Waldenstrom macroglobulinemia: biology, genetics, and therapy

Waldenstrom macroglobulinemia (WM) is a distinct clinicopathologic entity characterized by the presence of a lymphoplasmacytic lymphoma, a non-Hodgkin lymphoma, and IgM monoclonal gammopathy. WM is an indolent, uncommon malignancy mostly affecting the elderly. Patient outcomes have modestly improved since the introduction of rituximab to conventional cytotoxic chemotherapy more than 20 years ago. However, the pivotal discovery of the somatic 111D8S L265P mutation, harbored by most patients with WM, and the somatic CXCR4 WHIM mutations, similar to germline C7XCR4 mutations seen in the warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM) syndrome, present in approximately one-third of patients with WM, has fundamentally changed our understanding of this disease and expanded the potential therapeutic targets. Within this new paradigm, ibrutinib emerged as a promising new drug. Ibrutinib targets Bruton's tyrosine kinase, a downstream protein in the B-cell receptor pathway that is overactivated by the MYD88 L265 P mutation. A seminal Phase II trial of ibrutinib in previously treated WM patients showed impressive response rates and confirmed the effects of v1YD88 L265 P and CX(124 WHIM mutations in response to therapy. Ibrutinib is the first and only US Food and Drug Administration approved drug specifically for the treatment of WM. low ever, before ibrutinib can be established as the standard of care for WM, long-term data regarding efficacy and safety are required. Further research to address ibrutinib resistance and cot-e ffectiveness is also imperative before ibrutinib can gain widespread acceptance. This review will cover the present pathophysiologic understanding of WM in light laic recent MY D88 and CXCR4 discovery, as well as current and emergent treatment regimens with focus on ibrutinib.