Treatment-Related Cardiotoxicity in Children with Relapsed Acute Myeloid Leukemia - Natural History, Occurrence and Implications

项目摘要/摘要 急性髓系白血病(AML)是儿童和青少年中第二常见的恶性肿瘤。这个 近几十年来，儿童AML的预后有了显著改善，但仍有近一半的患者 遭受难治性疾病或在第一次缓解后复发。这些患者的预后相对较差， 复发后五年存活的概率只有35%。这是通过密集的 化疗可能导致严重的毒性，甚至与治疗相关的死亡。在那里有 在与急性髓细胞白血病一线治疗相关的实践中已基本标准化，在 复发性疾病的治疗--人们对此知之甚少。此外，考虑到 治疗和任何一家机构的患者数量都很少，关于毒性的信息很匮乏。 治疗难治性或复发性疾病的风险。心脏毒性是一种普遍存在的不良反应 急性髓系白血病治疗的后果。然而，鉴于一线临床试验数据库获取的数据不完整， 一旦患者复发，有关心脏毒性的开始、进展和潜在恢复的数据如下 一般限于一线治疗期间和之后不久以及长期治疗后期 生存能力。目前缺乏关于患者经历持续时间的数据，这排除了完整的 评估与急性髓细胞白血病治疗相关的增量风险，包括移植和挽救。数据在 在一线治疗期间早期出现心脏毒性如何影响复发疾病的治疗方法， 因此，抢救治疗对心脏功能和随后的生存结果的影响也很差。 明白了。拟议工作的目标是通过结合来自以下方面的数据来建立独特的数据资源 儿童肿瘤学组织(COG)临床试验数据库、电子病历(EMR)摘要 多中心急性髓细胞白血病队列、左心室测量的纵向定量超声心动图测量 (Lv)来自儿科健康信息系统的大小、收缩和舒张期功能以及管理数据， 这将使评估能够比较与各种方法相关的毒性和结果 难治性/复发性AML的治疗。具体来说，我们的目标包括以下几个方面：(1)确定自然 历史心脏毒性和从初诊到复发和早期治疗的递增效应 复发后随访，(2)量化流行的抢救疗法对患者的纵向变化的影响 左心室大小、收缩和舒张期功能与心肌病的发生率；(3)评估抢救 化疗和移植作为已记录的早期心脏毒性发作之间的联系的中介 在一线治疗期间，并降低了总存活率。

Project Summary/Abstract Acute myeloid leukemia (AML) is the second most common malignancy among children and adolescents. The prognosis of pediatric AML has improved significantly over recent decades, but still nearly half of patients suffer refractory disease or relapse following a first remission. These patients have a relatively poor prognosis, with a probability of five-year survival following relapse of only ~35%. This is achieved with intensive chemotherapy leading to potentially significant toxicity and even treatment-related mortality. While there has been substantial standardization in practice related to frontline therapy for AML, there is greater variability in treatment of relapsed disease – variability that is poorly understood. Furthermore, given the variability in treatment and the small numbers of patients at any one institution, there is a dearth of information on toxicity risks for the treatments being utilized for refractory or relapsed disease. Cardiotoxicity is a prevalent adverse consequence of AML therapy. However, given the incomplete data captured by frontline clinical trial databases once a patient experiences relapse, data on the onset, progression and potential recovery of cardiotoxicity are generally restricted to the time period during and shortly after frontline therapy and late in long-term survivorship. The current lack of data over the duration of the patient experience precludes a complete assessment of the incremental risks associated with AML therapy, including transplant and salvage. Data on how early cardiotoxicity onset during frontline therapy may impact approach to treatment for relapsed disease, the impact of salvage therapies on cardiac function, and subsequent survival outcomes is thus, also poorly understood. The aims of the proposed work are to establish a unique data resource by combining data from the Children's Oncology Group (COG) clinical trial databases, electronic medical record (EMR) abstraction for a multi-center AML cohort, longitudinal quantitative echocardiographic measures of measures of left ventricular (LV) size, systolic and diastolic function, and administrative data from the Pediatric Health Information System, that will enable assessments comparing toxicity and outcomes associated with the variety of approaches to therapy for refractory/relapsed AML. Specifically, our aims include the following: (1) determine the natural history cardiotoxicity and the incremental effects of treatment from initial diagnosis, through relapse and early post-relapse follow-up, (2) to quantify the influence of prevalent salvage therapies on longitudinal changes in LV size, systolic and diastolic function and the incidence of cardiomyopathy, and (3) to evaluate salvage chemotherapy and transplant as mediators of the documented association between early cardiotoxicity onset during frontline therapy and decreased overall survival.