What is the recommended use and dosage of Zanobrutinib (Bruton's tyrosine kinase inhibitor) for patients with mantle cell lymphoma or chronic lymphocytic leukemia?

Zanubrutinib Use and Dosage for MCL and CLL

Zanubrutinib is recommended at a dose of 160 mg twice daily for patients with relapsed/refractory mantle cell lymphoma and chronic lymphocytic leukemia, and is considered a preferred category 1 treatment option due to its high efficacy and favorable safety profile compared to other BTK inhibitors.

Indications and Efficacy

Mantle Cell Lymphoma (MCL)

• Approved for patients with MCL who have received at least one prior therapy
• Clinical efficacy in relapsed/refractory MCL:
  • Overall response rate (ORR) of 83.7% with 77.9% complete response rate 1
  • Median progression-free survival (PFS) of 33.0 months 1
  • 36-month PFS and overall survival rates of 47.6% and 74.8%, respectively 1

Chronic Lymphocytic Leukemia (CLL)

• Approved for both treatment-naïve and relapsed/refractory CLL
• In the SEQUOIA trial, zanubrutinib demonstrated superior efficacy compared to bendamustine-rituximab with:
  • PFS hazard ratio of 0.42 (95% CI 0.28-0.63, p<0.0001) 2
• Zanubrutinib is particularly effective in high-risk CLL patients, including those with TP53 aberrations

Waldenström Macroglobulinemia (WM)

• Also approved for WM (though not specifically asked about)
• In the phase III ASPEN trial, zanubrutinib was compared to ibrutinib showing:
  • 42-month PFS rate of 78% vs 70% for ibrutinib 2
  • Higher VGPR rates in patients with CXCR4 mutations (21% vs 10%) 2

Dosing Recommendations

• Standard dose: 160 mg twice daily orally, continuous dosing until disease progression or unacceptable toxicity 3, 1
• Alternative dosing of 320 mg once daily has also been studied with similar efficacy 4
• No dose adjustments required for age, but consider dose modifications for:
  • Severe hepatic impairment
  • Concomitant use of strong CYP3A inhibitors
  • Management of adverse events

Safety Profile and Advantages

Zanubrutinib offers several advantages over first-generation BTK inhibitors like ibrutinib:

1. Reduced cardiac toxicity:

   • Lower incidence of atrial fibrillation (4% vs 17% with ibrutinib) 2
   • No reported cases of atrial fibrillation/flutter in long-term follow-up studies 1

2. Common adverse events:

   • Neutropenia (most common grade ≥3 AE at 18.6%) 1
   • Upper respiratory tract infection (38.4%) 1
   • Rash (36.0%) 1
   • Decreased white blood cell count (33.7%) 1
   • Decreased platelet count (32.6%) 1

3. Safety considerations:

   • Infection rates, neutropenia, and bleeding are highest in the first 6 months of therapy and decrease thereafter 1
   • No reported cases of grade ≥3 cardiac adverse events, second primary malignancies, or tumor lysis syndrome in long-term follow-up 1

Clinical Considerations and Management

Patient Selection

• Particularly beneficial for:
  • Patients with cardiac comorbidities (lower risk of atrial fibrillation)
  • Patients with high-risk features (del17p, TP53 mutations)
  • Patients who experienced toxicity with other BTK inhibitors

Monitoring Recommendations

• Complete blood counts: Monitor regularly, especially during the first 6 months
• Infection surveillance: Highest risk in first 6 months of therapy
• Bleeding risk: Hold zanubrutinib 3 days before and after minor procedures, 7 days before and after major procedures

Drug Interactions

• Avoid concomitant use with strong CYP3A inhibitors/inducers when possible
• Consider non-warfarin anticoagulation if anticoagulation is needed

Treatment Algorithm

1. For relapsed/refractory MCL:

   • Zanubrutinib 160 mg twice daily until progression or unacceptable toxicity
   • Monitor for neutropenia and infections, especially in first 6 months

2. For CLL (first-line or relapsed):

   • Zanubrutinib 160 mg twice daily as continuous therapy
   • Particularly preferred for patients with:
     • TP53 aberrations
     • Cardiac comorbidities
     • Prior intolerance to other BTK inhibitors

3. Management of adverse events:

   • Grade 3-4 neutropenia: Consider G-CSF support
   • Infections: Appropriate antimicrobial therapy; prophylaxis may be considered in high-risk patients
   • Bleeding events: Temporary interruption for procedures or active bleeding

Zanubrutinib represents an important advancement in BTK inhibitor therapy with improved selectivity, leading to better tolerability while maintaining high efficacy in both MCL and CLL.