Novel patient biomarkers and mechanisms of TKI associated Cardiotoxicity

摘要： 近25万成年人患有慢性淋巴细胞白血病(CLL)。布鲁顿(氏)酪氨酸激酶抑制剂 (BTKI)显著提高CLL的存活率。然而，高达38%的患者发生了心房颤动(AF)和 其他心血管毒性。伊布鲁替尼是第一个被批准的具有这些毒性的BTKI，但我们的数据表明 新的BTKI(如阿卡拉布替尼、扎努布替尼)仍与心脏毒性有关。带BTKI的房颤研究进展 是具有挑战性的，并且是在患者中使用有效治疗的主要障碍。因此，有一个紧急的 需要确定房颤的风险患者，并更好地了解诱发BTKI相关的靶向通路 自动对焦。我们小组已经定义了BTKI的大多数早期心脏肿瘤学问题。我们还培育了动物 认为BTKI导致直接心脏毒性以及激活先天免疫的模型 可能导致心脏毒性和心律失常，并导致左房早期增加的反应 (LA)BTKI相关性房颤前的纤维化和容量(LA重塑)。我们将利用活跃的有氧运动- 俄亥俄州立大学和加州大学旧金山分校的肿瘤学项目和资源，以前瞻性地研究这些心血管效应 人类的BTKI。我们的临床前研究特别涉及到先天免疫反应的激活， 以循环中IL-6(和IL-17)作为BTKI相关房颤发生的关键介质的升高为标志，以及 这会导致左房重构和心脏毒性房颤。然而，目前还没有前瞻性的研究来测试 免疫激活在调解或预测心脏毒性事件中的作用。为了解决这些翻译和临床上的差距， 我们将招募120名慢性淋巴细胞性白血病患者启动BTKI，我们将前瞻性地使用连续心脏磁力 磁共振成像(CMR)和前沿免疫学技术来测试我们的假设，BTKI- 相关的房颤是由诱导心脏重构和心律失常的免疫激活增加所驱动的。在AIM 1、观察BTKI治疗前、治疗后2个月和治疗6个月后BTKI对LA纤维化和容量的影响。我们 将通过在1年后应用连续移动心电监测来确定BTKI相关房颤的负荷 BTKI入会。这些结果将与60名年龄、性别和心脏病风险相匹配的对照组和早期 CLL期，单独进行标准观察。正如我们观察到的那样，50%的BTKI治疗患者 随着高血压的发展，我们还将测量动态血压，并将其与CMR测量相关联。在目标2中， 我们将研究BTKI对先天免疫反应的影响，先天免疫反应定义了易受重塑和 通过研究循环中IL-6、IL-17的水平，并使用无偏倚的单细胞基因组学，系统地研究临床房颤 破译有助于重塑的免疫细胞及其关键的促炎途径。我们还将 定义这些参数与其他CMR度量的关系。最后，使用我们的BTKI动物模型，我们将 测试靶向抑制促炎通路对心脏毒性重构和房颤风险的影响。vt.在.的基础上 完成后，我们将获得对激酶抑制剂在心脏毒性中的机制作用的重要见解，因为 以及免疫失调如何导致血液系统恶性肿瘤患者的心律失常。

ABSTRACT: Nearly 250,000 adults are affected by chronic lymphocytic leukemia (CLL). Bruton’s Tyrosine kinase inhibitors (BTKIs) dramatically improve survival in CLL. However, up to 38% of patients develop atrial fibrillation (AF) and other cardiovascular toxicities. Ibrutinib is the first BTKI approved which has these toxicities but our data suggest new BTKIs (e.g., acalabrutinib, zanubrutinib) still associate with cardiotoxicity. The development of AF with BTKIs is challenging and is a major impediment in use of the effective therapies in patients. Thus, there is an urgent need to identify patients at risk for AF, and better understand targetable pathways that induce BTKI-associated AF. Our group has defined most of the early cardio-oncology issues with BTKIs. We have also developed animal models which suggest that BTKIs cause direct cardiotoxicity as well as an activation of the innate immune response that potentially contributes to cardiotoxicity and arrhythmia, and result in an early increase in left atrial (LA) fibrosis and volume (LA remodeling) preceding BTKI-associated AF. We will leverage the active cardio- oncology programs and resources here at OSU and at UCSF, to prospectively study these cardiovascular effects of BTKIs in humans. Our pre-clinical studies specifically implicate activation of the innate immune response, marked by elevation in circulating IL-6 (and IL-17) as key mediators of BTKI-associated AF development, and that this leads to LA remodeling and cardiotoxic AF. Yet, there are no prospective studies testing the effects of immune activation in mediating or predicting cardiotoxic events. To address these translational and clinical gaps, we will recruit 120 CLL patients initiating BTKIs and we will prospectively utilize serial cardiac magnetic resonance imaging (CMR) and leading-edge immunologic techniques to test our hypothesis, that BTKI- associated AF is driven by increased immune activation that induces cardiac remodeling and arrythmia. In Aim 1, we test the effect of BTKIs on LA fibrosis and volume pre-, 2, and 6 months after starting BTKI-therapy. We will determine the burden of BTKI-associated AF by applying serial mobile ECG monitoring over 1-year post- BTKI initiation. These results will be compared to 60 age-, gender-, and cardiac risk matched controls with early stage CLL, treated with standard observation alone. As we have observed that >50% of BTKI treated patients develop hypertension, we will also measure and relate ambulatory blood pressure to CMR measures. In Aim 2, we will examine the effects of BTKIs on innate immune response that define vulnerability to remodeling and clinical AF by studying circulating levels of IL-6, IL-17, and using unbiased single-cell genomics, systematically decipher the immune cells that contribute to remodeling and their key pro-inflammatory pathways. We will also define the relation of these parameters with other CMR measures. Finally, using our BTKI animal model, we will test the effect of targeted inhibition of pro-inflammatory pathways on cardiotoxic remodeling and AF risk. Upon completion, we will gain important insights into the mechanistic role of the kinase inhibitors in cardiotoxicity as well as how immune dysregulation contributes to arrhythmia in hematological malignancies.