Early Detection and Mechanisms of Cancer Immunotherapy Associated Cardiotoxicity

癌症免疫治疗相关心脏毒性的早期检测和机制

• 批准号: 10308333
• 负责人: Daniel Addison
• 金额: $ 16.57万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10308333
• 关键词: Adult; Affect; Agammaglobulinaemia tyrosine kinase; Age; Ambulatory Blood Pressure Monitoring; Animal Model; Animals; Anticoagulants; Arrhythmia; Atrial Fibrillation; Biological Markers; Blood Pressure; Blood Vessels; Breast; Cancer Patient; Cardiac; Cardiotoxicity; Cardiovascular Diseases; Chronic Lymphocytic Leukemia; Clinical Data; Clinical Research; Data; Development; Disease; Drug Interactions; Early Diagnosis; Event; Fibrosis; Gender; Generations; Gold; Heart Atrium; Heart Research; Hemorrhage; Hypertension; Imaging Techniques; Incidence; Inflammation; Inflammatory; Interleukin-6; Lead; Left; Left Atrial Function; Left Ventricular Ejection Fraction; Left Ventricular Mass; Legal patent; Link; Lung; Magnetic Resonance Imaging; Malignant Neoplasms; Matrix Metalloproteinases; Measurement; Measures; Monitor; Oncology; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Prevention strategy; Prospective Studies; Public Health; Reporting; Research; Risk; Safety; Serum; Signal Transduction; Specific qualifier value; TNF gene; Testing; Transforming Growth Factor beta; Troponin; Troponin I; Tyrosine Kinase Inhibitor; Ventricular; Work; animal data; base; cancer immunotherapy; cardiovascular disorder risk; cardiovascular health; career; cohort; cytokine; follow-up; imaging study; improved; innovation; insight; multidisciplinary; myocardial damage; novel; primary endpoint; primary outcome; prospective; protein-tyrosine kinase c-src; response; standard of care; tool

ABSTRACT Ibrutinib, a 1st generation nonselective Bruton’s tyrosine kinase inhibitor (BTKi), has dramatically improved sur- vival for chronic lymphocytic leukemia (CLL) patients, a disease affecting nearly 250,000 U.S. adults. However, up to 38% of CLL patients treated with ibrutinib develop atrial fibrillation (AF). The development of AF on ibrutinib is challenging as drug-drug interactions preclude many standard approaches to treatment, and the risk of bleed- ing when ibrutinib and anticoagulants are combined is markedly increased. Thus, there is need to better under- stand the mechanisms involved in the development of ibrutinib-associated AF, and ultimately identify preventive strategies. Recent animal studies suggest that ibrutinib-associated AF involves pathways through an increase in left atrial volume (LAV) and increased left atrial (LA) fibrosis. There are no clinical data characterizing the effect of ibrutinib on LAV or fibrosis; thus, in Aim 1, we test the effect of ibrutinib on LAV (primary outcome) and LA fibrosis by performing serial cardiac magnetic resonance imaging (CMR) in 50 patients pre- and at 6 months after stating ibrutinib. Additionally, in Aim 1, we will measure blood pressure using ambulatory blood pressure monitoring (ABPM). As background, >70% of ibrutinib-treated patients developed hypertension, and we hypoth- esize that ibrutinib-associated hypertension may be a key factor in the increase in LAV and fibrosis. Finally, in Aim 1, we will measure biomarkers of inflammation, fibrosis, and myocardial damage in relation to LAV. These results will be compared to 50 age-, gender-, and cardiovascular disease-risk matched controls with early CLL where standard of care is observation only. In Aim 2, we will compare the effects of the effects of ibrutinib, a first generation BTKi, with acalabrutinib, a second generation BTKi. In animal work, acalabrutinib was associated with a lower LAV and decreased LA fibrosis as compared to ibrutinib. We will do this by comparing the change in LAV and fibrosis among patients those on ibrutinib from Aim 1 and an additional matched-cohort (n=50) treated with acalabrutinib. Also, in Aim 2, we will compare the increase in blood pressure between these two therapies as conversely, based on our retrospective data, there were higher rates of hypertension with acalabrutinib than reported in cancer trials. Finally, in a 3rd exploratory aim, we will measure and compare AF incidence in our two cohorts (ibrutinib and acalabrutinib). The data in Aim 3 will provide preliminary data for subsequent studies com- paring AF development as a primary outcome between ibrutinib-treated patients and those treated with second generation BTKi’s. The current proposal brings together a multidisciplinary team to expand upon our preliminary data to test the link between ibrutinib and LA remodeling (volume, fibrosis), via CMR imaging techniques, while assessing the relationship between LA remodeling and the systolic blood pressure increase (via ABPM), and AF events. Upon completion, we expect to gain important insights into the association between BTKi use and the mechanism involved in the development of AF in CLL patients. These results will also ultimately inform subse- quent studies testing the most effective strategy for AF control in CLL patients receiving long-term BTKi therapy.

