# Early Detection and Mechanisms of Cancer Immunotherapy Associated Cardiotoxicity

> **NIH NIH K23** · OHIO STATE UNIVERSITY · 2024 · $165,672

## Abstract

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 pr...

## Key facts

- **NIH application ID:** 10897227
- **Project number:** 5K23HL155890-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Daniel Addison
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $165,672
- **Award type:** 5
- **Project period:** 2021-08-15 → 2025-03-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897227

## Citation

> US National Institutes of Health, RePORTER application 10897227, Early Detection and Mechanisms of Cancer Immunotherapy Associated Cardiotoxicity (5K23HL155890-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10897227. Licensed CC0.

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