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INTRODUCTION

SUMMARY

Waldenström macroglobulinemia (WM) is an indolent B-cell neoplasm manifested by the accumulation of clonal immunoglobulin (Ig) M secreting lymphoplasmacytic cells. MYD88 and CXCR4 somatic mutations are present in more than 90% and 30% to 35% of WM patients, respectively, and affect disease presentation, treatment outcome, and/or overall survival. Familial predisposition is common in WM. Asymptomatic patients should be observed. Patients with disease-related hemoglobin of less than 100 g/L, platelets less than 100 × 109/L, bulky adenopathy and/or organomegaly, symptomatic hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia, cold-agglutinin disease, or transformed disease should be considered for therapy. Plasmapheresis should be used for patients with symptomatic hyperviscosity and before administration of rituximab in those with high serum IgM levels to preempt a symptomatic IgM flare. The treatment choice should take into account specific goals of therapy, necessity for rapid disease control, risk of treatment-related neuropathy, immunosuppression and secondary malignancies, and planning for future autologous stem cell transplantation. Initial treatments include rituximab alone or combined with alkylating agents (bendamustine, cyclophosphamide); proteasome inhibitors (bortezomib, carfilzomib, ixazomib); nucleoside analogues (fludarabine, cladribine); and Bruton tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib). In patients with relapsed or treatment-resistant disease, an alternative frontline regimen, a BTK inhibitor (if not used previously) or an autologous stem cell transplantation can be considered.

DEFINITION AND HISTORY

Waldenström macroglobulinemia (WM) is a lymphoid neoplasm resulting from the accumulation, in the marrow and other organs, of a clonal population of lymphocytes, lymphoplasmacytic cells, and plasma cells, which secrete a monoclonal immunoglobulin (Ig) M.1 WM corresponds to lymphoplasmacytic lymphoma (LPL) as defined by the World Health Organization classification.2 Most cases of LPL are WM; less than 5% of cases can secrete IgA, IgG, κ or λ light chains, or be nonsecretory.

In 1944, Jan Waldenström, a Swedish physician-scientist, reported three cases of a disease he presciently thought was related to myeloma but for the absence of bone involvement and the scarcity of plasma cells in an infiltrate of small lymphocytes. He noted the increase in plasma protein concentration, marked increased serum viscosity, exaggerated bleeding and retinal hemorrhages, and virtually every other feature of the disorder in his case descriptions. In collaboration with a colleague, he showed, using ultracentrifugation and electrophoresis, that the abundant abnormal protein had a molecular weight of approximately 1 million and was not an aggregate of smaller proteins. The disease, which he described with such thoroughness, was later named in his honor.

EPIDEMIOLOGY

The age-adjusted incidence rate of WM is 3.4 per million in males and 1.7 per million in females in the United States (US). It increases in incidence geometrically with age.3,4 The incidence rate is higher among Americans of European descent.

Genetic factors play a role in the pathogenesis of WM. Approximately 20% of patients with WM in the US are of Ashkenazi Jewish ethnic ...

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