Phenotype-Genotype Associations with Symptoms During Childhood Leukemia Treatment

描述（由申请人提供）：在过去的三十年里，对儿童白血病治愈的关注已经导致生存率增加> 80%。然而，控制白血病治疗症状的努力并没有跟上促进治愈的新疗法的步伐。治疗期间的症状毒性可导致并发症、治疗延迟和治疗剂量减少。治疗中的妥协可能会对生活质量产生负面影响，更值得注意的是，危及长期生存的机会。本研究探讨了影响由氧化应激或细胞因子产生增加或由于遗传变异导致的抗氧化和抗炎防御系统的实际失败引起的症状毒性的生物学机制。重复测量研究设计用于评估400名3-18岁儿童和青少年在治疗的最强烈阶段诊断为白血病时所经历的治疗症状的数量和严重程度。症状包括疲劳、睡眠障碍、疼痛、抑郁、恶心、身体活动变化以及记忆和认知缺陷。将在诱导治疗后的4个时间点进行所有治疗性腰椎穿刺，获得CSF氧化应激和细胞因子生物标志物。将使用线性混合模型（LMM）确定症状群对生活质量的影响。LMM还将用于确定CSF氧化应激和细胞因子生物标志物对症状群的影响。我们还将评估具有与氧化应激和炎症通路相关的遗传变异的患者是否比没有这些遗传变异的患者具有更高的发展症状群的风险。这项研究是第一次寻找与氧化应激和炎症途径相关的遗传变异，并探索CNS氧化应激和细胞因子生物标志物及其与症状群的关系。了解白血病治疗过程中的症状群将为未来的干预措施铺平道路，这些干预措施可以减少毒性，并最大限度地减少治疗中可能损害儿童最佳治愈机会的延迟和剂量减少。

DESCRIPTION (provided by applicant): The focus on cure for childhood leukemia over the last three decades has resulted in increased survival rates of > 80%. However, efforts to manage leukemia treatment symptoms have not kept pace with new therapies that promote cure. Symptom toxicity during treatment can result in complications, treatment delays and therapy dose reductions. Compromise in therapy can negatively influence quality of life and even more notably, jeopardize chances for long-term survival. This study examines biologic mechanisms that influence symptom toxicities caused by increased oxidative stress or cytokine production or actual failure of the anti-oxidant and anti-inflammatory defense systems due to genetic variation. A repeated measures research design is used to evaluate the number and severity of treatment symptoms experienced by 400 children and adolescents, 3-18 years of age, with a diagnosis of leukemia during the most intense phase of treatment. Symptoms include fatigue, sleep disturbance, pain, depression, nausea, physical activity changes, as well as memory and cognition deficits. CSF oxidative stress and cytokine biomarkers will be obtained with all therapeutic lumbar punctures occurring at four time points during post-induction therapy. Linear mixed models (LMM) will be used to determine the influence that symptom clusters have on quality of life. LMM also will be used to determine the effect CSF oxidative stress and cytokine biomarkers have on symptom clusters. We will also evaluate whether patients with genetic variants associated with the oxidative stress and inflammatory pathways have higher risk of developing symptom clusters than those without these genetic variants. This study is the first of its kind to search for genetic variants associated with the oxidative stress and inflammatory pathways as well as explore CNS oxidative stress and cytokine biomarkers, and their relationships with symptom clusters. Understanding symptom clusters during leukemia treatment will pave the way for future interventions that decrease toxicity and minimize delays and dose reductions in therapy that may compromise a child's best chance for cure.