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Children Treated for ALL Experience Varying Levels of Cognitive Deficits—and Genetic Susceptibility to Oxidative Stress Might be a Factor

May 18, 2015

Numerous studies have shown that children treated for acute lymphoblastic leukemia (ALL) experience increased rates of cognitive deficits in terms of attention span, working memory, and processing complex information. Studies have also shown—and doctors have anecdotally reported—that not all children experience these cognitive declines to the same degree. Demographic factors alone have not been able to account for these variations.

Now, a new study in the Journal of Clinical Oncology (JCO) examines one possible factor in this cognitive variation—polymorphisms (that is, variations) in genes that make some children more susceptible to oxidative stress, a process known to cause neural damage. The study, ”Polymorphisms in Genes Related to Oxidative Stress Are Associated with Inferior Cognitive Function after Therapy for Childhood ALL,” found that children with polymorphisms in three genes related to oxidative stress and/or neuroinflammation experienced greater cognitive decline. The study was published online, ahead of print, May 18.

“This is a novel finding and drives home the point that the susceptibility to oxidative stress is important in predicting which children are going to have greater cognitive deficits as side effects to chemotherapy,” said study first author, Peter Cole, MD, of Albert Einstein College of Medicine.

The connection between leukemia treatment, oxidative stress, and cognitive deficits

Oxygen is the key to life, but as Dr. Cole explained, too much can cause damage to the body.

“Having too much oxygen around the body produces reactive oxygen radicals. These are chemically active forms of oxygen that can cause damage to many parts of the body, notably the lining of blood vessels, but also nerves and heart tissue. “

One of the drugs known to enhance the production of reactive oxygen species is methotrexate, a drug that has been central to the successful treatment of childhood leukemia for over 60 years.

This connection between methotrexate and oxidative stress led the researchers to develop their hypothesis about cognitive deficits in survivors of ALL: Those whose genes made them more susceptible to the oxidative damage of methotrexate would show greater cognitive deficits.

“The question we asked was: Are there some people who are just genetically more susceptible to the side effects of chemotherapy?” said Dr. Cole.

To answer this question, the researchers—who hail from six major cancer centers in the United States and Canada and are all members of the Dana Farber Cancer Institute ALL Consortium—looked at the IQ scores of 350 child-survivors of ALL who had received methotrexate. The researchers then identified a panel of genetic polymorphisms that have been shown to increase susceptibility to oxidative damage.

Analysis showed that children who possessed one of three specific genes in the panel were more likely to have lower IQ scores and behavioral outcomes.

Knowing the risk factors for cognitive deficits paves the way for prevention

Dr. Cole said the study’s findings are exciting because they open the possibility of creating a treatment that could prevent oxidative damage— thus stopping the process that leads to cognitive deficits among children treated for ALL. In fact, Dr. Cole’s lab is currently testing one treatment by giving rats chemotherapy with or without the anti-oxidants vitamin C and E and seeing how this affects cognitive ability.

“My hope is that one day soon, we would come up with a cocktail of treatment that we would give to children who have increased genetic susceptibility to oxidative stress. We would be able to protect their brains without increasing the risk of relapse. That’s my dream.”


Peter D. Cole is an Associate Professor in the Department of Pediatrics, Hematology and Oncology, at Albert Einstein College of Medicine. He has been an ASCO member since 1997.

Abstract of the original JCO article.

PDF of the original JCO article.

Cole PD, Finkelstein Y, Stevenson KE, et al. Polymorphisms in genes related to oxidative stress are associated with inferior cognitive function after therapy for childhood ALL.  J Clin Oncol. Epub 2015 May 18.


The Exclusive Coverage series on ASCO.org highlights selected research from JCO and JOP with additional perspective provided by the lead or corresponding author.

@ 2014 American Society of Clinical Oncology


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