- Childhood Leukemia treatment with methotrexate (a chemotherapy agent ) may increase the long-term risk of problems with attention, organization and related neurocognitive skills later on.
- These neurocognitive problems were found to be side effect of methotrexate therapy.
- The biomarkers that were identified in methotrexate therapy patients were indicative of injury to neurons, axons and glial cells.
Problems with attention, organization and related neurocognitive skills were found develop in the long run, if the young patients who had Leukemia were treated with methotrexate therapy in childhood, finds a new study. The findings of this study are published in the journal of JAMA Oncology.
The researchers from the St. Jude Children's Research Hospital, analyzed the cerebrospinal fluid (CSF) of 235 pediatric patients who were treated with methotrexate (a chemotherapy drug) alone for acute lymphoblastic leukemia. This group also included 138 long-term survivors.
But Even before the treatment could have begun, some patients had proteins in their CSF, which indicates that there might have been an injury to cells that make up the white matter in the brain.
"This was a surprise. Until now, we had not suspected that leukemia, by itself, or the inflammatory response to the disease, may lead to changes that leave ALL survivors at risk for problems with executive functioning and processing speed later," said corresponding author Kevin Krull, Ph.D., a member of the St. Jude Department of Epidemiology and Cancer Control.
Thirty to 40 percent of childhood leukemia survivors treated with chemotherapy alone develop neurocognitive problems. Researchers had assumed the problems were a side effect of therapy, particular treatment with the chemotherapy agent methotrexate.
So finding elevated biomarkers in the CSF of some patients during methotrexate treatment was not unexpected, but previously, little was known about the neurotoxic mechanism involved. The biomarkers identified were indicative of injury to neurons, axons and glial cells.
Researchers also found evidence that genetic variation may influence patients' vulnerability to such treatment-related neuro-cognitive problems.
"Taken together, the results suggest that survivors' neurocognitive deficits are multifactorial and reflect a complex interaction among genetics, treatment intensity, and other factors," Krull said. "Monitoring CSF biomarkers and screening for genetic mediators of brain injury may help identify and intervene with survivors at risk for neurocognitive problems."
For this study, the researchers analyzed 235 samples of CSF that were collected five times before and during treatment. The samples were originally collected to monitor patients' response to treatment and check for relapse.
The samples used in the study were collected between 2000 and 2010. The analysis also included neurocognitive testing and brain imaging of 138 survivors who were at least eight years old and five years from their cancer diagnosis.
The patient's CSF was checked for five proteins and other biomarkers of brain cell damage related to treatment with either high-dose intravenous methotrexate or methotrexate delivered into the spinal fluid.
The defective biomarkers were present early in therapy, but changed and varied throughout the treatment process.
On the whole, the methotrexate treatment was associated with biomarkers that indicated 70 percent increased the risk for reduced neurocognitive functioning in long-term survivors.
They also checked for whether genetic variation were influencing the susceptibility of ALL pediatric patients to methotrexate injury. In order to rule this out, they checked patients' DNA for 42 different gene variants known to influence drug metabolism, neurodevelopment and oxidative stress.
This descriptive analysis identified a COMT variant gene that was associated with higher bad biomarker levels following methotrexate treatment. This gene encodes instructions for a protein involved in processing the neurotransmitter dopamine in the frontal regions of the brain.
"Dopamine is the primary neurotransmitter in executive functioning," Krull said. "This suggests that two independent processes might be coming together in some patients that influence their risk for diminished executive functioning."
- Yin Ting Cheung, Raja B. Khan, Wei Liu; et al. Association of Cerebrospinal Fluid Biomarkers of Central Nervous System Injury With Neurocognitive and Brain Imaging Outcomes in Children Receiving Chemotherapy for Acute Lymphoblastic Leukemia, JAMA Oncology (2018).DOI:10.1001/jamaoncol.2018.0089