Methotrexate May Cognitively Impair Pediatric Leukemia Patients

Patients administered high levels of methotrexate showed impaired cognitive function and altered brain anatomy.

Findings from a recent study suggest that patients with pediatric acute lymphoblastic leukemia (ALL) who receive high concentrations of methotrexate chemotherapy have trouble with mental flexibility, organization, and related skills.

Methotrexate is one of few chemotherapies that has the ability to cross from the blood into the brain and nervous system.

"With 5-year survival rates for pediatric ALL approaching 95%, researchers are focused on better understanding and reducing the neurotoxicity patients still experience during and sometimes long after treatment. It remains a relatively common problem even in the contemporary treatment era of chemotherapy only,” said first and corresponding author Kevin Krull, PhD. "This study is the first to show a clear dose-response effect between methotrexate concentrations in the blood during treatment and executive functioning in survivors. This information is essential for designing effective intervention to address the risk.”

The study, published in the Journal of Clinical Oncology, included 218 long-term survivors of pediatric ALL who received multi-drug chemotherapy into their cerebrospinal fluid. Patients included survived 5 years from their diagnosis and were at least 8-years-old.

Researchers calculated methotrexate concentrations by measuring levels of the drug in the blood during and after treatment, according to the study. They also checked levels of amino acid homocysteine and the chemotherapy drug dexamethasone.

It was found that higher levels of methotrexate and homocysteine were associated with low executive function, which includes mental flexibility, verbal fluency, memory, and processing speed. Researchers found that some patients had moderate-to-severe impairment.

High exposure to methotrexate was associated with increased activity in parts of the brain responsible for executive functioning and was associated with thicker brain cortex in prefrontal regions, according to the study.

A thicker brain cortex could suggest that high levels of methotrexate can cause neuronal pruning that occurs with aging.

Researchers also found that methotrexate was associated with changes in white matter that insulates neural connections.

"The neural connections remain, but as the concentrate of methotrexate in the blood increases, the integrity of the white matter breaks down, which could affect functions like processing speed," Dr Krull said.

The risks with methotrexate were unrelated to gender, age at diagnosis, or disease risk group, but the researchers found that dexamethasone levels were not linked to cognitive skills.

"Methotrexate has contributed to historically high cure rates for childhood leukemia," Dr Krull concluded. "While physicians may look for opportunities to reduce concentrations of the drug in the future, interventions are already in development to enhance executive function in patients on therapy as well as long-term childhood cancer survivors."