Leukemia Survivors Treated With Methotrexate as Children May Experience Cognitive Issues as Adults

Survivors of childhood leukemia who received chemotherapy involving high concentrations of methotrexate were found to be more likely to struggle with brain functionality in the long term.

Kevin R. Krull, PhD

Survivors of childhood leukemia who received chemotherapy involving high concentrations of methotrexate were found to be more likely to struggle with brain functionality in the long term, according to a study conducted at St. Jude Children’s Research Hospital.

Methotrexate is one of the few chemotherapy drugs entering the brain and nervous system from the blood. Previous research suggested neurotoxic effects with use of the drug, but the studies led to conflicting results. However, in this St. Jude study, the researchers were able to identify an association between the two, finding that higher blood levels of methotrexate in pediatric patients treated for acute lymphoblastic leukemia (ALL) resulted in anatomical and functional changes in those regions of the brain concerned with executive function, such as mental flexibility, planning, and reasoning.

Brain MRIs revealed many alterations, such as increased activity in the frontal lobe region, a finding the researchers said may mean that the brains of survivors need to work harder to make up for weakened cognitive functioning.

“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,” according to study author Kevin R. Krull, PhD, a member of the St. Jude Department of Epidemiology and Cancer Control. “This information is essential for designing effective interventions to address the risk.”

The study, published online in the Journal of Clinical Oncology, followed 218 long-term pediatric ALL survivors enrolled in the St. Jude Total Therapy XV clinical trial between 2000 and 2010. Eligible participants were aged ≥8 years and at least 5 years had elapsed since their diagnosis and treatment with multidrug intrathecal chemotherapy delivered directly to the cerebrospinal fluid rather than brain irradiation to prevent their cancer from recurring in the central nervous system.

Researchers analyzed results from neurocognitive testing, functional MRIs during an executive function task, and structural MRIs with diffusion tensor imaging. Methotrexate levels in the blood were measured before, during, and after treatment. Researchers also analyzed blood levels of homocysteine, an amino acid marker of the methotrexate activity, and dexamethasone.

Intelligence was found to be within normal limits in the study participants (mean, 98; standard deviation 14), compared with a mean 100 (standard deviation, 15) in the general population; however, measurements of executive function, including mental flexibility, verbal fluency, working memory, and processing speed, in these patients were lower than the general population, with lower scores on these tests associated with higher concentrations of methotrexate and homocysteine.

Krull explained that the higher methotrexate exposure was associated with changes in the white matter that insulates neural connections in the same region, possibly affecting functions like processing speed. This exposure was also linked to thicker brain cortex in prefrontal regions, which might mean the normal pruning that comes with age is being disrupted.

Unlike methotrexate and homocysteine exposure, dexamethasone levels were not related to executive function or other cognitive skills, the researchers noted.

“Methotrexate has contributed to historically high cure rates for childhood leukemia,” noted Krull. “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.”

With nearly 95% of pediatric patients with ALL surviving beyond 5 years, researchers said they are now focusing on reducing the side effects and neurotoxicity of the treatment, including finding ways to enhance survivors’ cognitive function both during and after treatment. Krull is conducting a pilot study investigating an approach combining electrical stimulation of the prefrontal cortex with cognitive training to help mitigate these effects.

Krull KR, Cheung YT, Liu W, et al. Chemotherapy pharmacodynamics and neuroimaging and neurocognitive outcomes in outcomes in long-term survivors of childhood acute lymphoblastic leukemia [published online ahead of print June 6, 2016]. J Clin Oncol.