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INTRODUCTION

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SUMMARY

Waldenström macroglobulinemia (WM) is an indolent B-cell neoplasm manifested by the accumulation of clonal immunoglobulin (Ig) M secreting lymphoplasmacytic cells. MYD88L265P and CXCR4 WHIM (warts, hypogammaglobulinemia, infections, myelokathexis)-like somatic mutations are present in more than 90 percent, and 30 to 35 percent of WM patients, respectively, and impact 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 10g/dL, 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 prerituximab for 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. Frontline treatments include rituximab alone or combined with alkylating agents (bendamustine, cyclophosphamide), proteasome inhibitors (bortezomib, carfilzomib), or nucleoside analogues (fludarabine, cladribine). In case of relapsed or treatment-resistant patients, an alternative frontline regimen or autologous stem cell transplantation can be considered. Novel targeted agents for the treatment of WM include everolimus and ibrutinib.

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Acronyms and Abbreviations

CD16, FcγRIIIa receptor; CD40L, CD40 ligand; CDR, complement determination region; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; GM1, ganglioside M1; HCV, hepatitis C virus; Ig, immunoglobulin; IL, interleukin; κ, kappa light chain; LPL, lymphoplasmacytic lymphoma; MAG, myelin-associated glycoprotein; R-CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab; R-CP, cyclophosphamide, prednisone, and rituximab; R-CVP, cyclophosphamide, vincristine, prednisone, and rituximab; sCD27, soluble CD27; WHO, World Health Organization; WM, Waldenström macroglobulinemia.

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DEFINITION AND HISTORY

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Waldenström macroglobulinemia (WM) is a lymphoid neoplasm resulting from the accumulation, predominantly in the marrow, 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 in the Revised European-American Lymphoma (REAL) and World Health Organization (WHO) classification systems.2,3 Most cases of LPL are WM; less than 5 percent of cases are IgA-secreting, IgG-secreting, or nonsecreting LPL.

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In 1944, Jan Waldenström, a Swedish physician-scientist, reported in Acta Medica Scandinavica 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 the 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 ...

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