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: 9755500
• 负责人: Kelly Diringer Getz
• 金额: $ 14.52万
• 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/9755500
• 关键词: Acute; Acute Myelocytic Leukemia; Address; Adult; Age; Anthracyclines; 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; Comorbidity; 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 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; 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; 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.

项目概要/摘要 心脏毒性是基于蒽环类药物的强化化疗方案的常见后果 显着提高儿童癌症治愈率。鉴于治疗小儿急性 骨髓性白血病（AML）是所有儿科癌症中蒽环类药物累积剂量最高的， 这些患者发生相关短期和长期心脏病的风险特别高， 死亡。最近一项儿童 AML 治疗的从头研究表明，左心室病变的发生率为 12% 治疗一年内出现收缩功能障碍（LVSD；射血分数 < 50%）。患有 LVSD 的患者有 无事件生存期和总生存期（OS）显着降低，可能与蒽环类药物剂量减少有关。 总体而言，这些数据表明，预防、早期发现和减轻心脏毒性对于心脏毒性至关重要。 患者的长期生存。不幸的是，关于自然历史的信息非常缺乏。 儿科 AML 的心脏毒性、其发生的有意义的预测因素以及心脏治疗的有效性 预防或治疗毒性的定向药物疗法。这种知识差距可能是由于 作为合作团体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并更好地 预测其发生，以改善 AML 儿童的预后。通过利用三个独特的数据 资源，即儿童肿瘤组临床试验数据、儿科健康信息系统 数据库以及来自费城儿童医院 (CHOP) 的详细电子病历数据和 德克萨斯儿童医院的这项研究将解决整个心脏毒性风险连续体的重要问题。 具体目标是（1）确定心脏毒性进展和解决的不同轨迹及其 临床和人口统计学相关性，（2）比较心脏导向的直接和间接影响 对复发风险和 OS 的干预措施，以及 (3) 确定心血管 (CV) 合并症的患病率 及其在预测开始 AML 治疗的儿科患者心脏毒性方面的价值。 在该 K01 奖项的支持下，申请人 Kelly D. Getz 博士、公共卫生硕士将获得培训和 心血管流行病学、心脏肿瘤学研究以及高级纵向和生命历程统计方面的指导 方法。为了完成这些培训目标，Getz 博士组建了支持性的多学科指导团队 团队由她的主要导师 Richard Aplenc 博士领导。她的培训计划满足了期望的目标 通过课程、研讨会、会议、临床观察和定向阅读来培养能力。她 将受益于 CHOP 和大学的丰富资源和机会 宾夕法尼亚州。她的长期职业目标是以创造性的方式利用现有的数据资源，以实现 流行病学研究将影响临床实践并改善心血管和肿瘤学结果 患有癌症的儿童。