Chronic Health Conditions in Survivors of Down Syndrome-Associated Leukemia

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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.