Targeted therapies, which have become mainstay of the treatment of B-cell malignancies, can have significant safety concerns especially when given for prolonged periods. Adverse events associated with BTK inhibitors, which are becoming increasingly used to treat various B-cell malignancies, need to be characterized for clinicians to make informed treatment decisions. Here we characterize the safety profile of Zanubrutinib, a covalent BTK inhibitor with high selectivity for BTK over other kinases.

Data from clinical studies are important to understand treatment-related adverse events and to compare safety of different BTK inhibitors. Moreover, it is necessary to take account of individual patients’ factors such as prior treatments, and comorbidities in the process of selecting and managing appropriate BTK inhibitors for each individual.

Pharmacologic Basis for the Safety Profile

Zanubrutinib use is supported by its highly selective BTK inhibition, which is intended to provide similar or greater BTK inhibition with less inhibition of other pivotal kinases, enabling sustained B-cell receptor signaling inhibition with fewer off-target effects.

The difference in the cardiovascular safety profile of zanubrutinib versus ibrutinib was demonstrated in head-to-head studies. Zanubrutinib exhibited less atrial fibrillation (AF) in the ALPINE study of relapsed/refractory CLL/SLL patients (22% AF ibrutinib-treated patients vs 6% Zanubrutinib-treated patients), and extended follow-up continued to show lower rates of AF in Zanubrutinib-treated patients with CLL/SLL.

Cardiovascular Safety in Clinical Trials

Given the aging and comorbidities of patients with B-cell malignancies, cardiovascular (CV) events are of special concern when considering the use of BTK inhibitors. In the ALPINE study, Zanubrutinib demonstrated clinical activity in patients with relapsed/refractory CLL/SLL, and reported PFS and atrial fibrillation outcomes comparing Zanubrutinib with Ibrutinib.

In the long-term ALPINE analysis, the prevalence of atrial fibrillation/flutter and hypertension were stable or decreased over time. These findings contribute to the understanding of the cardiovascular safety of zanubrutinib and its use for extended periods in patients with relapsed or refractory CLL/SLL.

Hemorrhage and Other Adverse Events

Bleeding and hemorrhage are important adverse events for the class of BTK inhibitors. The prevalence of hemorrhage has declined over time and is listed in the long-term follow-up of the ALPINE study. As with any treatment, the risk of bleeding can be increased by concomitant medications that affect hemostasis. All factors that can affect hemostasis in a patient should be considered when evaluating the safety and tolerability of a patient on BTK inhibitor therapy.

Monitor patients for bleeding events of any severity particularly when on concomitant treatments that affect hemostasis. Considering the patient’s previous treatments, co-morbidities, lab values, and all concomitant treatments, assess the risk versus benefit of continuing a BTK inhibitor. The frequency and character of infections other than hemorrhage and major hemorrhage showed a decline in their frequency over time as well and were listed as grade ≥3 or serious in nature.

Evidence Across B-Cell Malignancies

The safety of zanubrutinib has also been evaluated in a variety of clinical trials in other B-cell malignancies including mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), and Waldenstrom’s macroglobulinemia (WM). Zanubrutinib is currently approved by the US FDA for the treatment of various malignancies including various forms and stages of CLL/SLL as well as WM.

Additional comparison data for cardiovascular and bleeding related adverse events were reported from analyses of long-term follow-up data in patients with WM from the ASPEN study. Rates of atrial fibrillation, hypertension, and bleeding events, including overall and any-grade events, were reported for each treatment arm across multiple follow-up periods.

Individualizing Safety Assessment

Clinical trial safety information should be reviewed in conjunction with a patient’s individual characteristics such as cardiovascular history, hypertension, bleeding risk, infection risk, concomitant medications, patient laboratory abnormalities and treatment duration.

There are several specific cautions and adverse reactions listed in the Prescribing Information for Zanubrutinib including tachyarrhythmias and hypothyroidism. The management of adverse reactions and monitoring of patients on Zanubrutinib should be approached with the same diligence as managing other adverse reactions in patients with B-cell malignancies.

Translating Clinical Trial Findings Into Practice

Whether evaluating a treatment’s efficacy or safety, clinical trials can provide an accumulation of crucial information to further understand a treatment’s full scope of use. For zanubrutinib, such information for efficacy and safety has been collected in head-to-head clinical studies to assess its tolerability compared to ibrutinib, as well as in long-term studies to establish the frequency and changes in safety events found during treatment.

Key information to consider when monitoring patients on Zanubrutinib for healthcare professionals includes information from clinical trials. However, it is essential to remember that the patients in the clinical trials may not be representative of all patients with B-cell malignancies and their associated medical history, co-morbidities, previous treatment(s), lab values, and medications that a healthcare provider can prescribe for a patient. All this information and the current FDA approval and prescribing information for Zanubrutinib must be considered when making treatment decisions for patients with B-cell malignancies.

Medical Disclaimer: The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice, clinical guidelines, or a recommendation for any specific treatment.

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