Grant R01CA169398

Phenotype-Genotype Associations with Symptoms During Childhood Leukemia Treatment

The focus on cure for childhood leukemia over the last three decades has resulted in increased survival rates of > 80%. However, efforts to manage leukemia treatment symptoms have not kept pace with new therapies that promote cure. Symptom toxicity during treatment can result in complications, treatment delays and therapy dose reductions. Compromise in therapy can negatively influence quality of life and even more notably, jeopardize chances for long-term survival. This study examines biologic mechanisms that influence symptom toxicities caused by increased oxidative stress or cytokine production or actual failure of the anti-oxidant and anti-inflammatory defense systems due to genetic variation. A repeated measures research design is used to evaluate the number and severity of treatment symptoms experienced by 400 children and adolescents, 3-18 years of age, with a diagnosis of leukemia during the most intense phase of treatment. Symptoms include fatigue, sleep disturbance, pain, depression, nausea, physical activity changes, as well as memory and cognition deficits. CSF oxidative stress and cytokine biomarkers will be obtained with all therapeutic lumbar punctures occurring at four time points during post-induction therapy. Linear mixed models (LMM) will be used to determine the influence that symptom clusters have on quality of life. LMM also will be used to determine the effect CSF oxidative stress and cytokine biomarkers have on symptom clusters. We will also evaluate whether patients with genetic variants associated with the oxidative stress and inflammatory pathways have higher risk of developing symptom clusters than those without these genetic variants. This study is the first of its kind to search for genetic variants associated with the oxidative stress and inflammatory pathways as well as explore CNS oxidative stress and cytokine biomarkers, and their relationships with symptom clusters. Understanding symptom clusters during leukemia treatment will pave the way for future interventions that decrease toxicity and minimize delays and dose reductions in therapy that may compromise a child's best chance for cure.