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Methotrexate-Induced Neurotoxicity Does Not Preclude Rechallenge in Children With ALL

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Key Points

  • Methotrexate-related clinical neurotoxicity was transient and did not prevent retreatment in most patients.
  • Polymorphisms in genes related to neurogenesis may contribute to susceptibility to neurotoxicity.

In a study reported in the Journal of Clinical Oncology, Bhojwani et al from St. Jude Children’s Research Hospital assessed clinical, pharmacokinetic, and genetic risk factors for methotrexate-related clinical neurotoxicity and asymptomatic leukoencephalopathy in children with acute lymphoblastic leukemia (ALL). They found that methotrexate-related clinical neurotoxicity is transient, with most patients being able to receive subsequent methotrexate treatment, and that polymorphisms in genes related to neurogenesis may contribute to susceptibility to neurotoxicity.

Does Not Preclude Retreatment

In the study, prospective brain magnetic resonance imaging was performed at four time points in 369 children with ALL treated in a contemporary study that included five courses of high-dose methotrexate and 13 to 25 doses of triple intrathecal therapy. Overall, 14 patients (3.8%) developed methotrexate-related clinical neurotoxicity.

Although age > 10 years vs ≤ 10 years (P = .003) and standard/high risk vs low risk disease (P = .016) were associated with increased risk for neurotoxicity on univariate analysis, no risk factor examined was significant in a multivariable model. Of 13 patients rechallenged with intrathecal or high-dose methotrexate, 12 did not have recurrence of neurotoxicity.

Risk for Leukoencephalopathy

Leukoencephalopathy was identified in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. On univariate analysis, higher cumulative number of triple intrathecal therapies (P = .023), higher plasma methotrexate-to-leucovorin ratio at 42 hours, and higher homocysteine concentration in treatment course 1 were associated with increased risk of leukoencephalopathy. On multivariate analysis, only high 42-hour plasma methotrexate to leucovorin ratio was associated with increased risk (P = .038).

Genetic Associations

A genome-wide association study identified multiple single nucleotide polymorphisms associated with clinical neurotoxicity, with many annotated to genes. Pathway analyses of these genes based on Gene Ontology biologic processes showed an overrepresentation of the neuron projection development pathway (GO:0031175; P = .036) and axon guidance pathway (GO:007411; P = .047).

For example, of significant single nucleotide polymorphisms (P < .0001) that were annotated to known genes, 73% (8 of 11) were in genes involved in neurogenesis: TRIO, PRKG1, ANK1, COL4A2, NTN1, and ASTN2 are involved in neuronal development and migration and/or axon guidance; SSPN is involved in glial cell death; and DKK2 is involved in Wnt/β-catenin signaling, which influences neural development.

The investigators concluded, “[Methotrexate]-related clinical neurotoxicity is transient, and most patients can receive subsequent [methotrexate] without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to [methotrexate]-related neurotoxicity.”

Deepa Bhojwani, MD, of St. Jude Children’s Research Hospital, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by National Institutes of Health grants and by the American Lebanese Syrian Associated Charities. The study authors reported no potential conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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