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 ...