Waldenstrom Macroglobulinemia

Updated: Feb 18, 2017
  • Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

Practice Essentials

Waldenström macroglobulinemia, one of the malignant monoclonal gammopathies, is a chronic, indolent, lymphoproliferative disorder. [1] It is characterized by the presence of a high level of a macroglobulin (immunoglobulin M [IgM]), elevated serum viscosity, and the presence of a lymphoplasmacytic infiltrate in the bone marrow. (See Pathophysiology, Etiology, and Workup.)

A clonal disease of B lymphocytes, Waldenström macroglobulinemia is considered to be a lymphoplasmacytic lymphoma, as defined by the Revised European American Lymphoma Classification (REAL) and World Health Organization (WHO) classification.

The clinical manifestations of Waldenström macroglobulinemia result from the presence of the IgM paraprotein and malignant lymphoplasmacytic cell infiltration of the bone marrow and other tissue sites. The clinical presentation is similar to that of multiple myeloma except that (1) organomegaly is common in Waldenström macroglobulinemia and is uncommon in multiple myeloma and (2) lytic bony disease and renal disease are uncommon in Waldenström macroglobulinemia but are common in multiple myeloma. (See Pathophysiology, Presentation, and Workup.)

Waldenström macroglobulinemia is not curable, but a number of therapies have shown activity in the disease. Data from randomized trials remain sparse, however. [2, 3]

For asymptomatic patients without end-organ damage, management consists of careful observation. In symptomatic patients, monotherapy with rituximab is the usual choice, especially for nonbulky disease. Bulky symptomatic disease may require combination regimens, such as chemotherapy. [4] Ibrutinib has demonstrated efficacy as monotherapy for rituximab-resistant cases, especially those with mutations in the MYD88 gene. [5, 6] Hyperviscosity syndrome may mandate emergency plasmapheresis. Autologous stem cell transplantation is a consideration in select cases. (See Treatment.)

Complications

Complications of Waldenström macroglobulinemia include the following:

  • Visual disturbances secondary to hyperviscosity syndrome
  • Diarrhea and malabsorption secondary to gastrointestinal (GI) involvement
  • Renal disease (less common)
  • Amyloidosis of the heart, kidney, liver, lungs, and joints
  • Bleeding manifestations secondary to platelet dysfunction and coagulation factor and fibrinogen abnormalities due to interaction with plasma IgM
  • Peripheral neuropathy
  • Raynaud phenomenon secondary to cryoglobulinemia
  • Increased predisposition to infection due to B-cell dysfunction (disease related) or T-cell dysfunction (therapy related, particularly after nucleoside analogues)
  • Cardiac failure
  • Increased incidence of lymphomas, myelodysplasia, and leukemias
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Pathophysiology

The clinical manifestations of this disorder result from 2 important factors. First, secretion of the IgM paraprotein leads to hyperviscosity and vascular complications because of physical, chemical, and immunologic properties of the paraprotein. These complications include the following:

  • Hyperviscosity syndrome
  • Cryoglobulinemia types 1 and 2
  • Coagulation abnormalities
  • Sensorimotor peripheral neuropathy
  • Cold agglutinin disease and anemia
  • Primary amyloidosis
  • Tissue deposition of amorphous IgM in the skin, GI tract, kidneys, and other organs

Second, neoplastic lymphoplasmacytic cells infiltrate the bone marrow, spleen, and lymph nodes. Less commonly, these cells can infiltrate the liver, lungs, GI tract, kidneys, skin, eyes, and central nervous system (CNS). Infiltration of these organs causes numerous clinical symptoms and signs.

Occasionally, IgM paraprotein has (1) rheumatoid factor activity, (2) antimyelin activity that can contribute to peripheral neuropathy, and (3) immunologically related lupus anticoagulant activity.

A study by Pasricha et al found that bone marrow features, particularly the degree of plasma cell infiltration, correlates with IgM paraprotein concentration at diagnosis. Thus, evaluation of the plasma cell compartment in the bone marrow at baseline and after therapy may be helpful. [7]

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Etiology

No definite etiology exists for Waldenström macroglobulinemia. Environmental, familial, genetic, and viral factors have been reported. IgM monoclonal gammopathies of undetermined significance (MGUS) are considered a precursor of Waldenström macroglobulinemia.

A possible role for genetic factors has been suggested by reports of familial clustering of Waldenström macroglobulinemia. In one study, approximately 20% of 181 serial Waldenström macroglobulinemia patients presenting to a tertiary referral had a first-degree relative with either Waldenström macroglobulinemia or another B-cell lymphoproliferative disease. Reports of familial cases suggest a genetic predisposition. [8, 9]

Hepatitis C, hepatitis G, and human herpesvirus 8 have been implicated, but as yet, no strong data support a causative link between these viruses and Waldenström macroglobulinemia.

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Epidemiology

Waldenström macroglobulinemia is a relatively rare condition, with the 1500 cases diagnosed per year in the United States accounting for approximately 2% of hematologic malignancies. The incidence rate for Waldenström macroglobulinemia in the United States is higher among whites, with people of African descent representing only 5% of all patients. In the United Kingdom, the annual incidence of the disease is 10.3 per million. [10]

Waldenström macroglobulinemia is a disease of elderly individuals. Most patients present in the seventh or eighth decade of life. The median age at diagnosis in the United States is 65 years, with a slight male predominance.

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Prognosis

Waldenström macroglobulinemia is an indolent disorder, and patients survive for a median of approximately 78 months. Kaplan-Meier survival curves of patients with Waldenström macroglobulinemia do not show a plateau. [11]

Different studies have been performed to assess prognosis. Patients with a nodular type of bone marrow involvement tend to do better than those with diffuse involvement.

Poor prognostic factors include the following:

  • Age older than 65 years
  • Hemoglobin value of less than 10 g/dL
  • Albumin level less than 4.0 g/dL
  • Elevated beta-2-microglobulin level

A study by Kastritis et al found that despite the evolution of treatment to include nucleoside analogues and other novel agents, no significant improvement in the outcome of patients with Waldenström macroglobulinemia has been noted since the late 20th century. [12]

In contrast, a study by Castillo et al that was based on the Surveillance, Epidemiology and End Results database found that relative survival rates were higher in patients diagnosed with Waldenström macroglobulinemia during 2001-2010 than those diagnosed during 1980-2000: 5-year relative survival rates were 78% versus 67%, respectively, and 10-year relative survival rates were 66% versus 49%, respectively. Relative survival improved in whites and other races, but not in blacks. [13]

Morbidity and mortality

The most important causes of death in Waldenström macroglobulinemia include progression of the proliferative process, infection, cardiac failure, renal failure, strokes, and GI bleeding. Transformation to a more aggressive immunoblastic variant is less common (6% of cases).

Treon et al reported that somatic mutations in MYD88 and CXCR4 in patients with Waldenström macroglobulinemia are determinants of clinical presentation and overall survival. Patients with MYD88 (L265P) and CXCR4 with warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome/nonsense (NS) mutations had significantly higher bone marrow disease involvement and symptomatic disease requiring therapy, including hyperviscosity syndrome. [14]

Patients with MYD88 (L265P) and WHIM/frameshift (FS) CXCR4 mutations or wild type CXCR4 had intermediate bone marrow involvement, while those with wild type MYD88 and CXCR4 had the lowest bone marrow disease burden. Risk of death was not affected by CXCR4 mutation status, but was markedly increased by wild type MYD88 status (hazard ratio 10.54). [14]

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