Waldenström Macroglobulinemia

Key Features

Essentials of Diagnosis

• Monoclonal immunoglobulin M (IgM) paraprotein

• Infiltration of bone marrow by plasmacytic lymphocytes

• Absence of lytic bone disease

• L265P mutation in the gene MYD88

General Considerations

• Syndrome of IgM hypergammaglobulinemia

• Occurs in the setting of a low-grade non-Hodgkin lymphoma characterized by B-cells that are morphologically a hybrid of lymphocytes and plasma cells

• Cells characteristically secrete IgM paraprotein, and this macroglobulin causes many clinical manifestations

Demographics

• Occurs mainly in patients aged 60–79

Clinical Findings

Symptoms and Signs

• Insidious fatigue related to anemia

• Mucosal or gastrointestinal bleeding is related to engorged blood vessels and platelet dysfunction with hyperviscosity syndrome (usually when viscosity > 4 times that of water)

• Nausea, vertigo, or visual disturbances

• Alterations in consciousness from mild lethargy to stupor and coma with hyperviscosity syndrome

• Symptoms of cold agglutinin disease or chronic demyelinating peripheral neuropathy from IgM paraprotein

• Hepatosplenomegaly or lymphadenopathy may be present

• Retinal vein engorgement

• Purpura may be present

• Bone tenderness absent

Differential Diagnosis

• Monoclonal gammopathy of unknown significance

• Plasma cell myeloma

• Chronic lymphocytic leukemia

• Lymphoma

Diagnosis

Laboratory Tests

• Anemia is nearly universal, and rouleaux formation common

• White blood cell and platelet count are usually normal

• Peripheral blood smear: abnormal plasmacytic lymphocytes may be present in small numbers

• Serum protein electrophoresis (SPEP) demonstrates monoclonal IgM spike in β-globulin region

• Serum viscosity is usually increased above normal (> 1.4–1.8 times viscosity of water)

• No direct correlation between paraprotein concentration and serum viscosity

• Antiglobulin (Coombs), cold agglutinin, or cryoglobulin tests may be positive because of IgM paraprotein

• If macroglobulinemia is suspected but the SPEP shows only hypogammaglobulinemia, repeat the SPEP while maintaining blood at 37°C, because the paraprotein may precipitate at room temperature

• No evidence of kidney failure

Imaging Studies

• Bone radiographs are normal

Diagnostic Procedures

• Bone marrow aspiration and biopsy

  • Characteristic infiltration by the plasmacytic lymphocytes

  • The L265P mutation in MYD88 is detectable in more than 90% of patients

Treatment

Medications

• Rituximab

  • Dosage: 375 mg/m² intravenously weekly for 4–8 weeks

  • Cytotoxic agent needs to be initiated at the same time for patients with hyperviscosity

• BTK inhibitors, ibrutinib (420 mg orally daily) and zanubrutinib, have shown significant activity

• Proteasome inhibitors (bortezomib and carvilzomib)

• Lenalidomide

• Bendamustine

• Combination therapy for advanced disease

  • Addition of bendamustine to other agents shows excellent response rates

• See Table 39–3