Waldenstrom Macroglobulinemia

Waldenström’s macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma, is a type of cancer affecting two types of B cells, lymphoplasmacytoid cells and plasma cells. Both cell types are white blood cells. WM is characterized by having high levels of a circulating antibody, immunoglobulin M (IgM), which is made and secreted by the cells involved in the disease. WM is an “indolent lymphoma” (i.e., one that tends to grow and spread slowly) and a type of lymphoproliferative disease which shares clinical characteristics with the indolent non-Hodgkin lymphomas.WM is commonly classified as a form of plasma cell dyscrasia. Similar to other plasma cell dyscrasias that, for example, lead to multiple myeloma, WM is commonly preceded by two clinically asymptomatic but progressively more pre-malignant phases, IgM monoclonal gammopathy of undetermined significance (i.e. IgM MGUS) and smoldering Waldenström’s macroglobulinemia. The WM spectrum of dysplasias differs from other spectrums of plasma cell dyscrasias in that it involves not only aberrant plasma cells but also aberrant lymphoplasmacytoid cells and that it involves IgM while other plasma dyscrasias involve other antibody isoforms.

WM is a rare disease, with only about 1,500 cases per year in the United States. While the disease is incurable, it is treatable. Because of its indolent nature, many patients are able to lead active lives, and when treatment is required, may experience years of symptom-free remission.

Signs and symptoms
Signs and symptoms of WM include weakness, fatigue, weight loss, and chronic oozing of blood from the nose and gums.Peripheral neuropathy occurs in 10% of patients. Enlargement of the lymph nodes, spleen, and/or liver are present in 30–40% of cases. Other possible signs and symptoms include blurring or loss of vision, headache, and (rarely) stroke or coma.

Waldenström’s macroglobulinemia is characterized by an uncontrolled clonal proliferation of terminally differentiated B lymphocytes. The most commonly associated mutations, based on whole-genome sequencing of 30 patients, are a somatic mutation in MYD88 (90% of patients) and a somatic mutation in CXCR4 (27% of patients).An association has been demonstrated with the locus 6p21.3 on chromosome 6.There is a two- to threefold increased risk of WM in people with a personal history of autoimmune diseases with autoantibodies, and a particularly elevated risk associated with liver inflammation, human immunodeficiency virus, and rickettsiosis.

There are genetic factors, with first-degree relatives of WM patients shown to have a highly increased risk of also developing the disease.There is also evidence to suggest that environmental factors, including exposure to farming, pesticides, wood dust, and organic solvents, may influence the development of WM

There is no single accepted treatment for WM.There is marked variation in clinical outcome due to gaps in knowledge of the disease’s molecular basis. Objective response rates are high (> 80%) but complete response rates are low (0–15%).Recently, Yang et al. showed that the MYD88 L265P mutation induced activation of Bruton’s tyrosine kinase, the target of the drug ibrutinib. Among previously treated patients, ibrutinib induced responses in 91% of patients, and at 2 years 69% of patients had no progression of disease and 95% were alive (Treon et al., New England Journal of Medicine 2015). Based on this study, the Food and Drug Administration approved ibrutinib for use in WM in 2015.

There are different treatment flowcharts: Treon and mSMART.

WM patients are at higher risk of developing second cancers than the general population, but it is not yet clear whether treatments are contributory.

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