SUMMARY Down syndrome (DS) is a genetic disorder characterized by a constitutional trisomy of chromosome 21, neurocognitive delay, phenotypic features, co-occurring structural birth defects, and an increased risk for chronic health conditions (CHC) such as thyroid disease, osteopenia, seizure disorder, and visual/hearing problems. Children with DS have a 10-20 fold excess risk for acute leukemia (AL) compared with the general population, and are also at significantly greater risk for acute therapy-related toxicities. However, few studies have reported late effects of cancer therapy in survivors of DS-AL, and none have investigated whether these CHC differ from those experienced by children with DS and no history of cancer. Therefore, although a higher than expected incidence of late effects is reported in DS-AL survivors, the prevalence and severity of these CHC relative to the CHC associated with DS is unknown. Further, AL treatment confers well-described risks for deficits in attention, processing speed, and executive function, but only one small case series has investigated neuro-psychological (NP) outcomes in DS-AL survivors. Due to a systematic exclusion from research based on their differing baseline health status, DS-AL survivors are an at-risk population that is largely unstudied. To address this critical knowledge gap, we will characterize late effects experienced by DS-AL childhood cancer survivors by determining the prevalence and severity of CHC and clinical and NP outcomes in DS-AL survivors. Recruiting from DS participants in Children’s Oncology Group studies and registries, our methods include both medical record data abstraction and prospective in-person and survey-based assessments. Aim 1 will establish an annotated and comprehensively-characterized, contemporary cohort of DS-AL survivors. Aim 2 will leverage access to a well-established cohort of DS persons without cancer history to compare CHC and NP outcomes with those observed in DS-AL survivors. Aim 3 will identify clinical, genetic, and biological risk determinants of late effects in DS-AL survivors. Based on our strong preliminary data, we hypothesize that the prevalence and severity of specific CHC and adverse clinical and NP outcomes will exceed those observed in non-DS AL and in matched DS controls without cancer history. Further, we expect that DS ALL susceptibility loci will extend to association with risk for CHC, and correspond with incidence of co-occurring birth defects. Last, we anticipate that shorter telomere length is associated with adverse NP outcomes. Our multi-disciplinary team has a strong history of collaboration and expertise in leukemia and cancer survivorship (Gramatges), DS- AL (Rabin), epidemiology of cancer and birth defects (Lupo), DS-associated CHC (Rosser), NP outcomes in DS survivors (Jacola), and CHC in survivors of childhood cancer (Chow). With the support of the Children’s Oncology Group, this multi-site, national study will characterize cancer treatment outcomes in DS-AL survivors. We anticipate our results will improve survivorship care by informing clinical practice guidelines for DS-AL survivors, mitigating outcome disparities in this vulnerable population.

PROJECT NARRATIVE Children with Down syndrome are at increased risk for acute leukemia treatment-related toxicities, but few studies have investigated survivorship outcomes in this subgroup. The proposed work will compare chronic health conditions, neuropsychological outcomes, and quality of life in Down syndrome survivors of acute leukemia to age and sex-matched children with Down syndrome and no history of cancer. Our objective is to comprehensively characterize outcomes in survivors of Down syndrome-associated acute leukemia and identify related risk factors, in order to inform clinical practice guidelines for survivorship care of this understudied and vulnerable population.