Neurotoxicity Associated with Treatment of Acute Lymphoblastic Leukemia Chemotherapy and Immunotherapy

Int J Mol Sci. 2022 May 15;23(10):5515. doi: 10.3390/ijms23105515.


Immunotherapy is a milestone in the treatment of poor-prognosis pediatric acute lymphoblastic leukemia (ALL) and is expected to improve treatment outcomes and reduce doses of conventional chemotherapy without compromising the effectiveness of the therapy. However, both chemotherapy and immunotherapy cause side effects, including neurological ones. Acute neurological complications occur in 3.6-11% of children treated for ALL. The most neurotoxical chemotherapeutics are L-asparaginase (L-ASP), methotrexate (MTX), vincristine (VCR), and nelarabine (Ara-G). Neurotoxicity associated with methotrexate (MTX-NT) occurs in 3-7% of children treated for ALL and is characterized by seizures, stroke-like symptoms, speech disturbances, and encephalopathy. Recent studies indicate that specific polymorphisms in genes related to neurogenesis may have a predisposition to MTX toxicity. One of the most common complications associated with CAR T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS). Mechanisms of neurotoxicity in CAR T-cell therapy are still unknown and may be due to disruption of the blood-brain barrier and the effects of elevated cytokine levels on the central nervous system (CNS). In this review, we present an analysis of the current knowledge on the mechanisms of neurotoxicity of standard chemotherapy and the targeted therapy in children with ALL.

Keywords: acute lymphoblastic leukemia; chemotherapy; immunotherapy; neurotoxicity.

Publication types

  • Review

MeSH terms

  • Asparaginase
  • Child
  • Drug-Related Side Effects and Adverse Reactions* / drug therapy
  • Humans
  • Immunologic Factors / therapeutic use
  • Immunotherapy, Adoptive / adverse effects
  • Methotrexate / adverse effects
  • Neurotoxicity Syndromes* / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / complications
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy


  • Immunologic Factors
  • Asparaginase
  • Methotrexate

Grants and funding

This research received no external funding.