BTK Inhibitors and Other Targeted Therapies in Waldenström Macroglobulinemia

Waldenstrom macroglobulinemia (WM) is a rare, non-Hodgkin lymphoma that remains incurable. Rituximab, an anti-CD20 monoclonal antibody has been the cornerstone of treatment against WM, and its combination with an alkylator, bendamustine, achieves durable remission in treatment-naive patients with symptomatic WM. However, novel "druggable" targets that have been identified within the clonal lymphoplasmacytic cells in WM have resulted in a rapid development of targeted therapies in both the frontline and relapsed and refractory (R/R) settings. Several agents directed against the known targets have shown promising efficacy, with mostly manageable toxicities. The class of Bruton's tyrosine kinase (BTK) inhibitors has transformed the therapeutic landscape for patients with WM, given their convenient oral dosing and strong efficacy, with high rates of attainment of very good partial response (VGPR). The tolerability of the next-generation BTK inhibitors appears to be superior to that of the first-in-class agent, ibrutinib. Targeted therapies from other classes have also demonstrated efficacy in both single-agent and combination regimens. Inhibitors of proteasome BCL-2, mTOR and PI-3 kinase have demonstrated efficacy in WM. Emerging therapies under investigation will continue to further shape the management paradigm, especially in the R/R setting. These include bispecific antibodies, radiotherapeutic agents and chimeric antigen receptor T-cell (CART) cell therapies. This review outlines the current literature and future direction of targeted therapies in WM.