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.

摘要： 儿童急性髓系白血病(AML)接受最大累积蒽环类药物暴露 在一线治疗期间(&gt；440 mg/m2)，暴露会导致非常详细的心脏并发症。这个 儿科AML急性、短期心脏毒性的重要性最近由我们的小组使用 儿童肿瘤学组(COG)临床试验数据。具体地说，近40%的患者经历了左 需要进行化疗修改的室性收缩功能障碍(LVSD)，21%的患者患有LVSD 符合中度至危及生命的心肌病或心力衰竭。超过70%的LVSD是第一 在一线治疗期间被记录下来，并与总存活率绝对下降13%相关 (OS)。值得注意的是，OS在早期心脏毒性中的下降大于任何随机试验的改善 迄今为止，在儿童急性髓系白血病合作组试验中报道了干预措施。尽管有这种临床影响，但没有 早期化疗相关心脏毒性的临床预测模型。心脏毒性预测 到目前为止开发的模型只关注长期儿童癌症幸存者，因为缺乏 数量足够大且特征良好的新急性髓系白血病队列。指南和临床实践中的变异性 是在回声监测和识别心脏结果方面存在差异的肥沃土壤，但详细描述 不同种族/民族的儿童急性髓细胞白血病患者的生存结局差异不包括ECHO分析 粘连或心功能障碍。通过这一应用，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，结合纵向 所有患者的临床监测超声心动图中的左心室大小、舒张期和收缩功能指数 参加了COG AML的两项试验，AAML0531和AAML1031。有了这个独特的数据集，我们将使用新颖的， 开发模型的复杂分析方法：(1)不断更新对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的LVSD的左心室功能轨迹 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)和检测三种不同回声频率的心脏毒性监测方案的LVSD 儿童急性髓系白血病患者。第一种模式应该能够进行个性化的化疗修改，并更早 启动心脏导向药物，从而改善生存结果。第二个模型应该通知 更个性化、更循证的非治疗心脏毒性监测建议，可能 从而提高遵从性并降低不必要测试的成本。第三个分析将提供一个 儿童急性髓细胞白血病患者治疗中超声心动图监测的数据驱动指南。