Impact of initial dosing and subsequent dose reduction of zanubrutinib in patients with Waldenström macroglobulinemia

Zanubrutinib is the preferred Bruton tyrosine kinase inhibitor for Waldenström macroglobulinemia (WM), yet data on dosing strategies remain limited. We evaluated 236 WM patients who received zanubrutinib monotherapy between 2018 and 2025. We assessed the impact of initial dosing and subsequent dose reductions on very good partial response (VGPR) and progression-free survival (PFS). Multivariate logistic and Cox models identified independent predictors of VGPR and PFS. Among 236 patients, 193 (82%) initiated 160 mg twice-daily, 22 (9%) initiated 320 mg daily, and 21 (9%) initiated sub-standard-dosing (<320 mg daily). With a median follow-up of 33 months (95% CI, 30.4-35.2), standard-dose regimens produced comparable outcomes: VGPR 39% (71/184) with 160 mg twice-daily vs. 40% (8/20) with 320 mg daily (p=0.90), and 30-month PFS rate 89% vs. 89% (p=0.86). Sub-standard initiation yielded inferior efficacy, with VGPR of 14% (3/21; p=0.03) and a 30-month PFS rate of 54% (p<0.001). In multivariable analysis, sub-standard-dose initiation independently predicted lower VGPR attainment (OR 0.10; p=0.04) and worse PFS (HR 11.09; p=0.001). In contrast, subsequent, toxicity-driven, dose reductions after standard-dose initiation that occurred in 51/215 (24%), patients did not worsen outcomes (VGPR 49% vs. 36%, p=0.09; 30-month PFS rate 95% vs. 88%, p=0.13) and improved symptoms in 34/51 (67%), particularly for rheumatologic and gastrointestinal toxicities. In conclusion, findings from this largest off-trial WM cohort support standard-dose zanubrutinib initiation with either 320 mg daily or 160 mg twice daily, while suggesting that dose reductions may be better reserved for toxicity management after standard-dose initiation rather than used preemptively.