Is zanubrutinib (Brukinsa) the best treatment option for patients with mutated MYD88 Waldenstrom's macroglobulinemia or mantle cell lymphoma?

Is Zanubrutinib (Brukinsa) the Best Treatment for Mutated MYD88 Waldenström's Macroglobulinemia or Mantle Cell Lymphoma?

For MYD88-mutated Waldenström's macroglobulinemia, zanubrutinib is a preferred first-line option with superior safety compared to ibrutinib, particularly regarding cardiac toxicity, though it carries higher neutropenia risk. 1, 2 For mantle cell lymphoma, zanubrutinib is highly effective in previously treated patients, achieving 84% overall response rates. 3

Waldenström's Macroglobulinemia with MYD88 Mutation

First-Line Treatment Positioning

• The NCCN designates zanubrutinib as a Category 1 preferred regimen for treatment-naïve symptomatic WM patients. 1
• Zanubrutinib demonstrates particular advantage in patients with CXCR4 co-mutations, producing higher very good partial response rates (21% vs 10%) and superior 42-month progression-free survival (73% vs 49%) compared to ibrutinib. 1
• The MYD88 L265P mutation is present in >90% of WM patients and predicts excellent response to BTK inhibitors. 1, 4

Comparative Efficacy Data

• In the ASPEN trial comparing zanubrutinib versus ibrutinib head-to-head in MYD88-mutated WM, both agents achieved similar overall response rates (77.5% vs 77.8%), but zanubrutinib trended toward higher VGPR rates using modified criteria (28.4% vs 19.2%). 3, 5
• Long-term follow-up at 36 months shows zanubrutinib maintains an overall response rate of 95.9% with VGPR/CR rates increasing over time: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24 months. 6
• The 3-year progression-free survival rate with zanubrutinib is 80.5%, with 84.8% overall survival. 6

Critical Safety Advantages

Zanubrutinib demonstrates a 4-fold reduction in atrial fibrillation compared to ibrutinib (4% vs 17%), making it strongly preferred for patients with cardiac risk factors. 1, 7, 5

• Lower rates of most non-hematologic adverse events including contusion, diarrhea, peripheral edema, hemorrhage, and muscle spasms compared to ibrutinib. 1, 5
• Major hemorrhage occurs in only 3.9% of patients, and bleeding risk overall is 26-39% for any grade. 7, 6

Important Safety Caveat

Zanubrutinib carries 2-fold higher neutropenia risk: any grade neutropenia in 29% versus 13% with ibrutinib, and grade ≥3 neutropenia in 20% versus 8%. 1, 7

• A larger proportion of patients require granulocyte colony-stimulating factor support. 1, 7
• Monitor complete blood counts vigilantly and maintain low threshold for G-CSF support. 2, 7

When to Choose Alternatives

• For patients with high IgM levels or symptomatic hyperviscosity, bortezomib-containing regimens are preferred initially to avoid IgM flare associated with rituximab-based therapy. 1, 2
• Patients with pre-existing neuropathy should avoid bortezomib and use zanubrutinib or bendamustine-rituximab instead. 2
• MYD88 wild-type patients derive minimal benefit from BTK inhibitors (0% response rate in ASPEN) and should receive chemoimmunotherapy instead. 1, 2, 3

Mantle Cell Lymphoma

Efficacy in Previously Treated MCL

Zanubrutinib achieves 84% overall response rates in previously treated mantle cell lymphoma patients, with 59% complete responses in the pivotal BGB-3111-206 study. 3

• Median duration of response is 19.5 months (95% CI: 16.6 to not estimable). 3
• In the BGB-3111-AU-003 study, 84% overall response rate was achieved with median duration of response of 18.5 months. 3
• Responses are durable, with 72.7% of patients remaining on treatment at median follow-up of 36 months. 6

MCL-Specific Considerations

• Zanubrutinib is FDA-approved for MCL patients who have received at least one prior therapy. 3, 8
• The drug demonstrates efficacy regardless of MIPI risk score or presence of blastoid variant. 3
• Treatment discontinuation due to adverse events occurs in only 13% of patients. 6

Practical Management Algorithm

Patient Selection for Zanubrutinib

1. Confirm MYD88 mutation status before initiating BTK inhibitor therapy - this is essential as wild-type patients show no benefit. 1, 2, 4
2. Assess CXCR4 mutation status - co-mutation predicts delayed but still excellent response to zanubrutinib. 1, 4
3. Evaluate cardiac history - zanubrutinib is strongly preferred over ibrutinib in patients with atrial fibrillation risk factors. 2, 7
4. Screen for neuropathy - if present, zanubrutinib is preferred over bortezomib-based regimens. 2
5. Measure baseline IgM - if >4,000 mg/dL with hyperviscosity symptoms, consider bortezomib-based therapy first or prophylactic plasmapheresis. 1, 2

Drug-Drug Interactions to Avoid

Never combine zanubrutinib with warfarin due to increased bleeding risk; use alternative anticoagulation strategies. 7, 9

• Avoid azole antifungals when possible due to CYP3A4 inhibition leading to increased zanubrutinib levels and toxicity. 9
• Ciprofloxacin significantly increases zanubrutinib plasma concentrations and requires dose adjustment. 9

Perioperative Management

Hold zanubrutinib 3-7 days before and after surgical procedures to minimize bleeding risk. 2, 7

Monitoring Requirements

• Perform complete blood counts regularly with low threshold for G-CSF support given higher neutropenia rates. 2, 7
• Monitor for signs of infection despite neutropenia, as grade ≥3 infection rates remain similar to ibrutinib (1.1-1.2 events per 100 person-months). 5
• Routine antibiotic or antifungal prophylaxis is NOT recommended; instead maintain high clinical suspicion and rapid diagnostic workup for infections. 9

Relapsed/Refractory Disease

For patients relapsing within 12 months of chemoimmunotherapy, BTK inhibitors including zanubrutinib are the treatment of choice. 2

• Zanubrutinib shows particular benefit in patients with altered TP53, demonstrating improved progression-free survival compared to ibrutinib in this high-risk subset. 4
• For acquired resistance to covalent BTK inhibitors, consider pirtobrutinib or venetoclax. 4