Grant: CIHR Fellowship

Leukemia accounts for about 30% of childhood cancers. A severe complication of antileukemic therapy in children is the tumor lysis syndrome characterized by significant metabolic alterations. Rasburicase is a drug frequently used to prevent and treat this syndrome, but is contraindicated in patients having a severe deficiency of an enzyme called glucose-6-phosphate dehydrogenase (G6PD). The children having this condition are at high risk of potentially life-threatening hemolytic anemia after exposure to certain medications, including rasburicase. Some genetic variations in G6PD gene have been associated with an abnormality in the activity of this enzyme and with adverse effects of drugs. However, few data are available regarding the association of such genetic variations with enzyme activity and occurrence of severe toxicities in children. In addition, since the child has unique biological parameters, data from adult cannot be reliably extrapolated to pediatric population. The better understanding of this relationship will help improve therapy in childhood leukemia by promoting optimal and safe use of this drug. To do so, in a cohort of 1000 children with leukemia and treated with raburicase, 1) the relationships between genetic variations in G6PD gene, enzyme activity and drug toxicity will be evaluated, and 2) new predictive markers of severe toxicity induced by rasburicase will be identified. 3) The most robust markers will be validated prospectively in children newly diagnosed with leukemia and their clinical utility for future implementation in the clinic will also be explored. With these complementary strategies, we will identify genetic markers that are highly predictive of the enzymatic activity associated with drugs and with clinical outcome in the specific context of pediatric oncology, a field that remains still largely unexplored.