What is the recommended use and dosage of Zanubritinib (Bruton's tyrosine kinase inhibitor) for patients with B-cell malignancies?

Zanubrutinib for B-Cell Malignancies: Recommended Use and Dosage

Zanubrutinib is recommended at a dose of 160 mg twice daily for patients with B-cell malignancies, including Waldenström macroglobulinemia (WM), chronic lymphocytic leukemia (CLL), and mantle cell lymphoma (MCL), as a preferred category 1 treatment option due to its high efficacy and favorable safety profile compared to other BTK inhibitors. 1

Indications and Efficacy

Waldenström Macroglobulinemia (WM)

• Zanubrutinib is a preferred regimen for primary therapy (category 1) 2
• In the phase III ASPEN trial comparing zanubrutinib to ibrutinib:
  • 42-month PFS rate: 78% for zanubrutinib vs 70% for ibrutinib 2
  • Higher VGPR rates in patients with CXCR4 mutations: 21% vs 10% 2
  • No statistical difference in overall VGPR between groups (28% vs 19%; P=0.09) 2

Chronic Lymphocytic Leukemia (CLL)

• Zanubrutinib demonstrated superior efficacy compared to bendamustine-rituximab in the SEQUOIA trial with a PFS hazard ratio of 0.42 (95% CI 0.28-0.63, p<0.0001) 1
• In phase 1 studies, zanubrutinib showed an overall response rate of 96.2% in CLL/SLL patients with estimated 12-month PFS of 100% 3

Mantle Cell Lymphoma (MCL)

• Approved for treating adults with MCL who have received at least one prior therapy 4
• In relapsed/refractory MCL patients, zanubrutinib demonstrated:
  • Overall response rate of 84% with 25% achieving complete response
  • Median duration of response of 18.5 months
  • Median PFS of 21.1 months 5

Dosing and Administration

• Standard dose: 160 mg twice daily orally 1
• Alternative dosing: 320 mg once daily has been studied but twice daily dosing achieves more sustained complete BTK occupancy in lymph nodes (89% vs 50%; P=0.0342) 3
• Continue treatment until disease progression or unacceptable toxicity 1

Safety Profile and Advantages Over Other BTK Inhibitors

Reduced Cardiac Toxicity

• Significantly lower incidence of atrial fibrillation compared to ibrutinib (4% vs 17%) 2, 1
• Lower incidence of most nonhematologic adverse events compared with ibrutinib 2

Common Adverse Events

• Hematologic: Neutropenia (higher incidence than ibrutinib - 29% vs 13% for any grade, 20% vs 8% for grade ≥3) 2
• Non-hematologic: Contusion (22%), headache (22%), diarrhea (18%), anemia (15%), cough (15%), pyrexia (12%), fatigue (10%) 2

Management of Adverse Events

• Grade 3-4 neutropenia: Consider G-CSF support (more patients received G-CSF with zanubrutinib compared to ibrutinib) 2, 1
• Bleeding events: Temporary interruption for procedures or active bleeding 1

Patient Selection Considerations

• Particularly beneficial for patients with:
  • Cardiac comorbidities (due to lower risk of atrial fibrillation) 1
  • CXCR4 mutations in WM (better outcomes than with ibrutinib) 2
  • Previous intolerance to other BTK inhibitors 6

BTK Inhibitor Switching

• For patients intolerant to ibrutinib or acalabrutinib, zanubrutinib is a viable option:
  • Most intolerance events (70-83%) do not recur with zanubrutinib
  • When events do recur, they typically present at lower severity 6
  • Disease control rate of 93.8% in patients switched to zanubrutinib due to intolerance 6

Zanubrutinib represents an important advancement in BTK inhibitor therapy for B-cell malignancies, offering improved selectivity, sustained target occupancy, and a more favorable toxicity profile compared to first-generation BTK inhibitors while maintaining high efficacy across multiple B-cell malignancies.