What are the side effects of zanabrutinib (Bruton's tyrosine kinase inhibitor)?

Zanabrutinib Side Effects

Zanabrutinib demonstrates a significantly more favorable safety profile compared to ibrutinib, particularly with substantially lower rates of atrial fibrillation (4% vs 17%) and most nonhematologic adverse events, though it carries a 2-fold higher risk of neutropenia. 1

Hematologic Adverse Events

Neutropenia is the most significant hematologic concern with zanabrutinib:

• Any grade neutropenia occurs in 29% of patients (compared to 13% with ibrutinib) 1
• Grade ≥3 neutropenia occurs in 20-23% of patients (compared to 8% with ibrutinib) 1, 2, 3
• Grade 4 neutropenia occurs in 10% of patients 2
• A larger proportion of patients require granulocyte colony-stimulating factor support compared to ibrutinib 1

Other hematologic toxicities include:

• Thrombocytopenia: 8% grade ≥3 (2.5% grade 4) 2, 3
• Anemia: 8% grade ≥3 2, 3
• Monitor complete blood counts regularly and adjust dosing as needed 2

Cardiovascular Adverse Events

Zanabrutinib has markedly reduced cardiovascular toxicity compared to ibrutinib:

• Atrial fibrillation occurs in only 4% of patients (versus 17% with ibrutinib), with grade ≥3 cases in 1.9% 1, 2
• Hypertension occurs in 3-5% of patients (grade ≥3 in 2-3%) 4, 3
• Ventricular arrhythmias are rare (0.3% grade ≥3) 2
• Patients with cardiac risk factors, hypertension, and acute infections are at increased risk 2
• Monitor for palpitations, dizziness, syncope, dyspnea, and chest discomfort 2

Bleeding Events

Hemorrhagic complications occur but are generally manageable:

• Overall bleeding risk: 26-39% for any grade, 2% for grade ≥3 4, 3
• Bruising/contusion occurs in 25-37% of patients 5, 3
• Major hemorrhage occurs in 4% of patients 3
• Avoid concomitant warfarin use; carefully evaluate benefit-risk in patients requiring anticoagulation 4, 2
• Hold zanubrutinib 3-7 days before and after surgical procedures (similar to ibrutinib) 1

Infectious Complications

Infections are common and represent a significant cause of morbidity:

• Upper respiratory tract infections occur in 38-39% of patients 2, 3
• Pneumonia occurs in 21% of patients (11% grade ≥3) 2, 3
• Urinary tract infections occur in 15% of patients 2, 3
• Overall infection rate is 65%, with grade ≥3 infections in 14-26% 4, 2
• Fatal infections occurred in 3.2% of patients in pooled analyses 2
• Hepatitis B reactivation has been reported 2
• Consider prophylaxis for herpes simplex virus, pneumocystis jirovecii pneumonia, and other infections in high-risk patients 2

Gastrointestinal Adverse Events

• Diarrhea occurs in 13-23% of patients (grade ≥3 in 2%) 5, 3
• Nausea occurs in variable frequencies 1
• Constipation occurs in 31% of patients 6
• These occur at lower rates than with ibrutinib 1

Musculoskeletal Symptoms

• Musculoskeletal pain occurs in 24-31% of patients (grade ≥3 in 2%) 2, 3
• Myalgia occurs in 15% of patients (grade ≥3 in 9.4%) 5, 6
• Arthralgia occurs in 13% of patients 5

Dermatologic Adverse Events

• Rash occurs in 25-27% of patients 2, 3
• Most rashes are mild (grade 1-2) 3

Other Common Adverse Events

• Fatigue occurs in 10-21% of patients 1, 4, 5
• Cough occurs in 21% of patients 3
• Pyrexia occurs in 12-21% of patients 4, 3

Hepatotoxicity

Drug-induced liver injury (DILI) is a serious but rare complication:

• Severe, life-threatening, and potentially fatal cases of DILI have occurred with BTK inhibitors including zanubrutinib 2
• Evaluate bilirubin and transaminases at baseline and throughout treatment 2
• If DILI is suspected, withhold zanubrutinib; upon confirmation, discontinue permanently 2

Second Primary Malignancies

• Second primary malignancies occur in 14% of patients 2
• Non-melanoma skin cancers occur in 8% of patients 2
• Other solid tumors occur in 7% (including melanoma in 1%) 2
• Hematologic malignancies occur in 0.7% 2
• Advise sun protection and monitor for development of second malignancies 2

Treatment Discontinuation and Dose Modifications

Zanabrutinib demonstrates excellent tolerability:

• Treatment discontinuation due to adverse events occurs in only 10% of patients 3
• Dose reductions for adverse events occur in 8% of patients 3
• This compares favorably to ibrutinib, where approximately 20% discontinue due to toxicity 7

Key Clinical Pitfalls to Avoid

• Do not overlook neutropenia monitoring: Unlike ibrutinib, zanubrutinib has higher neutropenia rates requiring more vigilant CBC monitoring and potential G-CSF support 1
• Do not assume all BTK inhibitors have equivalent cardiac toxicity: Zanabrutinib's 4-fold lower atrial fibrillation rate makes it preferable in patients with cardiac risk factors 1
• Do not combine with warfarin: Use alternative anticoagulation strategies if needed 4, 2
• Do not continue therapy if DILI develops: Permanent discontinuation is required upon confirmation 2