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： 患有急性髓样白血病（AML）的儿童获得最大的累积蒽环类药物暴露 在前线治疗（> 440 mg/m2）期间，这种暴露会导致非常描述的心脏并发症。 最近，我们的小组描述了小儿AML急性，短期心脏毒性的重要性 儿童肿瘤学组（COG）临床试验数据。具体而言，几乎40％的患者剩下 心室收缩功能障碍（LVSD）警告化疗修饰，21％患有LVSD 与中度至威胁生命的心肌病或心力衰竭一致。超过70％的LVSD是第一个 在一线治疗期间记​​录，与总体生存的绝对降低13％有关 （OS）。值得注意的是，早期心脏毒性的OS下降大于任何随机的改进 在小儿AML合作小组试验中报告的干预措施。尽管有这种临床影响，但没有 早期化学疗法相关心脏毒性的临床预测模型。心脏毒性预测 由于缺乏 足够大的，良好的从头AML队列。指南和临床实践的变异性 是回声监测和心脏结果识别差异的沃土，但描述的 小儿AML种族/种族的生存结果差异尚未包括​​回声的分析 依从性或心脏功能障碍。在此应用程序中，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学，临床，基因组，治疗和毒性数据，结合纵向 来自患者的所有临床监视超声心动图的LV大小，舒张和收缩功能的指标 参加了两项COG AML试验AAML0531和AAML1031。有了这个独特的数据集，我们将使用小说， 复杂的分析方法开发：（1）不断更新早期心脏毒性的预测 （2）预测LV功能轨迹导致LV功能轨迹导致持续或恶化的LVSD AML治疗后的早期/中度窗口，（3）比较癌症治疗结果（EFS和 OS）和检测LVSD，用于三个具有不同回声频率的心脏毒性监测时间表 小儿AML患者。第一个模型应实现个性化的化学疗法修改，并更早 心脏指导药物的启动，从而改善了生存结果。第二个模型应告知 对非治疗心脏毒性监测的更个性化的，基于证据的建议，可能 导致依从性提高并降低了不必要的测试的成本。第三个分析将提供 数据驱动的针对AML儿科患者的疗法超声心动图监测的指导。