Research Hospital
Kevin Krull, PhD (left) and Yin Ting Cheung, PhD Photo by Seth Dixon/ St. Jude Children’s
Chemotherapeutic agents have been associated with neurocognitive side effects in survivors of pediatric acute lymphoblastic leukemia (ALL).
Now, researchers have found evidence to suggest that genetics and ALL itself can increase the risk for long-term problems with attention, organization, and related neurocognitive skills.
The researchers reported these findings in JAMA Oncology.
The team evaluated patients enrolled in the Total XV St. Jude clinical trial, analyzing the cerebrospinal fluid (CSF) of 235 pediatric ALL patients treated with chemotherapy alone.
The CSF had been collected at 5 times before and during treatment (between 2000 and 2010). The analysis included neurocognitive testing and brain imaging of 138 ALL survivors who were at least 8 years old and 5 years from their cancer diagnosis.
The researchers found that, even before treatment began, some patients had proteins in their CSF that suggested injury to glial cells.
“This was a surprise,” said study author Kevin Krull, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“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.”
Previously, researchers had assumed neurocognitive problems were a side effect of ALL therapy, particularly treatment with methotrexate.
So finding elevated biomarkers in the CSF of some patients during methotrexate treatment was not surprising, but, previously, little was known about the neurotoxic mechanism involved. The biomarkers identified were indicative of injury to neurons, axons, and glial cells.
The researchers checked patients’ CSF for 5 proteins and other biomarkers of brain cell damage related to treatment with either high-dose intravenous methotrexate or intrathecal methotrexate.
The biomarkers were present early on but changed and varied throughout treatment. For example, biomarkers of demyelination were present in some patients newly diagnosed with ALL and then decreased during treatment.
Others, including biomarkers of inflammation and neuronal damage, increased as treatment progressed.
Overall, methotrexate treatment was associated with biomarkers that signaled as much as a 70% increased risk for reduced neurocognitive functioning in long-term ALL survivors.
The researchers also looked for evidence that genetic variation might influence the susceptibility of pediatric ALL patients to methotrexate injury.
The team checked patients’ DNA for 42 gene variants known to influence drug metabolism, neurodevelopment, and oxidative stress.
The analysis identified a variant of the COMT gene that was associated with higher biomarker levels following methotrexate treatment. The 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,” Dr Krull noted. “This suggests that 2 independent processes might be coming together in some patients that influence their risk for diminished executive functioning.”
“Taken together, the results suggest that survivors’ neurocognitive deficits are multifactorial and reflect a complex interaction among genetics, treatment intensity, and other factors. Monitoring CSF biomarkers and screening for genetic mediators of brain injury may help identify and intervene with survivors at risk for neurocognitive problems.”