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: 10674527
• 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/10674527
• 关键词: Adult; Affect; Agammaglobulinaemia tyrosine kinase; Age; Ambulatory Blood Pressure Monitoring; Animal Model; Animals; Anticoagulants; Aorta; Arrhythmia; Atrial Fibrillation; Biological Markers; Blood Pressure; Blood Vessels; Breast; Cancer Patient; Cardiac; Cardiotoxicity; Cardiovascular Diseases; Chronic Lymphocytic Leukemia; Clinical; Clinical Data; Data; Development; Disease; Drug Interactions; Early Diagnosis; Event; Expectancy; Fibrosis; Gender; Generations; 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; 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; blood pressure elevation; cancer immunotherapy; cardiac magnetic resonance imaging; cardiovascular disorder risk; cardiovascular health; career; cohort; cytokine; follow-up; imaging study; improved; inhibitor therapy; 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 伊布鲁替尼是第一代非选择性Bruton‘s酪氨酸激酶抑制剂(BTKi)，它显著改善了患者的临床症状。 慢性淋巴细胞白血病(CLL)患者的存活时间，这是一种影响近25万美国成年人的疾病。然而， 在接受伊布鲁替尼治疗的慢性淋巴细胞性白血病患者中，多达38%的患者发生了心房颤动(AF)。伊布鲁替尼治疗房颤的研究进展 是具有挑战性的，因为药物-药物的相互作用排除了许多标准的治疗方法，以及出血的风险- 联合应用伊布鲁替尼和抗凝剂时，ING明显增加。因此，有必要更好地- 了解与伊布鲁替尼相关的房颤发生的机制，并最终确定预防 战略。最近的动物研究表明，伊布鲁替尼相关的房颤涉及通过增加 左房容量(LAV)和左房(LA)纤维化增加。目前还没有临床数据表明 Ibrutinib对LAV或纤维化的影响；因此，在目标1中，我们测试了ibrutinib对LAV(主要结局)和 50例患者在治疗前和治疗6个月后进行连续心脏磁共振成像(CMR)检测左房纤维化 在陈述了伊布鲁替尼之后。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%接受伊布鲁替尼治疗的患者出现高血压，我们假设- 推测伊布鲁替尼相关性高血压可能是左房静脉血容量增加和纤维化的关键因素。最后，在 目的1，我们将测量炎症、纤维化和心肌损伤的生物标记物与左心静脉的关系。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 在那里，护理的标准只是观察。在目标2中，我们将比较伊布鲁替尼的效果，第一次 一代BTKi，与阿卡拉布替尼，第二代BTKi。在动物实验中，阿卡拉布替尼与 与伊布鲁替尼相比，左房血流速度更低，左房纤维化程度更轻。我们将通过比较变化来实现这一点 在服用AIM 1的伊布鲁替尼和另一组配对队列(n=50)治疗的患者中，左肺静脉和肝纤维化的发生率 使用阿卡拉布替尼。此外，在目标2中，我们将比较这两种疗法的血压升高。 相反，根据我们的回顾数据，服用阿卡拉布替尼的高血压患病率高于服用阿卡拉布替尼的患者。 在癌症试验中被报道。最后，在第三个探索性目标中，我们将测量和比较两个国家的房颤发生率。 队列(伊布鲁替尼和阿卡拉布替尼)。AIM 3中的数据将为后续的研究提供初步数据。 伊布鲁替尼治疗的患者和再次治疗的患者之间的主要结局是房颤的发生 目前的提案汇集了一个多学科团队，以扩展我们的初步 通过CMR成像技术测试ibrutinib和LA重构(容量、纤维化)之间的联系的数据，同时 评估左房重构与收缩压升高(通过ABPM)和房颤的关系 事件。完成后，我们希望对BTKi的使用和 CLL患者发生房颤的机制。这些结果最终也将为Subse- QUENT研究测试接受长期BTKi治疗的CLL患者最有效的房颤控制策略。

项目成果

2022 AHA/ACC Key Data Elements and Definitions for Cardiovascular and Noncardiovascular Complications of COVID-19: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards.

• DOI: 10.1016/j.jacc.2022.03.355
• 发表时间: 2022-07-26
• 期刊: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
• 影响因子: 24
• 作者: Bozkurt, Biykem;Das, Sandeep R.;Addison, Daniel;Gupta, Aakriti;Jneid, Hani;Khan, Sadiya S.;Koromia, George Augustine;Kulkarni, Prathit A.;LaPoint, Kathleen;Lewis, Eldrin F.;Michos, Erin D.;Peterson, Pamela N.;Turagam, Mohit K.;Wang, Tracy Y.;Yancy, Clyde W.
• 通讯作者: Yancy, Clyde W.

Lack of Cardiotoxicity Endpoints in Prospective Trials Involving Chest Radiation Therapy: A Review of Registered, Latter-Phase Studies.

• DOI: 10.3389/fonc.2022.808531
• 发表时间: 2022
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Prasad RN;Miller ED;Addison D;Bazan JG
• 通讯作者: Bazan JG

The underutilization of preventive cardiovascular measures in patients with cancer: an analysis of the Behavioural Risk Factor Surveillance System, 2011-22.

癌症患者预防性心血管措施未充分利用：行为危险因素监测系统分析，2011-22。

• DOI: 10.1093/eurjpc/zwad146
• 发表时间: 2023
• 期刊: European journal of preventive cardiology
• 影响因子: 8.3
• 作者: Sayed,Ahmed;Munir,Malak;Addison,Daniel;Abushouk,AbdelrahmanI;Dent,SusanF;Neilan,TomasG;Blaes,Anne;Fradley,MichaelG;Nohria,Anju;Moustafa,Khaled;Virani,SalimS
• 通讯作者: Virani,SalimS

Long-term effectiveness of empiric cardio-protection in patients receiving cardiotoxic chemotherapies: A systematic review & bayesian network meta-analysis.

接受心脏毒性化疗的患者经验性心脏保护的长期有效性：系统评价

• DOI: 10.1016/j.ejca.2022.03.024
• 发表时间: 2022
• 期刊: European journal of cancer (Oxford, England : 1990)
• 作者: Sayed,Ahmed;Abdelfattah,OmarM;Munir,Malak;Shazly,Omar;Awad,AhmedK;Ghaith,HazemS;Moustafa,Khaled;Gerew,Maria;Guha,Avirup;Barac,Ana;Fradley,MichaelG;Abela,GeorgeS;Addison,Daniel
• 通讯作者: Addison,Daniel

Cardiovascular toxicities associated with bispecific T-cell engager therapy.

与双特异性 T 细胞接合疗法相关的心血管毒性。

• DOI: 10.1136/jitc-2023-008518
• 发表时间: 2024
• 期刊: Journal for immunotherapy of cancer
• 影响因子: 10.9
• 作者: Sayed,Ahmed;Munir,Malak;Ghazi,SanamM;Ferdousi,Mussammat;Krishan,Satyam;Shaaban,Adnan;Habib,Alma;Kola-Kehinde,Onaopepo;Ruz,Patrick;Khan,Sarah;Sharma,Sneha;Meara,Alexa;Mahmood,Syed;Feldman,Stephanie;Yang,EricH;Kim,Jiwon;Epp
• 通讯作者: Epp