Dexrazoxane and Prevention of Anthracycline-Related Cardiomyopathy

右雷佐生与蒽环类药物相关心肌病的预防

• 批准号: 10656913
• 负责人: Eric Jessen Chow
• 金额: $ 45.56万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-05 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10656913
• 关键词: Dexrazoxane; Prevention; Anthracycline; Related; Cardiomyopathy

PROJECT SUMMARY Five-year survival among children with cancer now exceeds 80%. Late cardiovascular disease, including cancer therapy-related cardiomyopathy/heart failure (CHF), has now become the leading non-cancer cause of premature morbidity and mortality among childhood cancer survivors. Anthracycline and related drugs have been well-documented to be the single most important risk factor associated with subsequent development of CHF among cancer survivors. Anthracyclines, despite their known cardiotoxicity, continue to be an integral part of many contemporary pediatric cancer treatment protocols. Dexrazoxane (DRZ) is an EDTA-like bisdioxopiperazine that decreases oxygen free radicals via intracellular iron chelation, and is FDA-approved for use as a cardioprotectant in adults being treated with high-dose anthracyclines for breast cancer. The American Society of Clinical Oncology recommends considering its use for all adults exposed to high doses of anthracyclines. However, concerns regarding DRZ’s safety and efficacy have limited its use in children. Four national phase 3 clinical trials that featured upfront DRZ randomization were conducted among more than 1,200 children with leukemias and lymphomas from 1995-2001. Patients were treated with a range of anthracycline (specifically, doxorubicin) doses still commonly used today. While some short- and intermediate- term data up to 5-years from these trials suggest that DRZ-exposed children had less acute cardiotoxicity and pathologic left ventricular remodeling, longer term data are lacking. The proposed research will attempt to ascertain long-term cardiovascular health in this population of childhood cancer survivors now that 15-20 years have elapsed since cancer diagnosis. Specifically, we will leverage the study infrastructure we have developed within the Children’s Oncology Group (COG; a member of the NCI’s National Clinical Trials Network) in order to prospectively ascertain current cardiac function via echocardiography and overall cardiovascular health among at least 200 survivors. This sample size will allow us to definitively determine if survivors randomized to DRZ have decreased markers of CHF compared with those treated on the standard non-DRZ arms. We will then combine prospective echocardiographic data with archived data collected by the original clinical trialists and those available from participating COG institutions to examine whether DRZ exposure is associated with a differential trajectory of echocardiographic change over time. Finally, we will deploy a variety of approaches, including use of administrative and insurance databases, to capture long-term adverse health outcomes from almost the entire study population. We believe successful completion of the proposed research will allow us to determine whether DRZ provides long-term cardioprotection, with immediate clinical implications for current patients and drug regulatory policy.

项目概要 目前癌症儿童的五年生存率超过 80%。晚期心血管疾病，包括 癌症治疗相关的心肌病/心力衰竭（CHF）现已成为导致癌症的主要非癌症原因 儿童癌症幸存者的过早发病率和死亡率。蒽环类及相关药物 已被充分证明是与后续发展相关的单一最重要的风险因素 癌症幸存者中的 CHF。尽管蒽环类药物具有已知的心脏毒性，但仍然是其不可或缺的一部分 许多当代儿科癌症治疗方案的一部分。右雷佐生 (DRZ) 是一种类似 EDTA 的药物 双二氧代哌嗪通过细胞内铁螯合减少氧自由基，并已获得 FDA 批准用于 用作接受高剂量蒽环类药物治疗乳腺癌的成人的心脏保护剂。这 美国临床肿瘤学会建议考虑将其用于所有暴露于高剂量的成人 蒽环类药物。然而，对 DRZ 安全性和有效性的担忧限制了其在儿童中的使用。四 以预先 DRZ 随机化为特征的国家 3 期临床试验在超过 1995 年至 2001 年间，有 1,200 名儿童患有白血病和淋巴瘤。患者接受了一系列治疗 至今仍常用蒽环类（特别是阿霉素）剂量。虽然一些短期和中期 这些试验长达 5 年的长期数据表明，接触 DRZ 的儿童的急性心脏毒性较小，并且 病理性左心室重构，缺乏长期数据。拟议的研究将尝试 确定儿童癌症幸存者群体的长期心血管健康状况 15-20 年后 自癌症诊断以来已经过去了。具体来说，我们将利用我们开发的研究基础设施 儿童肿瘤学组（COG；NCI 国家临床试验网络的成员）内的顺序 通过超声心动图前瞻性地确定当前的心脏功能和整体心血管健康状况 至少有200名幸存者。这个样本量将使我们能够明确确定幸存者是否被随机分配到 与标准非 DRZ 治疗组相比，DRZ 减少了 CHF 标志物。我们将 然后将前瞻性超声心动图数据与原始临床试验人员收集的存档数据相结合 以及参与 COG 机构提供的用于检查 DRZ 暴露是否与 超声心动图随时间变化的差异轨迹。最后，我们将部署多种方法， 包括使用行政和保险数据库来捕获长期不良健康结果 几乎整个研究人群。我们相信成功完成拟议的研究将使我们能够 确定 DRZ 是否提供长期心脏保护作用，对当前的临床具有直接意义 患者和药品监管政策。

项目成果

Challenges associated with retrospective analysis of left ventricular function using clinical echocardiograms from a multicenter research study.

• DOI: 10.1111/echo.14983
• 发表时间: 2021-03
• 期刊: Echocardiography (Mount Kisco, N.Y.)
• 作者: Sachdeva R;Stratton KL;Cox DE;Armenian SH;Bhat A;Border WL;Leger KJ;Leisenring WM;Meacham LR;Sadak KT;Narasimhan S;Chow EJ;Nathan PC
• 通讯作者: Nathan PC