No, You Should Not Discontinue Brukinsa
BTK inhibitors like Brukinsa (zanubrutinib) should not be stopped unless there is toxicity or disease progression—stable blood tests with persistent elevated IgM after 2 years does not constitute treatment failure and is not an indication to discontinue therapy. 1
Why Continuation is Critical
Persistent IgM is Expected and Not a Reason to Stop
The International Workshop on Waldenström's Macroglobulinemia explicitly states that BTK inhibitors should not be stopped unless toxicity or disease progression is suspected, and that increases in serum IgM and reductions in hemoglobin can occur if the drug is held—these changes should not be regarded as treatment failure 1
Elevated IgM alone, in the absence of clinical symptoms or other markers of progression, does not indicate disease progression and is not a criterion for treatment discontinuation 1
Your MYD88-positive status is particularly favorable for continued BTK inhibitor therapy, as this mutation predicts excellent response to zanubrutinib 2, 3
Consequences of Stopping BTK Inhibitors
Rapid IgM rebound occurs following discontinuation of BTK inhibitors, with documented increases in serum IgM levels and decreases in hemoglobin when therapy is held 1
The NCCN Guidelines specifically recommend continuing BTK inhibitor therapy until disease progression or unacceptable toxicity, and advise monitoring for IgM rebound after discontinuation if therapy must be stopped 1
Relapses are common after discontinuation of BTK inhibitors, even in patients who achieved good responses 1
Long-Term Safety and Efficacy Data Support Continuation
Long-term zanubrutinib data at 36 months median follow-up shows 72.7% of patients remained on treatment, with an estimated 3-year progression-free survival rate of 80.5% 2
The VGPR/CR rate increases over time with continued therapy: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24 months—demonstrating that deeper responses develop with prolonged treatment 2
Zanubrutinib has a favorable long-term safety profile with acceptable toxicity, including lower rates of atrial fibrillation (5.2%), major hemorrhage (3.9%), and grade 3 diarrhea (2.6%) compared to first-generation BTK inhibitors 2, 4
What "Stable Blood Tests" Actually Means
Response Assessment in WM
Response evaluation in WM is based on serial measurements of monoclonal IgM in serum and relative reduction of IgM, not complete normalization 1
Bone marrow assessments are not routinely recommended for response evaluation except to establish complete response, and discordant results between IgM reduction and bone marrow infiltration have been reported with BTK inhibitors 1
If your blood counts (hemoglobin, platelets) are stable and you have no symptoms of hyperviscosity, lymphadenopathy, or other disease manifestations, this represents disease control—not treatment failure 1, 5
When to Consider Stopping
Only Two Valid Reasons to Discontinue
Unacceptable toxicity: Specific toxicities that would warrant discontinuation include recurrent atrial fibrillation/flutter, major hemorrhage requiring intervention, severe infections, or other grade 3-4 adverse events that significantly impair quality of life 1
Disease progression: True progression requires evidence beyond elevated IgM alone, such as worsening anemia, thrombocytopenia, increasing lymphadenopathy/splenomegaly, new hyperviscosity symptoms, or rising bone marrow involvement on biopsy 1
What is NOT a Reason to Stop
- Persistent elevated IgM in the absence of other progression markers 1
- Achieving a "plateau" in response after 2 years (deeper responses continue to develop over time) 2
- Desire to take a "drug holiday" (this will lead to disease rebound) 1
Practical Monitoring Approach
- Continue zanubrutinib at current dose (typically 160 mg twice daily or 320 mg once daily) 2
- Monitor CBC, comprehensive metabolic panel, and IgM every 3 months 1
- Watch for symptoms of hyperviscosity (visual changes, headache, bleeding, neurologic symptoms) if IgM rises above 4,000 mg/dL 1
- Assess for cardiovascular toxicity (atrial fibrillation) and bleeding complications at each visit 2, 4
- Consider bone marrow biopsy only if there is clinical concern for progression that is discordant with IgM levels 1