Waldenstrom Macroglobulinemia: Genomic Aberrations and Treatment
Waldenström macroglobulinemia (WM) is a rare, indolent, and monoclonal immunoglobulin M-associated lymphoplasmacytic disorder with unique clinicopathologic characteristics. Over the past decade, remarkable progress has occurred on both the diagnostic and
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Abstract
Waldenström macroglobulinemia (WM) is a rare, indolent, and monoclonal immunoglobulin M-associated lymphoplasmacytic disorder with unique clinicopathologic characteristics. Over the past decade, remarkable progress has occurred on both the diagnostic and therapeutic fronts in WM. A deeper understanding of the disease biology emanates from the seminal discoveries of myeloid differentiation primary response 88 (MYD88) L265P somatic mutation in the vast majority of cases and C-X-C chemokine receptor, type 4, mutations in about a third of patients. Although WM remains an incurable malignancy, and the indications to initiate treatment are largely unchanged, the therapeutic armamentarium continues to expand. Acknowledging the paucity of high-level evidence from large randomized controlled trials, herein, we evaluate the genomic aberrations and provide a strategic framework for the management in the frontline as well as the relapsed/refractory settings of symptomatic WM. Keywords
Waldenstrom’s macroglobulinemia MYD88 CXCR4 IgM BTK inhibitors
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Definition
The first accounts of Waldenström macroglobulinemia (WM), an eponymous disease, were reported about seven decades ago in two patients who exhibited ‘‘several symptoms suggesting myelomatosis,’’ but with ‘‘decided differences’’ [1]. P. Kapoor S.M. Ansell E. Braggio (&) Mayo Clinic, Scottsdale, AZ, USA e-mail: [email protected] © Springer International Publishing Switzerland 2016 A.M. Roccaro and I.M. Ghobrial (eds.), Plasma Cell Dyscrasias, Cancer Treatment and Research 169, DOI 10.1007/978-3-319-40320-5_16
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Lymphadenopathy, oronasal bleeding, anemia, thrombocytopenia lymphocytoid marrow infiltration, marked increase in globulin content, and high viscosity were distinct features documented in these cases [1]. The definition of WM has evolved over time. Currently, the World Health Organization (WHO) classifies it as a subset of a low-grade, non-Hodgkin lymphoma (NHL) with unique pathologic characteristics: immunoglobulin (Ig) M monoclonal gammopathy (macroglobulinemia) of any size and infiltration of bone marrow by clonal lymphoplasmacytic cells [2]. WM represents >95 % of lymphoplasmacytic lymphoma (LPL) cases. The requirement for a minimum marrow involvement or a minimum serum IgM concentration for the diagnosis of WM was eliminated in the Second International Workshop on WM [3]. A mature dataset of 213 patients with IgM monoclonal gammopathy of undetermined significance (MGUS)-the strongest predisposing factor for WM- attempts to shed light on the controversies surrounding the definition of WM. In this study, patients who underwent bone marrow biopsy (n = 27) had fewer than 10 % lymphoplasmacytic cells. Only 29 patients (14 %) developed NHL, WM, chronic lymphocytic leukemia (CLL) or light chain (AL) amyloidosis with a cumulative probability of progression at 1.5 % per year [4, 5]. Therefore, the Mayo Clinic criteria adopted at least 10 % marrow involvement by clonal lymphoplasmacytic cells and a serum monoclonal
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