Waldenström macroglobulinemia (WM), an incurable B-cell malignancy, is sensitive to Bruton tyrosine kinase (BTK) inhibition with ibrutinib, a first-generation BTK inhibitor. Off-target effects of ibrutinib against TEC- and EGFR-family kinases are implicated in some adverse events. Patients with CXCR4WHIM and MYD88L265P mutations or who are MYD88WT have less sensitivity to ibrutinib than those with MYD88L265P and CXCR4WT disease. Zanubrutinib, a next-generation BTK inhibitor with potent preclinical activity in WM and minimal off-target effects, showed sustained BTK occupancy in peripheral blood mononuclear cells from patients with B-cell malignancies and promising responses in advanced WM. Described here is a head-to-head Phase III study comparing efficacy and safety of zanubrutinib and ibrutinib in WM patients. Effect of MYD88 and CXCR4 mutation status will be assessed.
Keywords: BTK inhibitor; Bruton tyrosine kinase; Waldenström macroglobulinemia; clinical trial; zanubrutinib.