Chemotherapy Pharmacodynamics and Neuroimaging and Neurocognitive Outcomes in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia: Beyond the Abstract

Long-term survivors of childhood acute lymphoblastic leukemia (ALL) who are treated with high-dose intravenous methotrexate or intrathecal chemotherapy are at risk for neurocognitive impairment, particularly in cognitive processes such as processing speed, attention and executive function.

These difficulties emerge over time and manifest by five years from diagnosis. However, many children who receive these therapies do not experience significant impairment, suggesting the need for biomarkers to identify patients at greatest risk so that interventions can begin as early as possible. Prior research from our team demonstrated that, during chemotherapy, patients were at risk for developing white matter changes in the brain known as leukoencephalopathy. Prior to our study, there were no reports in the literature that documented the persistence or impact of leukoencephalopathy in long-term survivors of childhood ALL treated on contemporary chemotherapy-only protocols.

The aim of this study was to evaluate the impact of on-therapy leukoencephalopathy on long-term neurocognitive and neurobehavioral function, and white matter integrity in long-term survivors of ALL treated with contemporary risk-adapted chemotherapy. Our analysis included prospective neuroimaging from active therapy to long-term follow-up at 5 years or more post-diagnosis of ALL, and assessment of white matter integrity using diffusion tensor imaging (DTI) in the frontal and parietal lobes, as well as the frontostriatal tract. Survivors also completed a comprehensive battery of neurocognitive assessments and parents rated the survivors’ neurobehavioral functioning.  

The 213 survivors were on average 13.5 years old at the time of evaluation and 7.5 years post diagnosis of ALL. As compared to the general population, survivors were 1.6 to 3.2 times more likely to demonstrate problems across neurobehavioral domains such as working memory, planning and organizing information and initiation of complex tasks. A total of 51 survivors (27%) had a history of leukoencephalopathy during active therapy of which 78% had leukoencephalopathy at follow-up. Survivors with a history of leukoencephalopathy demonstrated more parent-rated neurobehavioral problems than those without leukoencephalopathy on symptoms of initiation and poor organization of materials. They were also more likely to have abnormal measures of white matter integrity on DTI, which were also associated with poorer neurobehavioral functioning. Regardless of the occurrence of leukoencephalopathy, survivors had worse performance than the general population on direct measures of higher-order cognitive abilities such as executive function and processing speed. 

To highlight, most survivors of childhood ALL treated with contemporary chemotherapy-only protocols will not develop significant neurocognitive or neurobehavioral problems. However, survivors who develop leukoencephalopathy during chemotherapy are at a higher risk for neurodevelopmental abnormalities. Leukoencephalopathy during chemotherapy is also predictive of persistent white matter microstructural changes as observed on DTI during long-term survivorship. Our previous research has demonstrated that for the significant subset of patients who develop neurocognitive and neurobehavioral problems, the abnormalities can have a negative impact on educational attainment, future employment and level of adult independence. Thus, early repeated screening and early intervention is essential and close monitoring of neurobehavioral development in this population is warranted. Future research should determine whether early preventive cognitive and/or educational interventions in survivors who develop leukencephalopathy can reduce the risk for long-term neurobehavioral problems.

Written by: Yin Ting Cheung and Noah Sabin

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