Zanubrutinib in the treatment of Waldenström Macroglobulinemia.

Waldenström Macroglobulinemia (WM) is an uncommon malignancy of IgM-secreting lymphoplasmacytic cells. The spectrum of acquired somatic mutations is heterogeneous, with MYD88 mutations occurring in more than 90%. Recurrent mutations in CXCR4, KMT2D, ARID1A, TERT, and TP53 are also detected, with some of these impacting prognosis or treatment response. The recognition of B-cell receptor (BCR) signalling in B-cell neoplasm pathophysiology led to the clinical development of the first-in-class Bruton tyrosine kinase inhibitor (BTKi) ibrutinib. Despite efficacy, off-target inhibition of TEC, EGFR, CSK and other kinases impact its safety and tolerability. The second-generation BTKi, zanubrutinib and acalabrutinib, are better tolerated with lower rates of discontinuation. Zanubrutinib is more selective for BTK than other structurally related kinases. While there have not been any studies directly comparing acalabrutinib to zanubrutinib, the efficacy of zanubrutinib was superior to ibrutinib in WM patients with MYD88 wild type, CXCR4 or TP53 mutations. However, patients with CXCR4 and TP53 mutations receiving BTKi still fare worse than those without, highlighting the need for other therapeutic strategies. Herein, we review the clinical development of zanubrutinib in WM including the impact of genetic subtypes and advise on the management of adverse events and drug resistance.