PROJECT SUMMARY / ABSTRACT Cognitive impairment is a well-established adverse outcome in survivors of hematologic malignancy (HM) treated with and without blood or marrow transplantation (BMT). Cognitive impairment significantly challenges survivors’ independence and ability to return to work, in addition to reducing their ability to follow complex treatment management plans which has been associated with worse survival outcomes in older adults with HM. In a large prospective study of HM patients treated with BMT, we found a high prevalence (up to 36%) of global cognitive deficits, which persisted up to 3y. Older age, male sex, lower education and income, lower cognitive reserve, as well as genetic variants on blood brain barrier, telomere homeostasis, and DNA repair genes were associated with increased risk of cognitive impairment. In order to address the need to mitigate the risk of cognitive deficits, we conducted a study to examine the feasibility of a 12-week, home-based, cognitive training intervention in HM patients treated with allogeneic BMT. To date, we have enrolled 43 evaluable patients, achieving 60.4% consent rate, 77.3% randomization rate, 20.7% post-randomization attrition and median intervention adherence of 83.3%. Preliminary results show an intervention effect in improved processing speed (p=0.006) among patients with baseline impairment. Cognitive function, however, is a complex phenotype involving several domains best tackled using a multi-component approach that involves both compensatory (e.g. cognitive training) and enhancement of molecular pathways (e.g. nutritional ketosis) mechanisms. Ketogenic interventions have consistently shown cognitive improvements as early as 6-8 weeks in the non-oncology space including patients with mild cognitive impairment, Alzheimer's disease and dementia. While the brain's ability to use glucose as an energy source is reduced with aging; circulating plasma ketone bodies are an effective alternative due to their water solubility and ability to cross the blood brain barrier. In addition, nutritional ketosis upregulates DNA repair pathways, enhances synaptic plasticity, and reduces inflammation. These effects on cognitive outcomes in HM survivors have not been explored. We aim to explore the feasibility of integrating exogenous ketogenic supplementation to the existing 12-week cognitive training intervention, examine intervention effects using objectively measured cognitive function, and examine the sustained effects of the multi-component intervention. The study will be conducted by a qualified multidisciplinary team of investigators with experience in intervention and cancer survivorship research at the University of Alabama at Birmingham. Our established feasibility of enrolling survivors in the cognitive training intervention provides the needed infrastructure to test these aims with the future goal of implementation of a definitive multi-component cognitive randomized clinical trial in HM...