Predicting and Monitoring for Cardiac Toxicity in Pediatric AML

儿科 AML 心脏毒性的预测和监测

• 批准号: 10659987
• 负责人: Richard Aplenc
• 金额: $ 81.94万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-25 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659987
• 关键词: Acute; Acute Myelocytic Leukemia; Address; Adherence; Algorithms; Anthracycline; Area; Cardiac; Cardiomyopathies; Cardiotoxicity; Child; Childhood; Childhood Acute Myeloid Leukemia; Clinical; Clinical Trials; Clinical Trials Cooperative Group; Data; Data Set; Data Sources; Derivation procedure; Detection; Development; Disparity; EFRAC; Echocardiography; Ensure; Ethnic Origin; Evaluation; Frequencies; Functional disorder; Future; Genetic; Genomics; Goals; Guidelines; Heart failure; Insurance; Insurance Coverage; Intervention; Intervention Studies; Joints; Knowledge; Left; Left Ventricular Ejection Fraction; Left ventricular structure; Life; Measurement; Measures; Mediating; Modeling; Modification; Monitor; Myocardial dysfunction; Neoadjuvant Therapy; Outcome; Patients; Pattern; Pediatric Oncology Group; Performance; Pharmaceutical Preparations; Phase; Phenotype; Play; Publishing; Race; Randomized; Recommendation; Recovery; Reporting; Resolution; Risk; Role; Schedule; Shortening Fraction; Testing; Time; Toxic effect; Treatment outcome; Treatment-related toxicity; Update; Validation; Ventricular; Work; analytical method; cancer therapy; chemotherapy; childhood cancer survivor; clinical practice; clinical predictive model; clinical trial enrollment; cohort; cost; early experience; early onset; ethnic disparity; ethnic minority; evidence based guidelines; experience; heart function; improved; improved outcome; indexing; leukemia relapse; leukemia treatment; novel; outcome disparities; participant enrollment; patient population; pediatric patients; personalized chemotherapy; predictive modeling; preservation; racial disparity; racial minority; relapse risk; social health determinants; socioeconomics; survival outcome; survivorship; whole genome

Abstract: Children with acute myeloid leukemia (AML) receive the maximum cumulative anthracycline exposure during frontline therapy (>440 mg/m2), an exposure that causes very well-described cardiac complications. The importance of acute, short-term cardiotoxicity in pediatric AML has been described recently by our group using Children’s Oncology Group (COG) clinical trial data. Specifically, nearly 40% of patients experienced left ventricular systolic dysfunction (LVSD) warranting chemotherapy modifications, and 21% suffered LVSD consistent with moderate to life-threatening cardiomyopathy or heart failure. Over 70% of LVSD was first documented during frontline therapy and was associated with a 13% absolute decrease in overall survival (OS). Notably, the decline in OS from early cardiotoxicity is larger than the improvement from any randomized intervention reported to date in pediatric AML cooperative group trials. Despite this clinical impact, there are no clinical prediction models for early chemotherapy associated cardiac toxicity. The cardiotoxicity prediction models developed to date focus exclusively on long-term childhood cancer survivors due to the absence of a sufficiently large and well-characterized de novo AML cohort. The variability in guidelines and clinical practice is fertile ground for disparities in echo monitoring and identification of cardiac outcomes, yet the well described disparities in survival outcomes by race/ethnicity in pediatric AML have not included analyses of echo adherence or cardiac dysfunction.With this application, we propose to develop a highly unique dataset including detailed demographic, clinical, genomic, treatment, and toxicity data, combined with longitudinal indices of LV size, diastolic, and systolic function from all clinical surveillance echocardiograms for patients enrolled on two COG AML trials, AAML0531 and AAML1031. With this unique data set, we will use novel, sophisticated analytic methods to develop models that: (1) continually update predictions of early cardiotoxicity risk during frontline therapy, (2) predict LV functional trajectories leading to persistent or worsening LVSD in the early/moderate time window after AML therapy, and (3) compare cancer treatment outcomes (EFS and OS) and detection of LVSD for three cardiotoxicity monitoring schedules with different echo frequencies in pediatric AML patients. The first model should enable personalized chemotherapy modifications and earlier initiation of cardiac-directed medications, thus improving survival outcomes. The second model should inform more personalized, evidence-based recommendations for off-treatment cardiotoxicity surveillance, potentially leading to improved adherence and reducing costs of unnecessary testing. The third analyses will provide a data driven guidance for on-therapy echocardiogram monitoring for pediatric patients with AML.

抽象的： 患有急性髓系白血病 (AML) 的儿童接受最大累积蒽环类药物暴露 在一线治疗期间（>440 mg/m2），这种暴露会导致非常详细的心脏并发症。 我们的小组最近描述了儿科 AML 中急性、短期心脏毒性的重要性 具体来说，儿童肿瘤学组 (COG) 的临床试验数据显示，近 40% 的患者经历了左转。 心室收缩功能障碍 (LVSD) 需要调整化疗，21% 的人患有 LVSD 与中度至危及生命的心肌病或心力衰竭一致，超过 70% 的 LVSD 是首先发生的。 在一线治疗期间记​​录，与总生存期绝对下降 13% 相关 值得注意的是，早期心脏毒性导致的 OS 下降幅度大于任何随机试验的改善幅度。 迄今为止，儿科 AML 合作小组试验中报告了干预措施，尽管有这种临床影响，但还没有。 早期化疗相关心脏毒性的临床预测模型。 迄今为止开发的模型仅关注长期儿童癌症幸存者，因为缺乏 足够大且特征明确的新 AML 队列 指南和临床实践的可变性。 是回声监测和心脏结果识别方面存在差异的沃土，但已有详细描述 儿科 AML 中按种族/民族划分的生存结果差异未包括 echo 分析 依从性或心脏功能障碍。通过此应用程序，我们建议开发一个高度独特的数据集 包括详细的人口统计、临床、基因组、治疗和毒性数据，并结合纵向数据 来自患者所有临床监测超声心动图的左心室大小、舒张和收缩功能指数 注册了两项 COG AML 试验 AAML0531 和 AAML1031 有了这个独特的数据集，我们将使用新颖的、 复杂的分析方法来开发模型：(1) 不断更新早期心脏毒性的预测 一线治疗期间的风险，(2) 预测导致持续或恶化 LVSD 的 LV 功能轨迹 AML 治疗后的早期/中期时间窗口，以及 (3) 比较癌症治疗结果（EFS 和 OS）和 LVSD 检测，用于不同回波频率的三种心脏毒性监测方案 第一个模型应该能够实现个性化化疗修改和更早的治疗。 启动针对心脏的药物，从而改善生存结果。 可能会为治疗后心脏毒性监测提供更个性化、基于证据的建议 第三个分析将提供一个改进的依从性并减少不必要的测试的成本。 儿童 AML 患者治疗中超声心动图监测的数据驱动指南。