How to Manage the Adverse Events Associated with Zanubrutinib Therapy

Zanubrutinib is a covalent and highly selective BTK inhibitor. BTK inhibitors can be administered for extended periods of time to sustain a durable inhibition of the B-cell receptor signaling pathway. Thus, knowledge of the adverse events, their management, and monitoring is crucial for the treatment of patients with B-cell malignancies. For healthcare professionals, it is important to consider the specific type of malignancy for which a patient is treated, the patient’s pre-treatment clinical status, prior treatments, concomitant medications and the duration of treatment with Zanubrutinib.

For healthcare professionals managing the adverse events occurring in patients receiving Zanubrutinib, it is essential to consider the primary and/or secondary malignancies being treated, as well as the patients’ pre-existing medical conditions and other co-medications (including anticancer therapies) that can impact their safety profiles while on therapy for extended periods of time. Reference to the current US Prescribing Information for this medication is the best place to begin with information regarding adverse reactions, including approved indications, cautions, and contraindications as well as dosage modification for various clinical presentations.

Understanding Safety Profile

The B-cell receptor signaling pathway involves BTK and several other kinases within the downstream pathway. By forming a covalent, irreversible bond with the Cys481 of BTK, Zanubrutinib maintains greater than 95% BTK occupancy at trough levels, with sustained BTK inhibition throughout the dosing interval. Zanubrutinib has demonstrated high BTK selectivity in clinical studies.

As is the case with any drug, the safety of patients treated with Zanubrutinib should be monitored for a host of adverse events including cardiovascular events, bleeding events, serious infections and other toxicities.

Cardiovascular Adverse Events

BTK inhibitors, like all drugs, have the potential for a variety of adverse reactions. For Zanubrutinib, the cardiovascular adverse reactions have been of particular interest. Many patients with B-cell Malignancies also have risk factors for cardiovascular disease (e.g. hypertension).

The ALPINE study was a Phase 3 clinical trial comparing Zanubrutinib to ibrutinib for the treatment of patients with CLL/SLL that were previously treated. This trial compared the progression free survival outcomes in patients treated with Zanubrutinib and ibrutinib. Additionally, difference in rates of atrial fibrillation were seen with Zanubrutinib treated patients compared to patients treated with ibrutinib.

Assessment of cardiovascular history may be considered prior to the initiation of treatment, as well as assessment for symptoms or clinical findings that suggest arrhythmia in patients with existing cardiovascular comorbidities.

Monitoring for Bleeding

Bleeding events can occur during treatment with a BTK inhibitor and must be assessed in terms of their potential impact. Patients can be at increased risk of bleeding due to a variety of reasons including prior cancer therapy and their current cancer treatment.

It is also important to assess other medications that a patient is on before and during treatment with Zanubrutinib and determine how they may affect the risk of bleeding. Monitor for bleeding and determine the appropriate course of action for clinically significant bleeding events.

An individualized risk vs. benefit assessment must be made for all events, whether minor or serious. The fact that a patient has experienced a minor bleeding event does not necessarily mean that the therapy needs to be discontinued. Due consideration must also be given to the severity of the event(s) and to the underlying malignancy and its potentially fatal course.

Managing Infection Risk

Patients with B-cell malignancies generally have compromised immune systems due to their cancer or previous treatment. Moreover, some treatments can have additional, even unpredictable, immunologic effects and increase the risk for infections.

Consideration must also be given to the potential for Zanubrutinib to cause treatment-related infections (e.g. by opportunistic pathogens), and for the duration of time that any patient with a B-cell malignancy is immunocompromised following any anticancer therapy.

Patients should have their suspected infections evaluated as quickly as possible. Management of the infection should consider the type and severity of the infection as well as the patient’s clinical situation. The healthcare provider can use preventive and supportive care measures as needed in the management of cancer as well as its treatment.

Considering Other Adverse Events

Monitoring for all possible adverse events occurs on an ongoing basis. The clinician must consider the laboratory values obtained on the patient as well as symptoms which the patient is experiencing and consider all the patient’s current medications which could affect the patient negatively while on BTK inhibitor therapy.

A single approach does not exist to handle adverse events occurring during Zanubrutinib treatment. Each event must be evaluated on a case-by-case basis in consideration of the patient’s clinical situation and approved indication. Therefore, healthcare professionals must assess each individual case in detail.

Zanubrutinib is approved by FDA for the treatment of adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and for adults with Waldenström’s macroglobulinemia. It is also approved for adults with mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and follicular lymphoma (FL) under certain circumstances and for the treatment of patients with MCL who have received at least one prior therapy and have received at least two prior therapies in patients with FL who have received two or more prior therapies.

Individualizing Adverse-Event Management

In managing patients on Zanubrutinib, it is also important to weigh the benefits of treatment against potential adverse effects, to achieve optimal disease control with tolerable therapy. This can include a thorough review of cardiovascular history, potential for bleeding, potential for infections, key lab values, other medicines a patient is taking, and a history of previous cancer therapy.

Monitoring adverse events and their management is an ongoing process during the treatment with Zanubrutinib, as the clinical condition of a patient and even co-morbidities, as well as other treatments with co-medications can change during a prolonged period of treatment.

Clinical trial evidence which compares drugs including efficacy and adverse events is very useful; however, participants of clinical trials are limited to a certain number of patients, and thus, do not reflect all types of patients who are treated with the drugs in real clinical settings. Hence, it is necessary to interpret data from clinical trials and compare with data from other sources in reference to individual patients and the current US Prescribing Information.

Translating Safety Evidence into Practice

The safety of Zanubrutinib, the pharmacologic actions of the drug, data from clinical trials comparing the drug to other treatments, and the treatment experience gained over long periods of time by patients taking the drug all must be taken into account in the ongoing assessment and management of patients taking Zanubrutinib for adverse events.

When treating a patient with Zanubrutinib, healthcare professionals should consider a patient-specific approach to managing adverse reactions during treatment. Monitoring for adverse reactions that are clinically significant, knowing how concomitant medications can increase the potential for adverse reactions, and treating for adverse reactions are relevant to the use of Zanubrutinib.The decision to continue, modify, or discontinue Zanubrutinib in patients with hematologic malignancies should be individualized to each patient’s specific condition and disease, and based on the most current approved product information.

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.