Should the current regimen of 320 mg Brukinsa (zanubrutinib) daily be continued in a patient with Waldenstrom's macroglobulinemia, mantle cell lymphoma, and lytic lesions, given a 56% reduction in IgM after 12 months?

Continue Brukinsa 320 mg Daily

The current regimen of 320 mg Brukinsa (zanubrutinib) daily should be continued, as the 56% IgM reduction represents a solid Partial Response (PR) and the FDA-approved dosing is to continue until disease progression or unacceptable toxicity. 1

Response Assessment

Your patient has achieved a Partial Response (PR), which is defined by the International Workshop on Waldenström's Macroglobulinemia (IWWM) as ≥50% reduction in serum IgM without new signs or symptoms of disease. 2 A 56% reduction clearly meets this threshold and represents clinically meaningful disease control associated with improved progression-free survival. 2

• PR (50-89% IgM reduction): Your patient is here at 56% 2
• VGPR (≥90% IgM reduction): Would require further reduction 2
• Minor Response (25-49% IgM reduction): Your patient has exceeded this 2

Why Continue Treatment

BTK inhibitors like zanubrutinib should not be stopped unless there is disease progression or unacceptable toxicity. 3 The IWWM specifically warns that increases in serum IgM and reductions in hemoglobin can occur if the drug is held, and these changes should not be regarded as treatment failure. 3

Consequences of Stopping

• Rapid IgM rebound occurs following discontinuation of BTK inhibitors, with documented increases in serum IgM levels and decreases in hemoglobin when therapy is held 3
• Relapses are common after discontinuation, even in patients who achieved good responses 3
• The NCCN Guidelines explicitly recommend continuing BTK inhibitor therapy until disease progression or unacceptable toxicity 3

FDA-Approved Dosing

The FDA label for Brukinsa states the recommended dosage is 160 mg orally twice daily OR 320 mg orally once daily until disease progression or unacceptable toxicity. 1 Your patient is on the approved once-daily regimen.

Monitoring Going Forward

Since your patient has achieved PR at 12 months, continue the following surveillance:

• Monitor CBC, comprehensive metabolic panel, and IgM levels every 3 months for the first 2 years, then every 4-6 months 2
• Watch for hyperviscosity symptoms (visual changes, headache, bleeding, neurologic symptoms) if IgM rises above 4,000 mg/dL 3
• 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 3

Important Caveat About IgM Monitoring

With BTK inhibitors like zanubrutinib, these agents can suppress IgM levels independent of tumor cell killing in some patients. 2 If blood counts (hemoglobin, platelets) are stable and there are no symptoms of hyperviscosity, lymphadenopathy, or other disease manifestations, this represents disease control—not treatment failure. 3

• Bone marrow assessments are not routinely recommended for response evaluation except to establish complete response, as discordant results between IgM reduction and bone marrow infiltration have been reported with BTK inhibitors 3
• Consider bone marrow biopsy only if there is clinical concern for progression that is discordant with IgM levels 3

Duration of Response Considerations

Remissions lasting ≥12 months are considered durable responses. 2 Your patient is at the 12-month mark with a PR, which is an excellent outcome. The ASPEN trial demonstrated that median duration of response and progression-free survival were not reached with zanubrutinib, with 85% of patients progression-free at 18 months. 4

Valid Reasons to Discontinue (None Currently Apply)

Only stop zanubrutinib if:

Disease Progression (requires evidence beyond elevated IgM alone):

• Worsening anemia or thrombocytopenia 3
• Increasing lymphadenopathy or splenomegaly 3
• New hyperviscosity symptoms 3
• Rising bone marrow involvement on biopsy 3

Unacceptable Toxicity:

• Recurrent atrial fibrillation/flutter 3
• Major hemorrhage requiring intervention 3
• Severe infections 3
• Other grade 3-4 adverse events that significantly impair quality of life 3

Special Considerations for Lytic Lesions

While lytic lesions are mentioned in your patient's presentation, this is an unusual feature for Waldenström macroglobulinemia (more typical of multiple myeloma). 5 However, this does not change the management approach—continue zanubrutinib as the response to therapy is favorable and there are no contraindications to continuation.

Comparative Efficacy Data

Zanubrutinib demonstrated similar efficacy to ibrutinib in the ASPEN trial, with a trend toward better response quality (28% VGPR rate vs 19% with ibrutinib, though not statistically significant) and significantly less toxicity, particularly cardiovascular toxicity. 4 The major response rates were 77-78% in both arms, with 84-85% of patients progression-free at 18 months. 4