Preventing Fatal Infections in Children with Down Syndrome During Treatment for Acute Lymphoblastic Leukemia

SUMMARY Children with Down syndrome (DS) have a 20-fold increased risk of developing acute lymphoblastic leukemia (ALL), a rate that is significantly higher than the general population. Survival of children with DS and ALL (DS-ALL) remains inferior to that of children without DS due to both excess relapse and infection- related mortality (IRM). In the non-DS population, overall survival is over 90%, while children with DS-ALL have an overall survival closer to 80%. Unfortunately, the increased intensity of chemotherapy regimens responsible for recent survival gains in childhood ALL has led to unacceptably high rates of IRM in children with DS. Understanding the basis for IRM in this population is critical to improving their survival rates and disease outcomes. Currently, there are no biomarkers to stratify children with DS-ALL based on identification of those at high risk for IRM. Further, there is a gap in our knowledge of the mechanisms underlying this increase in IRM in DS-ALL patients. The ability to identify DS-ALL patients at high risk of IRM will allow treatment modification and supportive care to be provided at treatment onset to prevent mortality of these patients from fungal, bacterial and viral infections. In this proposal we will utilize DS mouse models treated with ALL chemotherapy regimens, expose them to infectious pathogens and screen for circulating biomarkers that will be validated in blood from DS-ALL patients with and without severe infectious toxicity. Proposed studies will also validate candidate germline genomic variants associated with risk of severe infection in children with DS during ALL chemotherapy. Our studies will focus on defects in the innate immune system as the underlying basis for increased IRM in children with DS-ALL. Reducing IRM in DS-ALL patients is critical to improving outcomes in this vulnerable population.