Early Detection and Mechanisms of Cancer Immunotherapy Associated Cardiotoxicity

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.