Resistance Mechanism for Zanubrutinib in Marginal Zone Lymphoma

Marginal zone lymphoma (MZL) is the third most common B-cell non-Hodgkin lymphoma and tends to follow the relapsing course typical of other indolent lymphomas, meaning that many patients receive multiple lines of therapy. Brüton's tyrosine kinase inhibitors (BTKis) have been a promising addition to the treatment landscape of relapsed MZL; however, development of resistance to these agents remains a significant problem that warrants further characterization. This case report presents a patient with relapsed MZL receiving the BTKi zanubrutinib who experienced large cell transformation of their lymphoma in concert with the development of mutations predictive of resistance to BTKi therapy, specifically BTK C481S and PLCG2 D334H. To our knowledge, this is the first reported case of a patient with MZL acquiring co-mutations in BTK and PLCG2 in concert with the development of disease progression while receiving BTKi therapy. Outcomes for patients with MZL who develop resistance to BTKis have not been fully characterized, but are poor in other B-cell malignancies that have acquired BTKi resistance, such as mantle cell lymphoma and chronic lymphocytic leukemia. Improved understanding of the genetic and molecular drivers of MZL is leading to new treatment strategies. Further studies of novel therapeutic approaches are ongoing to improve outcomes for patients with MZL, including those who acquire resistance to BTKis.