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

项目总结/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 儿童癌症治愈率的显著提高。鉴于治疗小儿急性 骨髓性白血病（AML）涉及所有儿科癌症中最高累积剂量的蒽环类药物， 这些患者的相关短期和长期心脏病发病率的风险特别高， mortality.最近一项关于儿童AML初治治疗的研究表明，12%的左心室 收缩功能障碍（LVSD;射血分数< 50%），治疗一年内。那些患有LVSD的人 无事件生存期和总生存期（OS）均显著降低，可能与蒽环类药物剂量降低有关。 总的来说，这些数据表明，预防、早期发现和减轻心脏毒性对治疗至关重要。 患者的长期生存。不幸的是，缺乏关于自然历史的信息， 儿童AML的心脏毒性，其发生的有意义的预测因素，以及心脏- 用于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 作为合作组肿瘤学试验的一部分采集的相关数据有限。 该提案的总体目标是更好地了解心脏毒性的发展， 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 数据库和来自费城儿童医院（CHOP）的颗粒状电子病历数据， 这项研究将解决心脏毒性风险连续体中的重要问题。 具体目的是（1）确定心脏毒性进展和消退的不同轨迹， 临床和人口统计学相关性，（2）比较心脏定向的直接和间接影响 对复发风险和OS进行干预，以及（3）确定心血管（CV）合并症的患病率 以及它们在预测开始AML治疗的儿科患者的心脏毒性中的价值。 在K 01奖的支持下，申请人Kelly D. Getz博士，公共卫生硕士，将获得培训， CV流行病学、心脏肿瘤学研究以及高级纵向和生命过程统计学方面的导师 方法.为了完成这些培训目标，Getz博士组织了一个支持性的、多学科的指导小组， 团队由她的主要导师Richard Aplenc，MD，PhD领导。她的培训计划满足了 通过课程，研讨会，会议，临床观察和指导阅读的能力。她 将受益于CHOP和大学的出色深度资源和机会。 宾夕法尼亚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， 将影响临床实践并改善CV和肿瘤学结局的流行病学研究， 患有癌症的儿童。

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.