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 心脏毒性是以蒽环类药物为基础的强化化疗方案的常见后果 对儿童癌症治愈率的显著提高负责。鉴于对儿科急症的治疗 髓系白血病(AML)在所有儿童癌症中涉及最高累积剂量的蒽环类药物， 这些患者特别容易出现相关的短期和长期心脏并发症和 死亡率。最近的一项儿童急性髓细胞白血病新疗法的研究表明，左心室的发生率为12%。 收缩功能障碍(LVSD；射血分数&50%)，在治疗一年内。那些有LVSD的人有一个 无事件和总存活率(OS)的显著降低，可能与蒽环类药物剂量的减少有关。 总体而言，这些数据表明，预防、及早发现和缓解心脏毒性对 患者的长期生存。不幸的是，关于人类自然历史的信息十分匮乏 儿童急性髓细胞白血病的心脏毒性，其发生的有意义的预测因素，以及心脏治疗的有效性。 预防或治疗毒性的直接药物疗法。这种知识鸿沟很可能是 作为合作组肿瘤学试验的一部分而获得的有限相关数据。 这项建议的首要目标是更好地了解心脏毒性的发展和更好地 预测其发生，以改善儿童AML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)和 德克萨斯儿童医院，这项研究将解决心脏毒性风险连续体中的重要问题。 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，(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，以及(3)确定心血管(CV)合并症的患病率 以及它们在预测启动急性髓细胞白血病治疗的儿童患者心脏毒性方面的价值。 在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 在心血管流行病学、心脏肿瘤学研究以及高级纵向和生命过程统计方面的指导 方法：研究方法。为了完成这些培训目标，Getz博士组织了一个支持性的、多学科的指导 由她的主要导师理查德·阿普伦克领导的团队，医学博士。她的训练计划达到了预期的效果 通过课程作业、研讨会、会议、临床观察和定向阅读来提高能力。她 将受益于CHOP和牛津大学丰富的资源和机遇 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数据资源，以实现 将影响临床实践并改善心血管疾病和肿瘤预后的流行病学研究 患有癌症的儿童。