摘要 第一代非选择性布鲁顿酪氨酸激酶抑制剂（BTKi）伊替尼显著改善了肿瘤细胞的表面活性， 慢性淋巴细胞白血病（CLL）患者，一种影响近25万美国成年人的疾病。然而，在这方面， 高达38%的用伊鲁替尼治疗的CLL患者发展为心房纤颤（AF）。伊鲁替尼治疗房颤的进展 是具有挑战性的，因为药物相互作用排除了许多标准的治疗方法，以及出血的风险- 当伊鲁替尼和抗凝剂联合使用时，因此，有必要更好地根据- 站在发展中涉及的机制伊匹替尼相关的AF，并最终确定预防 战略布局最近的动物研究表明，伊替尼相关的AF涉及通过增加 左心房容积（LAV）和左心房（LA）纤维化增加。没有临床数据表征 因此，在目标1中，我们测试了伊鲁替尼对LAV的影响（主要结局）， 通过在50例患者术前和6个月时进行连续心脏磁共振成像（CMR）检查LA纤维化 伊鲁替尼之后。此外，在目标1中，我们将使用动态血压测量血压 监测（ABPM）。作为背景，>70%的伊替尼治疗患者发生高血压，我们假设 估计伊匹替尼相关高血压可能是LAV和纤维化增加的关键因素。最后在 目的1，我们将测量与LAV相关的炎症、纤维化和心肌损伤的生物标志物。这些 结果将与50名年龄、性别和心血管疾病风险匹配的早期CLL对照组进行比较 标准治疗是观察在目标2中，我们将比较伊鲁替尼的效果， 第二代BTKi与第二代BTKi的acalabrutinib。在动物实验中， 具有较低的LAV和减少的LA纤维化。我们将通过比较 目标1中接受伊鲁替尼治疗的患者和另一个匹配队列（n=50）治疗的患者的LAV和纤维化 与acalabrutinib。此外，在目标2中，我们将比较这两种疗法之间的血压升高 相反，根据我们的回顾性数据，使用acalabrutinib的高血压发生率高于 在癌症试验中报告。最后，在第三个探索性目标中，我们将测量并比较两组患者的房颤发生率。 队列（伊布替尼和阿克拉布替尼）。目标3中的数据将为后续研究提供初步数据， 将房颤发展作为伊匹替尼治疗患者和第二种治疗患者之间的主要结局 一代BTKi的。目前的建议汇集了一个多学科的团队，以扩大我们的初步 通过CMR成像技术测试伊曲替尼与LA重塑（体积、纤维化）之间联系的数据， 评估左心房重构与收缩压升高（通过ABPM）和房颤之间的关系 事件完成后，我们希望获得重要的见解BTKi的使用和之间的关联， CLL患者AF发生的机制。这些结果也将最终通知subse- 在接受长期BTKi治疗的CLL患者中测试AF控制的最有效策略的quent研究。