Is Brukinsa (zanubrutinib) the best treatment for Waldenstrom's macroglobulinemia with a B-cell disorder?

Is Brukinsa (Zanubrutinib) the Best Treatment for Waldenstrom's Macroglobulinemia?

Brukinsa (zanubrutinib) is one of the preferred first-line and relapsed/refractory treatment options for Waldenstrom's macroglobulinemia, with evidence suggesting superior tolerability compared to ibrutinib, though it is not definitively "best" as multiple equally effective options exist depending on clinical context. 1, 2

Treatment Setting Determines Optimal Choice

First-Line Therapy

For treatment-naïve symptomatic patients, zanubrutinib is listed as a preferred regimen (Category 1) alongside chemoimmunotherapy combinations (bendamustine-rituximab, cyclophosphamide-rituximab, bortezomib-rituximab) 1, 3. The choice depends on:

• Patients with high IgM or hyperviscosity: Bortezomib-containing regimens are preferred as primary choices to avoid IgM flare 1
• Patients with pre-existing neuropathy: Avoid bortezomib; zanubrutinib or bendamustine-rituximab are better options 1
• Patients with cardiac risk factors: Zanubrutinib has significantly lower atrial fibrillation rates (4%) compared to ibrutinib (17%) 4, 2
• Patients ineligible for chemoimmunotherapy: BTK inhibitors like zanubrutinib are specifically recommended 1

Relapsed/Refractory Disease

For patients relapsing within 12 months of chemoimmunotherapy, including rituximab-refractory patients, BTK inhibitors (including zanubrutinib) are the treatment of choice 1. Zanubrutinib achieved:

• Overall response rate of 95.9% 5
• VGPR/CR rate of 45.2% that increased over time 5
• 3-year progression-free survival of 80.5% 5

Head-to-Head Comparison: Zanubrutinib vs Ibrutinib

The ASPEN trial directly compared these BTK inhibitors in MYD88L265P WM patients 2:

Efficacy (comparable between agents):

• VGPR rates: 28% zanubrutinib vs 19% ibrutinib (not statistically significant, P=0.09) 2
• Major response rates: 77% vs 78% 2
• 18-month PFS: 84% vs 85% 2

Safety (zanubrutinib superior):

• Atrial fibrillation: 4% vs 17% 2, 4
• Lower rates of contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms 2
• Treatment discontinuation due to adverse events: lower with zanubrutinib 2

Critical caveat: Zanubrutinib has higher neutropenia rates (20-23% grade ≥3 vs 8% with ibrutinib), requiring more vigilant monitoring and potential G-CSF support 4

Why Zanubrutinib May Not Be "Best" for Everyone

Genomic Considerations

• MYD88 wild-type patients: May have no significant benefit from BTK inhibitors; chemoimmunotherapy may be preferable 1
• CXCR4 mutations: May affect response kinetics to BTK inhibitors 1

Clinical Scenarios Favoring Chemoimmunotherapy

• Patients seeking finite-duration therapy: Chemoimmunotherapy offers defined treatment courses vs indefinite BTK inhibitor therapy 6
• Patients with contraindications to anticoagulation: BTK inhibitors carry bleeding risk (26-39% any grade) and cannot be combined with warfarin 4, 7
• Patients requiring surgery: Zanubrutinib must be held 3-7 days pre/post-operatively 4, 7

Infection Risk

A fatal disseminated cryptococcal infection has been reported with zanubrutinib, highlighting the need for vigilance regarding opportunistic infections 8

Algorithmic Approach to Treatment Selection

Step 1: Assess urgency

• High IgM/hyperviscosity → Bortezomib-based regimen 1
• Standard presentation → Proceed to Step 2

Step 2: Evaluate cardiac history

• Atrial fibrillation history or cardiac risk factors → Zanubrutinib preferred over ibrutinib 4, 2
• No cardiac concerns → Proceed to Step 3

Step 3: Consider neuropathy

• Pre-existing neuropathy → Avoid bortezomib; use zanubrutinib or bendamustine-rituximab 1
• No neuropathy → Proceed to Step 4

Step 4: Assess MYD88 status

• MYD88 wild-type → Consider chemoimmunotherapy over BTK inhibitors 1
• MYD88L265P → BTK inhibitors or chemoimmunotherapy both appropriate 2

Step 5: Patient preference

• Prefers finite therapy → Chemoimmunotherapy 6
• Prefers oral, indefinite therapy with fewer infusions → Zanubrutinib 7, 5

Key Clinical Pitfalls to Avoid

• Do not overlook neutropenia monitoring with zanubrutinib, as it requires more frequent CBC checks and potential G-CSF support compared to ibrutinib 4
• Do not combine zanubrutinib with warfarin; use alternative anticoagulation strategies 4, 7
• Do not assume BTK inhibitors work equally in MYD88 wild-type disease; these patients may derive minimal benefit 1
• Do not start rituximab-based therapy in patients with very high IgM (>4000 mg/dL) without considering plasmapheresis or bortezomib first to prevent IgM flare 1
• Do not continue zanubrutinib through surgical procedures; hold 3-7 days before and after 4, 7