Ibrutinib-Treated Patients Show Higher Risk of Developing Cardiotoxicity

Seema A. Bhat, MD

Treatment with ibrutinib (Imbruvica) correlates with high cardiotoxic risk in patients with cancer, according to results from a registry-based cohort study. The findings show that myocardial fibrosis is a common cardiotoxic event.¹

Ibrutinib is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that has been proven to improve outcomes in patients with B-cell malignancies. However, hematologists and oncologists commonly report atrial fibrillation, hypertension, and ventricular arrhythmias during treatment with BTK inhibitors. Data from multiple clinical trials show that atrial fibrillation occurs in 5% to 16% of patients treated with ibrutinib, and hypertension occurs in up to 30%.²

The study included patients who underwent cardiac magnetic resonance imaging (CMR) for suspected ibrutinib-related cardiotoxicity. Patients were treated between 2012 and 2019 and their medical records were stored in the US Comprehensive Cancer Center registry. The primary goal of the study was to measure the presence of late gadolinium enhancement (LGE) fibrosis. The secondary end point was the occurrence of major adverse cardiac events (MACE) such as atrial fibrillation, heart failure, symptomatic ventricular arrhythmias, and sudden death of probable or definite ibrutinib association after CMR.¹

“The development of cardiac fibrosis has been documented with cancer treatment including anthracyclines and is a dreaded complication that leads to cardiac mechanical dysfunction, arrhythmias, and an increase in cardiovascular mortality. BTK inhibitors, especially ibrutinib, are associated with serious cardiac arrhythmias. Preclinical models have shown evidence of BTK inhibitor-induced myocardial injury in the form of inflammation and fibrosis,” Seema A. Bhat, MD, associate professor of Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, told Targeted Oncology™.

A total of 49 patients treated with ibrutinib were identified through the registry and of those, 22 were imaged after the start of treatment. The patient population had a mean age of 65 years, and 30% were women. The mean body mass index was 29 kilograms. The majority of the patient population (81.9%) had chronic lymphocytic leukemia (CLL). Most patients had a ECOG performance status of 0 to 2, and 1 patient with previously treated with an anthracycline.

Twenty-seven percent of patients included were hypertensive, 58% were treated with a beta blocker, and 70% had ibrutinib-related arrhythmias.

The median duration of treatment with ibrutinib was 14 months. LGE was found in 54.8% of patients, and it was determined to be associated with cumulative ibrutinib-dose and duration exposure (R2 = 0.57). Higher percentages of abnormal CMR measures were shown in patients who experienced elevated native T1 and elevated max T2 toxicities, compared with other toxicities (P = .01 and P = .01), respectively).

Of the patients with baseline coronary artery disease or heart failure with reduced ejection fraction, 58.6% had LGE compared with 13.3% in match controls (relative risk, 4.4; P = .002). Moreover, the mean native T1, max T2, and LGE positivity rates were increased compared with patients with similar demographics who were not treated with ibrutinib.

Results for the secondary end point showed a 39.4% rate of MACE at a median follow-up of 19 months. The toxicities found be MACE were native T1, LGE, and QTc interval prolongation.

“This is the first study showing such evidence in patients treated with ibrutinib and it correlated with higher cardiotoxicity risk. CMR may serve as an essential tool to assess patients, especially to estimate the risk of continuation of therapy in patients showing evidence of myocardial fibrosis on CMR. However, additional studies are needed to evaluate the role of CMR as a potential biomarker for BTK inhibitor associated cardiotoxicity,” said Bhat.

According to Bhat et al, choosing which anti-cancer therapies to use on a patient is a challenging decision for hematologists/oncologists. In some cases, alternative treatment can be used to limited cardiotoxicity.

“The risk of cardiotoxicity varies between different BTK inhibitors. For example, atrial fibrillation risk with acalabrutinib [Calquence] and zanubrutinib [Brukinsa], appears to be lesser compared to ibrutinib. In the ELEVATE-RR study [NCT02477696] the rate of all-grade atrial fibrillation/atrial flutter was significantly lower with acalabrutinib than with ibrutinib: 9.4% vs 16.0%, respectively. The difference was even more striking among patients without prior history of atrial fibrillation: 6.2% vs 14.9%, respectively. The ALPINE trial [NCT03734016] also showed a lower incidence of atrial fibrillation with zanubrutinib [5.2%] than with ibrutinib [13.3%],” Bhat explained. “These next generation BTK inhibitors are definitely an option for our patients. Then we have venetoclax, a BCL2 inhibitor, which is approved for treatment of CLL and does not have any known cardiotoxicity. The newer noncovalent BTK inhibitors like pirtobrutinib, which are still in clinical development, have been shown to have a very low incidence of arrhythmias and, when approved, will be another excellent option for our patients.”

In other cases, physicians should use predictive tools to weigh a patient’s risk for cardiotoxicity and remain active in the management adverse events when they develop.

“Cardiotoxicity is not a new concept in oncology. Anthracycline-induced cardiotoxicity was first reported in 1970s. We have known about the effects of trastuzumab [Herceptin] or radiation on the heart. However, with the more widespread use of newer targeted agents and immunotherapy cardiotoxicity has become a relatively frequent and potentially serious [adverse event] of cancer treatment. It is important for oncologists to identify patients at higher risk for treatment-related cardiotoxicity, consider a multidisciplinary approach in managing these patients in collaboration with cardio-oncologists and focus on research to find ways by which these adverse effects can be avoided or mitigated, especially focusing on cardioprotective strategies,” Bhat stated.

_REFERENCES:

_{1. Buck B, Chum AP, Patel M, et al. Cardiovascular magnetic resonance imaging in patients with ibrutinib-associated cardiotoxicity. JAMA Oncol. Published online February 2, 2023. doi:10.1001/jamaoncol.2022.6869}

_{2. Dong R, Yan Y, Zeng X, et al. Ibrutinib-associated cardiotoxicity: from the pharmaceutical to the clinical. Drug Des Devel Ther. 2022;20;16:3225-3239. doi:10.2147/DDDT.S377697.}