

Tang

, Yu

, Cai

, 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

Cited in this article [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 Cited in this article [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

Cited in this article [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

Cited in this article [1]

[6]

Rahiman

, Rajendran

, Sankhyan

, 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

Cited in this article [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 Cited in this article [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

Cited in this article [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 Cited in this article [3]

[10]

Thastrup

, Duguid

, Mirian

, 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

Cited in this article [2]

[11]

Mavrea

, Efthymiou

, Katsibardi

, 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

Cited in this article [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

Cited in this article [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

Cited in this article [1]

[14]

Harris

, Taylor

, Raghubar

, 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

Cited in this article [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 Cited in this article [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 . Cited in this article [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 Cited in this article [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 Cited in this article [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 Cited in this article [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

Cited in this article [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

Cited in this article [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

Cited in this article [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 Cited in this article [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 Cited in this article [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

Cited in this article [2]

[26]

Śliwa-Tytko

, Kaczmarska

, Lejman

, 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

Cited in this article [1]

[27]

Bhojwani

, Sabin

, Pei

, 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

Cited in this article [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

Cited in this article [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 Cited in this article [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

Cited in this article [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 Cited in this article [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

Cited in this article [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

Cited in this article [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 Cited in this article [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 Cited in this article [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 . Cited in this article [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 Cited in this article [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 Cited in this article [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 . Cited in this article [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

Cited in this article [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 . Cited in this article [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

Cited in this article [1]

[44]

Bansal

, Bhojwani

, Sun

, 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

Cited in this article [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

Cited in this article [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 . Cited in this article [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 Cited in this article [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 Cited in this article [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

Cited in this article [1]

[50]

Lisgaras

, de la Prida

, Bertram

, 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

Cited in this article [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

Cited in this article [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

Cited in this article [2]

[53]

Hooke

, Mathiason

, Kunin-Batson

, 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

Cited in this article [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 . Cited in this article [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 . Cited in this article [1]