Early Treatment-Related Cardiotoxicity and Subsequent Outcomes in Pediatric Acute Myeloid Leukemia: an Assessment of Development, Progression and Mitigation

小儿急性髓系白血病早期治疗相关的心脏毒性和后续结果：发展、进展和缓解的评估

• 批准号: 10170411
• 负责人: Kelly Diringer Getz
• 金额: $ 14.14万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-05 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170411
• 关键词: Acute; Acute Myelocytic Leukemia; Address; Adult; Age; Anthracycline; Cancer Patient; Cardiac; Cardiomyopathies; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular system; Chemotherapy-Oncologic Procedure; Child; Childhood; Childhood Acute Myeloid Leukemia; Clinical; Clinical Trials; Clinical Trials Cooperative Group; Competence; Complication; Computerized Medical Record; Creatinine; Data; Data Analyses; Database Management Systems; Detection; Development; Diagnosis; Doctor of Philosophy; Dose; EFRAC; Early Diagnosis; Early Intervention; Early treatment; Echocardiography; Educational workshop; Effectiveness; Equation; Event; Exposure to; Functional disorder; Glean; Glucose; Goals; Health Information System; Heart failure; Hypertension; Incidence; Inferior; Injury; Intervention; Knowledge; Laboratories; Left; Left Ventricular Dysfunction; Left Ventricular Ejection Fraction; Left Ventricular Function; Life Cycle Stages; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Mediating; Mediation; Mediator of activation protein; Mentored Research Scientist Development Award; Mentors; Mentorship; Methods; Modeling; Modification; Morbidity - disease rate; Muscle Cells; Myocardial dysfunction; Natural History; Oncology; Oncology Group; Outcome; Patients; Pattern; Pediatric Hospitals; Pediatric Oncology Group; Pennsylvania; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Philadelphia; Plasma; Predisposition; Prevalence; Prevention; Process; Quality of life; Race; Reading; Recovery; Relapse; Renal function; Reporting; Research; Resolution; Resources; Risk; Serum; Statistical Methods; Structure; Subgroup; Supportive care; Texas; Time; Toxic effect; Training; Treatment outcome; Universities; Ventricular; Weight; base; cardiovascular disorder epidemiology; cardiovascular disorder risk; cardiovascular risk factor; career; chemotherapeutic agent; chemotherapy; childhood cancer survivor; clinical development; clinical practice; cohort; comorbidity; data resource; dosage; epidemiology study; follow-up; glucose metabolism; heart function; heart preservation; hemodynamics; high risk; improved; improved outcome; insight; leukemia treatment; longitudinal course; mortality; multidisciplinary; oncology trial; overtreatment; pediatric patients; prevent; relapse risk; relative effectiveness; response; stem; survivorship; symposium

PROJECT SUMMARY/ABSTRACT Cardiac toxicity is a common consequence of the intensive anthracycline-based chemotherapy regimens responsible for dramatic improvements in childhood cancer cure rates. Given that treatment for pediatric acute myeloid leukemia (AML) involves the highest cumulative doses of anthracyclines among all pediatric cancers, these patients are at particularly high risk for the associated short- and long-term cardiac morbidity and mortality. A recent study of de novo pediatric AML therapy demonstrated a 12% incidence of left ventricular systolic dysfunction (LVSD; ejection fraction < 50%), within one year of treatment. Those with LVSD had a dramatic reduction in both event free and overall survival (OS), likely related to anthracycline dose reduction. Overall, these data suggest that the prevention, early detection and mitigation of cardiotoxicity is critical to the long-term survival of patients. Unfortunately, there is a dearth of information on the natural history of cardiotoxicity in pediatric AML, meaningful predictors of its occurrence, and the effectiveness of cardiac- directed pharmacotherapies in preventing or treating the toxicity. This knowledge gap is likely the result of the limited relevant data captured as part of cooperative group oncology trials. The overarching goal of this proposal is to better understand the development of cardiotoxicity and better predict its occurrence, in order to improve the outcomes of children with AML. By leveraging three unique data resources, namely Children’s Oncology Group clinical trial data, the Pediatric Health Information System database, and granular electronic medical record data from Children’s Hospital of Philadelphia (CHOP) and Texas Children’s Hospital, this study will address important questions across the cardiotoxicity risk continuum. The specific aims are to (1) identify distinct trajectories of cardiotoxicity progression and resolution and their clinical and demographic correlates, (2) compare the direct and indirect effects of cardiac-directed interventions on relapse risk and OS, and (3) determine the prevalence of cardiovascular (CV) comorbidities and their value in predicting cardiotoxicity in pediatric patients initiating AML treatment. With the support of this K01 award, the applicant, Kelly D. Getz, PhD, MPH, will acquire training and mentorship in CV epidemiology, cardio-oncology research, and advanced longitudinal and life course statistical methods. To complete these training goals, Dr. Getz assembled a supportive, multi-disciplinary mentoring team led by her primary mentor, Richard Aplenc, MD, PhD. Her training plan addresses the desired competencies through coursework, workshops, conferences, clinical observation, and directed readings. She will benefit from the outstanding depth of resources and opportunities at CHOP and the University of Pennsylvania. Her long-term career goal is to utilize existing data resources in creative ways to enable epidemiology studies that will impact clinical practice and improve both CV and oncologic outcomes for children with cancer.

项目摘要/摘要 心脏毒性是强化基于蒽环类的化疗方案的普遍结果 负责儿童癌症治疗率的显着改善。鉴于小儿急性的治疗 髓样白血病（AML）涉及所有儿科取消剂中最高累积剂量的蒽环类药物， 这些患者患有相关的短期和长期心脏发病率的风险尤其高 死亡。对新小儿AML疗法的最新研究表明，左心室的发生率为12％ 收缩功能障碍（LVSD；射血分数<50％），在治疗后一年。那些患有LVSD的人有一个 无事和总生存期（OS）的急剧减少可能与邻志剂量降低有关。 总体而言，这些数据表明，预防，早期检测和缓解心脏毒性对 患者的长期生存。不幸的是，有关自然历史的信息死亡 儿科AML的心脏毒性，其发生的有意义的预测指标以及心脏的有效性 定向药物疗法预防或治疗毒性。这个知识差距可能是 作为合作小组肿瘤学试验的一部分，捕获的相关数据有限。 该提案的总体目标是更好地了解心脏毒性的发展和更好 预测其发生，以改善AML儿童的结果。通过利用三个唯一数据 资源，即儿童肿瘤学组临床试验数据，小儿健康信息系统 来自费城儿童医院（CHOP）和 德克萨斯州儿童医院，这项研究将解决心脏毒性风险连续性的重要问题。 具体目的是（1）确定心脏毒性进展和分辨率的不同轨迹 临床和人口统计学相关，（2）比较心脏导向的直接和间接影响 对中继风险和OS的干预措施，以及（3）确定心血管（CV）合并症的患病率 它们在预测儿科患者中的心脏毒性方面的价值启动AML治疗。 在该K01奖的支持下，申请人Kelly D. Getz博士，MPH将获得培训，并 CV流行病学，心脏肿瘤研究以及高级纵向和生命课程统计数据 方法。为了完成这些培训目标，Getz博士组建了一项支持性的多学科指导 由她的主要导师Richard Aplenc，医学博士领导的团队。她的培训计划解决了所需的 通过课程，研讨会，会议，临床观察和定向阅读的能力。她 将受益于Chop和University的资源和机会的杰出深度 宾夕法尼亚州。她的长期职业目标是利用现有的数据资源以创造性的方式启用 流行病学研究将影响临床实践并改善简历和肿瘤学结果 患有癌症的儿童。