Treatment-Related Cardiotoxicity in Children with Relapsed Acute Myeloid Leukemia - Natural History, Occurrence and Implications

复发性急性髓系白血病儿童的治疗相关心脏毒性 - 自然史、发生情况和影响

• 批准号: 10663387
• 负责人: Kelly Diringer Getz
• 金额: $ 74.68万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663387
• 关键词: Acute Myelocytic Leukemia; Address; Adolescent; Cardiomyopathies; Cardiotoxicity; Chemotherapy-Oncologic Procedure; Child; Childhood; Childhood Acute Myeloid Leukemia; Clinical Trials Cooperative Group; Clinical Trials Database; Computerized Medical Record; Data; Diagnosis; Disease; Disease remission; Disease-Free Survival; Echocardiography; Effectiveness; Electronic Health Record; Evaluation; Functional disorder; Goals; Health Information System; Heart failure; Impact evaluation; Incidence; Injury; Institution; Knowledge; Left; Left Ventricular Function; Long Term Survivorship; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Mediating; Mediator; Morbidity - disease rate; Muscle Cells; Myocardial dysfunction; Natural History; Outcome; Patients; Pediatric Oncology Group; Phenotype; Probability; Prognosis; Recovery; Recurrent disease; Refractory; Refractory Disease; Regimen; Relapse; Risk; Salvage Therapy; Selection for Treatments; Source; Standardization; Stem cell transplant; Supportive care; Survivors; Time; Toxic effect; Transplantation; Treatment outcome; Variant; Ventricular; Work; adverse outcome; chemotherapy; clinical development; cohort; conditioning; data resource; experience; follow-up; functional decline; graft vs host disease; heart function; improved; improved outcome; leukemia treatment; mortality; prevent; standard of care; survival outcome; treatment effect; treatment risk; treatment trial

Project Summary/Abstract Acute myeloid leukemia (AML) is the second most common malignancy among children and adolescents. The prognosis of pediatric AML has improved significantly over recent decades, but still nearly half of patients suffer refractory disease or relapse following a first remission. These patients have a relatively poor prognosis, with a probability of five-year survival following relapse of only ~35%. This is achieved with intensive chemotherapy leading to potentially significant toxicity and even treatment-related mortality. While there has been substantial standardization in practice related to frontline therapy for AML, there is greater variability in treatment of relapsed disease – variability that is poorly understood. Furthermore, given the variability in treatment and the small numbers of patients at any one institution, there is a dearth of information on toxicity risks for the treatments being utilized for refractory or relapsed disease. Cardiotoxicity is a prevalent adverse consequence of AML therapy. However, given the incomplete data captured by frontline clinical trial databases once a patient experiences relapse, data on the onset, progression and potential recovery of cardiotoxicity are generally restricted to the time period during and shortly after frontline therapy and late in long-term survivorship. The current lack of data over the duration of the patient experience precludes a complete assessment of the incremental risks associated with AML therapy, including transplant and salvage. Data on how early cardiotoxicity onset during frontline therapy may impact approach to treatment for relapsed disease, the impact of salvage therapies on cardiac function, and subsequent survival outcomes is thus, also poorly understood. The aims of the proposed work are to establish a unique data resource by combining data from the Children's Oncology Group (COG) clinical trial databases, electronic medical record (EMR) abstraction for a multi-center AML cohort, longitudinal quantitative echocardiographic measures of measures of left ventricular (LV) size, systolic and diastolic function, and administrative data from the Pediatric Health Information System, that will enable assessments comparing toxicity and outcomes associated with the variety of approaches to therapy for refractory/relapsed AML. Specifically, our aims include the following: (1) determine the natural history cardiotoxicity and the incremental effects of treatment from initial diagnosis, through relapse and early post-relapse follow-up, (2) to quantify the influence of prevalent salvage therapies on longitudinal changes in LV size, systolic and diastolic function and the incidence of cardiomyopathy, and (3) to evaluate salvage chemotherapy and transplant as mediators of the documented association between early cardiotoxicity onset during frontline therapy and decreased overall survival.

项目总结/摘要 急性髓性白血病（AML）是儿童和青少年中第二常见的恶性肿瘤。的 近几十年来，儿童AML的预后有了显著改善，但仍有近一半的患者 患有难治性疾病或在第一次缓解后复发。这些患者的预后相对较差， 复发后5年生存率仅为~ 35%。这是通过密集的 化疗导致潜在的显著毒性，甚至治疗相关的死亡。虽然已经 与AML一线治疗相关的实践中已经基本标准化， 复发性疾病的治疗-了解甚少的变异性。此外，考虑到 由于任何一个机构的治疗和患者人数少，缺乏关于毒性的信息 治疗难治性或复发性疾病的风险。药物毒性是一种普遍的不良反应， AML治疗的后果。然而，鉴于一线临床试验数据库采集的数据不完整， 一旦患者经历复发，关于心脏毒性的发作、进展和潜在恢复的数据被 通常限于一线治疗期间和治疗后不久以及长期治疗后期 生存。目前缺乏患者经历持续时间内的数据，因此无法进行完整的 评估与AML治疗（包括移植和挽救）相关的增量风险。数据 一线治疗期间早期心脏毒性发作如何影响复发性疾病的治疗方法， 因此，挽救治疗对心脏功能和随后的生存结局的影响也很差 明白拟议工作的目的是通过合并来自以下方面的数据，建立一个独特的数据资源： 儿童肿瘤组（COG）临床试验数据库，电子病历（EMR）摘要， 一个多中心AML队列，纵向定量超声心动图测量左心室 (LV)尺寸、收缩和舒张功能以及来自儿科健康信息系统的管理数据， 这将使评估能够比较与各种方法相关的毒性和结果， 难治性/复发性AML的治疗。具体而言，我们的目标包括：（1）确定自然 心脏毒性史和从最初诊断到复发和早期治疗的增量效应 复发后随访，（2）量化流行挽救治疗对 左室大小、收缩和舒张功能以及心肌病的发生率;（3）评估挽救性治疗 化疗和移植作为早期心脏毒性发作之间相关性的介质 在一线治疗期间，总生存率下降。