The approval of the oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib alone and in combination with rituximab has expanded the treatment options for WM patients.
Ibrutinib, a Bruton's tyrosine kinase inhibitor has reformed the treatment of various B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia.
We present a review of ibrutinib, beginning with an overview of the Bruton tyrosine kinase pathway and clinically relevant gene mutations impacting treatment and prognosis for patients with Waldenstrom macroglobulinemia, followed by evidence supporting therapeutic indications for ibrutinib, and detailing its safety and efficacy evidence, current clinical guidelines, adverse effects and their management, and finally challenges of drug resistance.
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.
We therefore engineered BTK<sup>Cys481Ser</sup> and BTK<sup>WT</sup> expressing MYD88-mutated Waldenström macroglobulinemia (WM) and activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) cells and observed reactivation of BTK-PLCγ2-ERK1/2 signaling in the presence of ibrutinib in only the former.
The Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has been approved for the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia.
We also discuss the safety and efficacy data of alkylating agents, proteasome inhibitors, monoclonal antibodies, and Bruton tyrosine kinase inhibitors in patients with WM.
Development of new therapies including monoclonal antibodies, proteasome inhibitors, and Bruton tyrosine kinase inhibitors have made the management of WM increasingly complex.
In this review, we discuss the new developments that have occurred in WM over the past 15 years, with a focus on the role of ibrutinib, an oral Bruton's tyrosine kinase inhibitor that has recently been approved for WM in the United States, Europe, and Canada.
Clinically, two treatment strategies are used to disrupt these complementary yet mutually exclusive WM survival pathways via ibrutinib (targets BTK/MYD88 node) and bortezomib (targets 20 S proteasome).
We have also used loss-of-function approaches to investigate the growth and survival effects of Nampt on MW cells and further tested the anti-MW activity of dual Nampt and BTK inhibition in vitro and in vivo RESULTS: We found that Waldenström macroglobulinemia cells exhibit high levels of Nampt compared with normal B cells.
As a result of these findings and based on the design and execution of a prospective clinical trial, the FDA granted approval to ibrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, to treat patients with symptomatic WM.
By analogy to the successful treatment with BTK inhibitors, we propose that targeting pathways controlling integrin-mediated retention of the WM cells in the BM, thereby inducing 'homelessness' (anoikis) by mobilization of the malignant cells from their protective niches, may be an efficient treatment strategy for WM.
Here, we review novel therapeutic agents in Waldenström macroglobulinemia/lymphoplasmacytic lymphoma, which have emerged in the past decade and discuss their comparative efficacy and safety, with emphasis on a Bruton's tyrosine kinase (BTK) inhibitor, which has been recently approved by the US FDA, specifically for Waldenström macroglobulinemia/lymphoplasmacytic lymphoma.
The results establish BTK as a downstream target of MYD88 L265P signaling, and provide a framework for the study of BTK inhibitors alone, and in combination with IRAK inhibitors for the treatment of WM.