Drug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patients

Abstract

PurposeMethotrexate administration is associated with frequent adverse neurological events during treatment for childhood acute lymphoblastic leukemia. Here, we present evidence to support the role of common drug interactions and low vitamin B12 levels in potentiating methotrexate neurotoxicity.MethodsWe review the published evidence and highlight key potential drug interactions as well as present clinical evidence of severe methotrexate neurotoxicity in conjunction with nitrous oxide anesthesia and measurements of vitamin B12 levels among pediatric leukemia patients during therapy.ResultsWe describe a very plausible mechanism for methotrexate neurotoxicity in pediatric leukemia patients involving reduction in methionine and consequential disruption of myelin production. We provide evidence that a number of commonly prescribed drugs in pediatric leukemia management interact with the same folate biosynthetic pathways and/or reduce functional vitamin B12 levels and hence are likely to increase the toxicity of methotrexate in these patients. We also present a brief case study supporting out hypothesis that nitrous oxide contributes to methotrexate neurotoxicity and a nutritional study, showing that vitamin B12 deficiency is common in pediatric leukemia patients.ConclusionsUse of nitrous oxide in pediatric leukemia patients at the same time as methotrexate use should be avoided especially as many suitable alternative anesthetic agents exist. Clinicians should consider monitoring levels of vitamin B12 in patients suspected of having methotrexate-induced neurotoxic effects.

Reply: Methotrexate neurotoxicity due to drug interactions: an inadequate folinic acid effect

“…We thank Professor Cohen for his reply and his interesting points regarding the possible role of inadequate folinic acid rescue in contributing to neurotoxic side-effects of methotrexate. We can confirm that the patient reported in our article [1] had not received any previous exposure to any systemic methotrexate (oral or intravenous) even at low dose. In addition, the other published article on this possible interaction with nitrous oxide [2] reported a patient developing symptoms early during induction therapy on a protocol with a standard 3-drug induction (vincristine, asparaginase and corticosteroids).…”

Reply to: Comment on: Successful use of nitrous oxide during lumbar punctures: A call for nitrous oxide in pediatric oncology clinics

“…The authors present a case of severe and prolonged neurotoxicity with the use of nitrous for intrathecal methotrexate. The same case is presented in both papers . This anecdote is not adequate evidence to guide therapy.…”

Comment on: “Successful use of nitrous oxide during lumbar punctures: A call for nitrous oxide in pediatric oncology clinics”

“…Although this relatively small study did not record significant acute toxicity, we draw readers’ attention to a serious potential safety concern regarding the use of nitrous oxide in combination with methotrexate, the most commonly administered intrathecal drug in pediatric oncology. Two recent case reports describe severe neurotoxicity following the use of nitrous oxide anesthesia in pediatric leukemia patients receiving intrathecal methotrexate . Although these do not prove a causal relationship, there is a body of experimental and clinical data that support the theory that nitrous oxide may increase the toxicity of antifolate medications such as methotrexate .…”

“…Methotrexate‐related neurotoxicity is common, with 4–12% of children experiencing neurological adverse events during therapy . Importantly, adverse events often have delayed presentation several days or longer after methotrexate administration.…”

“…The same pathway is implicated in the pathogenesis of the serious neurological syndrome subacute combined degeneration of the cord, seen following nitrous oxide use in patients with untreated vitamin B 12 deficiency. As a second cautionary note, patients with hematological malignancies may be at increased risk for subclinical vitamin B 12 deficiency due to chronic proton pump inhibitor use, enteropathy, and/or malnutrition …”