Chronic Health Conditions in Survivors of Down Syndrome-Associated Leukemia

摘要 唐氏综合征(DS)是一种遗传性疾病，其特征是21号染色体的结构性三体， 神经认知延迟、表型特征、共发生的结构性出生缺陷，以及增加的风险 慢性健康状况(CHC)，如甲状腺疾病、骨量减少、癫痫发作障碍和视觉/听力 有问题。与普通儿童相比，DS儿童患急性白血病(AL)的风险增加10-20倍 而且发生与急性治疗相关的毒性的风险也要大得多。然而，很少有研究 已经报道了癌症治疗对DS-AL幸存者的晚期影响，没有人调查过这些 CHC与患有DS且没有癌症病史的儿童所经历的不同。因此，虽然一个更高的 DS-AL幸存者的晚期效应发生率高于预期，其患病率和严重程度 相对于与DS相关的CHC的CHC是未知的。此外，AL治疗会带来众所周知的风险 注意力、处理速度和执行功能方面的缺陷，但只调查了一个小病例系列 DS-AL幸存者的神经心理(NP)结局。由于系统性地被排除在基于 由于DS-AL幸存者的基线健康状况不同，他们是高危人群，在很大程度上没有得到研究。 为了解决这一关键的知识鸿沟，我们将描述DS-AL童年经历的迟发效应 通过确定DS-AL中CHC的患病率和严重程度以及临床和NP结局来确定癌症幸存者 幸存者。从儿童肿瘤学小组研究和登记的DS参与者招募，我们的方法 包括病历数据摘要以及预期的面对面和基于调查的评估。目标1 将建立一个经过注释和全面描述的当代DS-AL幸存者队列。目标 2将利用接触没有癌症病史的DS患者的良好队列来比较CHC和 与在DS-AL幸存者中观察到的结果相比，NP结果更好。目标3将确定临床、遗传和生物风险 DS-AL存活者远期效应的决定因素。根据我们强有力的初步数据，我们假设 特定慢性丙型肝炎的患病率和严重程度以及不良的临床和NP结局将超过 无癌症病史的非DS AL和匹配的DS对照组。此外，我们预计DS所有的易感性 基因座将延伸到与慢性丙型肝炎的风险相关，并与共同发生的出生缺陷的发生率相对应。 最后，我们预计较短的端粒长度与不良的NP结局有关。我们的多学科 团队在白血病和癌症生存(Gramatges)、DS- Al(Rabin)，癌症和出生缺陷流行病学(Lupo)，DS相关CHC(Rosser)，#年NP结果 DS幸存者(Jacola)和CHC儿童癌症幸存者(Chow)。 在儿童肿瘤学小组的支持下，这项多点的全国性研究将描述癌症的特征 DS-AL幸存者的治疗结果。我们预计，我们的结果将通过告知 DS-AL幸存者的临床实践指南，减轻了这一脆弱人群的结果差异。

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.