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： 急性髓性白血病（AML）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），这种暴露会引起非常明确的心脏并发症。的 我们的研究小组最近使用以下方法描述了急性短期心脏毒性在儿童AML中的重要性： 儿童肿瘤组（COG）临床试验数据。具体而言，近40%的患者经历了左 心室收缩功能不全（LVSD）导致化疗修改，21%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是第一次 在一线治疗期间记录，与总生存率绝对下降13%相关 （OS）。值得注意的是，早期心脏毒性导致的OS下降大于任何随机分组的改善。 迄今为止在儿童AML合作组试验中报告的干预。尽管有这种临床影响， 早期化疗相关心脏毒性的临床预测模型。心脏毒性预测 迄今为止开发的模型只关注长期的儿童癌症幸存者， 足够大且特征充分的初治AML队列。指南和临床实践的可变性 是超声心动图监测和心脏结局识别差异的肥沃土壤，然而， 儿童AML中按人种/种族划分的生存结局差异未包括超声心动图分析。 坚持或心脏功能障碍。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学、临床、基因组、治疗和毒性数据，结合纵向数据， 来自患者所有临床监测超声心动图的LV大小、舒张和收缩功能指数 入组了两项COG AML试验，AAML 0531和AAML 1031。有了这个独特的数据集，我们将使用新的， 复杂的分析方法，以开发模型：（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LVSD持续或恶化的LV功能轨迹， AML治疗后的早期/中度时间窗，和（3）比较癌症治疗结果（EFS和 OS）和LVSD检测的三种心脏毒性监测计划与不同的回波频率， 儿童AML患者。第一个模型应该能够实现个性化的化疗修改和早期 开始心脏定向药物治疗，从而改善生存结局。第二个模型应该告知 更个性化的，基于证据的治疗后心脏毒性监测建议，可能 导致改进的粘附性和减少不必要的测试的成本。第三次分析将提供一个 AML儿科患者治疗中超声心动图监测的数据驱动指南。