Waldenstrom Macroglobulinemia: Familial Predisposition and the Role of Genomics in Prognosis and Treatment Selection

Abstract

Waldenstrom macroglobulinemia (WM) is a non-Hodgkin lymphoma (NHL) characterized by the presence of a CD20 + lymphoplasmacytic bone marrow (BM) infiltrate and serum immunoglobulin M monoclonal protein. Both sporadic and familial forms exist. A remarkable improvement in outcome of nearly all age groups of WM patients may be primarily a consequence of successful integration of anti-CD20 monoclonal antibody, rituximab, to the conventional chemotherapy. However, the seminal discoveries of MYD88 (L265P) mutation, present in the vast majority (85-100 %), and CXCR4 (WHIM) mutations, identified in nearly a third of patients (who almost exclusively harbor the MYD88 (L265P) variant), have laid a solid foundation for a paradigm shift in our diagnostic and therapeutic approaches towards this rare hematologic malignancy. Given that 20-25 % of patients are asymptomatic at diagnosis and early intervention does not translate into survival benefit, we follow a risk-adapted approach and actively monitor this subset of "smoldering" patients. Those with low-grade cytopenias can generally be managed with an abbreviated course of rituximab monotherapy, while those with B symptoms, bulky lymphadenopathy, or profound disease-related cytopenias require more aggressive strategies, incorporating several courses of chemoimmunotherapy. For symptoms associated with hyperviscosity, prompt plasma exchange is warranted prior to initiation of cytoreductive therapy. Prospective data are unavailable to a support a unique approach in familial WM or initiation of rituximab maintenance post-induction. A multitude of potentially effective therapies targeting cell-survival pathways are in development and offer a more precise approach for WM patients. One such agent, ibrutinib, a Bruton's tyrosine kinase inhibitor, was recently granted approval. Off-study, we limit the use of ibrutinib to relapsed-refractory WM patients who harbor MYD88 mutations. Autologous stem-cell transplantation (ASCT) is another viable option in the relapsed setting for chemosensitive transplant-eligible patients. Unfortunately, despite substantial progress, achieving a minimal residual disease-negative state-a prerequisite for cure-is rare in WM.

Keywords: Cytogenetics; Ibrutinib; IgM monoclonal gammopathy; Indolent lymphoma; Lymphoplasmacytic lymphoma; MYD88 L265P, CXCR4 mutation; Novel therapies; Sporadic.