Survival rates for pediatric acute lymphoblastic leukemia (ALL) now exceed 80%. With this growing population of long-term survivors comes recognition that a considerable proportion experience one or more significant late effects. For children undergoing central nervous system (CNS) treatment, common late effects include neurocognitive impairment and neurobehavioral problems. Although these problems first manifest as subtle difficulties with attention and processing speed, they can evolve into deficits in higher order brain functions that significantly impact functional skills in a subset of long-term survivors. Attention and self- regulation are some of the critical foundation skills upon which these higher order brain functions are based (i.e. cognitive flexibility, fluency, working memory, planning, organization, and problem solving abilities). Collectively referred to as "executive functions", these skills are essential for development and maintenance of independent living skills, self-management, and educational and vocational success. Recent research indicates 20-40% of children treated for pediatric ALL experience significant neurocognitive problems. Furthermore, a similar percentage of survivors demonstrate significant symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD). We are currently unable to accurately identify patients at greatest risk for these long-term neurocognitive and neurobehavioral impairments. In addition to treatment and intrinsic patient characteristics, potential predictive factors include changes in cognitive or behavioral functioning and brain state during active chemotherapy. Cognitive and behavioral predictive factors include acute changes in attention and self-regulation, which are early manifestations of disrupted executive functions. Brain state factors include evidence of acute neurotoxicity, as expressed through brain imaging. The Total XV protocol at St. Jude Children's Research Hospital (SJCRH) provides a unique opportunity with which to examine the association between early changes in behavior and brain states and later development of executive functions and brain maturation in children who survive pediatric ALL. Between June 2000 and October 2007, 408 ALL patients with newly diagnosed ALL were enrolled and treated at SJCRH on this institutionally-developed protocol using a uniform chemotherapy-only treatment regimen. All children underwent brain magnetic resonance imaging (MRI) during active therapy, as well as cognitive and behavioral evaluations at the same time points. Through this proposal, we plan to utilize existing data collected during acute treatment in the prediction of long-term neurocognitive and brain maturation outcomes. We propose to collect new data on higher order executive functions, symptoms of psychopathology, and structural and functional brain imaging in survivors who are at least 8 years of age and greater than 5 years from diagnosis. The ultimate goal of this effort is to develop a risk model for neurocognitive late-effects in pediatric leukemia, such that early preventative interventions may be targeted to "at-risk" patients.

Public Health Relevance

We are currently unable to identify those pediatric ALL survivors who are at significant risk for future neurocognitive late effects. Accurate risk identification would permit the development of tailored behavioral treatments and/or preventative interventions designed to improve functional outcome and quality of life.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Behavioral Medicine, Interventions and Outcomes Study Section (BMIO)
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Muehrer, Peter R
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St. Jude Children's Research Hospital
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Krull, Kevin R; Bhojwani, Deepa; Conklin, Heather M et al. (2013) Genetic mediators of neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 31:2182-8
Krull, Kevin R; Hockenberry, Marilyn J; Miketova, Petra et al. (2013) Chemotherapy-related changes in central nervous system phospholipids and neurocognitive function in childhood acute lymphoblastic leukemia. Leuk Lymphoma 54:535-40