Bruton’s tyrosine kinase inhibitors (BTKis) have transformed treatment and prognosis for patients with chronic lymphocytic leukemia, mantle cell lymphoma, and other lymphomas. This class of medications works by impairing cell proliferation, migration, and activation of NF-χB. 

The side effect profile of BTKi therapy is fairly extensive, especially with first-generation medications, and can include cardiac toxicity presenting as arrhythmias or heart failure, as well as bleeding, infection, diarrhea, arthralgias, and hypertension.

Lipsky A, Lamanna N. Managing toxicities of Bruton tyrosine kinase inhibitors. Hematology Am Soc Hematol Educ Program. 2020;2020(1):336–345.

 

 

As well, recent studies have shown that second-generation BTKis, such as zanubrutinib, have significantly lower incidence of cardiovascular adverse events than their first-generation counterparts.

 

AF and bleeding risk with BTKis

 

Cardiac toxicity appears to be related, at least in part, to an on-target inhibition of BTK and associated kinases, and therefore, using a second-generation BTKi does not completely mitigate this risk. An article discussing cardiotoxicity with acalabrutinib notes that, in clinical trials, cardiac arrhythmias developed in 20% of patients on a first-generation BTKi, ibrutinib, with the most common type of arrhythmia being atrial fibrillation (AF).

Langerbeins P. Cardiotoxicity in patients treated with acalabrutinib. Blood. 2022;140(20):2096–2097.

 

Direct comparison of acalabrutinib, a second-generation BTKi, with ibrutinib demonstrated fewer cardiovascular events and a non-inferior progression-free survival of CLL. BTKs also inhibit platelet signaling selectively, increasing bleeding risk. Therefore, there is an increased risk of serious hemorrhage when using anticoagulation therapy for AF concurrently with a BTKi.

 

“The incidence of atrial fibrillation or flutter (a key secondary outcome) of any grade was lower in the zanubrutinib group than in the ibrutinib group (in 17 of 324 patients [5.2%] and in 43 of 324 patients [13.3%]), and the incidence of atrial fibrillation or flutter of grade 3 or higher was also lower in the zanubrutinib group (in 8 of 324 [2.5%] and in 13 of 324 [4.0%]),” the study authors wrote.

 

Cardiovascular risk stratification 

 

The International Consensus Statement states that a structured, conscientious approach to care including premedication cardiac screening and close monitoring after initiation of the drug is of utmost importance when considering use of a BTKi. Prior to a patient’s starting on a BTKi, a thorough cardiac history must be completed along with a cardiovascular physical examination and EKG. An echocardiogram may be considered in high-risk individuals to screen for heart failure as well as assess for valvular heart disease, which would increase the risk of AF. 

BTKis should not be initiated in patients with a history of ventricular arrhythmia, a family history of sudden cardiac death, severe, uncontrolled hypertension, and severe or uncontrolled congestive heart failure (LVEF <30%). Low-risk individuals can be started on a first- or second-generation BTKi; however, second-generation agents such as acalabrutinib or zanubrutinib are preferred in patients with established cardiovascular disease, such as hypertension, well-controlled AF, heart failure, or valvular heart disease.

However, physicians are advised to consider other treatment options if cardiovascular risk is a concern.

 

Managing cardiac side effects

 

As of yet, there is no standardized approach to care when AF begins while the patient is on BTKi treatment, per the International Consensus Statement. However, an interdisciplinary approach is strongly recommended. Some physicians choose to discontinue the medication altogether. Others choose to temporarily hold the BTKi while controlling the AF, then reinitiating treatment once the AF is controlled, if the patient is receiving a second-generation BTKi. The CHA2DS2VASc Risk Score can be used to determine if anticoagulation is indicated. If this is the case, warfarin is less preferred to other anticoagulants. 

One school of thought, write the authors of the cardiotoxicity article,  is that as serious cardiac side effects seem to be time dependent, a time-limited treatment regimen with a BTKi may reduce the risk of serious cardiac toxicity.