Cognitive challenges in some survivors of childhood leukemia linked with genetic variants

With long-term survival at an all-time high for children with acute lymphoblastic leukemia (ALL), the focus of researchers and clinicians has expanded to the quality of life after cure, and to addressing the puzzling question: why do some survivors experience minimal long-term complications following intensive treatment, while others are more affected by the toxicity of the same standard treatment protocols? In the largest study of its kind to date, a North American research team has found an explanation for the problems with memory, attention and learning that some children and teens experience following childhood ALL therapy: cognitive deficits are associated with variants in three genes related to the ability to combat oxidative stress or brain inflammation.

The study, published in the May 18 online edition of the Journal of Clinical Oncology, was conducted by researchers at The Children’s Hospital at Montefiore and Dana-Farber/Boston Children's Cancer and Blood Disorders Center, The Hospital for Sick Children (SickKids) and the Children’s Hospital of Eastern Ontario (CHEO).

“The way chemotherapy and other drugs may be metabolized varies from person to person, and we suspected that kids with a certain genetic makeup may be more vulnerable to the harsh effects of some of these drugs,” says Dr. Yaron Finkelstein, co-author of the study and Staff Physician in Clinical Pharmacology and Toxicology, Emergency Medicine and Associate Scientist at SickKids. “With this research, we showed that when children are genetically less capable of efficiently dealing with oxidative stress and repairing cellular damage imposed by toxic drugs, they are more prone to have cognitive deficits in the future.”

The researchers studied 350 survivors of childhood ALL about five years post-diagnosis, after treatments had ended and they had resumed school and other regular activities. The participants, aged one to 18 years at the beginning of treatment, had been treated at 10 North American centres with one of two Dana-Farber Cancer Institute ALL Consortium Protocols (95-01 or 00-01), which have been among the standard treatment protocols for the disease. A series of neurocognitive tests were conducted and results were correlated with data from genomic analysis obtained by using cutting-edge technology, to determine the presence of common variants in 23 genes previously shown to be related to drug metabolism, oxidative stress (a form of cellular damage whereby an imbalance between the production of free radicals impacts the body’s ability to detoxify their effects), brain inflammation, corticosteroids and folate physiology. Cognitive and behavioural deficits were found to be linked with variations in three genes – NOS3, SLCO2A1 and COMT – related to oxidative stress or brain inflammation.

Neurocognitive outcomes observed in the study included estimated IQ. While estimated IQ did not significantly differ from the general population for the entire patient group, it was significantly lower in leukemia survivors carrying specific variations of the NOS3 and SLCO2A1 genes. Additionally, in specific cognitive domains such as learning and attention, children carrying those variations experienced significant deficits, two to five times more than leukemia survivors who did not carry those variations. Overall, nearly 30 per cent of the study participants who were under 18 at the time of testing were enrolled in special education programs, in contrast to less than 10 per cent of the general population receiving this type of academic assistance.

“Clinicians have always wondered why there is a difference between patients receiving the same treatment in terms of the severity of their side effects,” says Dr. Peter Cole, lead author of the study,attending physician in the Division of Haematology-Oncology and Director of the Haematologic Malignancy Service, Children’s Hospital at Montefiore. “This research tells us that genetic differences between patients may explain some of the variability in reaction to treatment and we are hopeful it may soon be possible that genetic testing will help us predict which patients are going to be susceptible to various toxic reactions, and adjust their treatment accordingly.”.

Childhood ALL has become a cancer success story, with long-term survival occurring in more than 90 per cent of cases. Experts attribute this achievement to the evolution of treatment protocols, which are similar across North America, Europe and other parts of the world. The protocols primarily feature intensive chemotherapy, including chemotherapy delivered directly to the central nervous system, and some children also receive radiation to the brain. The therapies that are used today are less harsh than their predecessors.

Looking ahead, Finkelstein notes the team is looking at ways to address the vulnerability of some children to cognitive effects, ultimately aiming to mitigate or prevent the problems before they occur. “Now that we have identified a link between genetic variants and cognitive deficits, researchers need to work on counteracting the toxic effects of the drugs potentially by tailoring the dosage to the child’s genetic makeup, or by introducing a new, protective therapy into the mix,” says Finkelstein, who is also Associate Professor of Paediatrics, Pharmacology and Toxicology at the University of Toronto.

The research was supported by St. Baldrick’s Foundation, grants from the National Institutes of Health (NIH), the Michael J. Garil Fund for Leukemia Research, and SickKids Foundation.