Children with acute lymphoblastic leukemia (ALL) have a relatively good prognosis, but treatment can have tremendous impacts on growth and development, including effects on the central nervous system (CNS). This in turn affects school performance and neurocognitive function, but the relationship between ALL therapy and cognitive deficits is not well understood. Because children diagnosed with ALL typically begin treatment immediately, it is often difficult to evaluate cognitive function prior to therapy. If neurocognitive deficits are recognized later in life, it is unclear if therapy-associated CNS injury occurred, and often too late to institute appropriate interventions. This proposal aims to evaluate CNS structure and chemistry;and cognitive performance, after therapy begins (<6 weeks), and 12 months later. The study fills a void of a current study in the Children's Oncology Group (COG;www.childrensoncologygroup.org), AALL06N1 (Study of Neurocognitive Function in Children Treated for ALL), which is a study for children with high-risk B- lineage and T-cell ALL, but young children (3-6 year old) with ALL with standard- and intermediate-risk ALL are excluded from the study. Therefore, the proposed project bridges an important gap by studying 3-6 year old children with ALL with standard- and intermediate-risk disease who are at risk for CNS toxicity. Use of high resolution structural MRI (HRS-MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) may allow detection of early changes in CNS structure and metabolism prior to detecting abnormal cognitive function. Studies led by Drs. Linda Chang and Thomas Ernst are successfully being conducted in 3-6 year old children with other diseases, using non-invasive advanced MR techniques, including HRS-MRI, MRS, and DTI without conscious sedation, which is important in this age. Our goal is to identify early structural, chemical, and functional CNS changes in children with ALL with the long term objectives to develop interventions to prevent late neurocognitive sequelae and improve prognosis. Our Aims are: 1) To determine the effect of chemotherapy on the brain in children with ALL using high resolution MRI, proton MRS, and DTI within 6 weeks of starting chemotherapy and at 12 months after the initial scans;2) To characterize changes in neurocognitive function from chemotherapy exposure in children with ALL at baseline and at 12-months;3) To assess the relationship of abnormalities on MR scans with cognitive deficits identified from neurocognitive tests;and 4) To measure mitochondrial DNA levels in children and evaluate its association with minimal residual disease, neurocognitive testing, and brain metabolite levels. The significance lies in the potential of using sensitive tools (MRS and DTI) to detect early CNS changes before cognitive abnormalities are noted;and possibly improve morbidity in children who otherwise are not eligible for the open COG study. The proposal is innovative because the project utilizes expertise of Drs. Ernst and Chang in the field of neuroimaging to capture data from young children without the use of sedation to further our understanding of chemotherapy effects on developing brains. PUBLIC HEALTH RELEVANCE: Children diagnosed with acute lymphoblastic leukemia (ALL) have a relatively good prognosis, however treatment can impact a child's future growth and development, including effects on the central nervous system (CNS). This proposal aims to evaluate CNS structure and chemistry;and cognitive performance, after treatment begins (<6 weeks), and 12 months later in children (3-6 year old) with ALL diagnosed with standard- and intermediate-risk ALL.

R21CA139712

2009-06-20

2013-05-31