Waldenström Macroglobulinemia (WM) is a rare disease. The median age at diagnosis is 70 years and approximately 60 percent of patients are male. The etiology of WM is not fully understood. Approximately 90-95% of WM patients have mutations in the MYD88 L265P gene and 40% have recurrent mutations in the CXCR4 gene.

The clonal B cell population leads to abnormal monoclonal IgM production. The pentameric configuration of IgM molecules increases serum viscosity, slowing blood flow through capillaries. In patients with WM, clonal B cells can directly infiltrate hematopoietic tissues, causing cytopenias (e.g., anemia, thrombocytopenia, neutropenia), lymphadenopathy, hepatomegaly, and/or splenomegaly. Rarely, plasmacytoid lymphocytes may infiltrate the central nervous system or meninges.

Most patients with WM present with nonspecific constitutional symptoms but up to a quarter of patients may be asymptomatic at diagnosis. Common symptoms include weakness, fatigue, weight loss, and nose and gum bleeding.

Bone marrow aspiration and biopsy demonstrating lymphoplasmacytic lymphoma is an important component of the diagnosis of WM. The biopsy specimen is usually hypercellular and densely infiltrated with lymphoid and plasmacytoid cells. Intranuclear vacuoles containing IgM monoclonal protein (Dutcher bodies) are common in the malignant cells of WM.

The following criteria must be met for a diagnosis of WM:

• IgM monoclonal gammopathy (any level) must be present in the serum.

• ≥10% of the bone marrow biopsy specimen must show infiltration by small lymphocytes with plasmacytoid or plasma cell differentiation (lymphoplasmacytic features or lymphoplasmacytic lymphoma) and an intertrabecular pattern.

• The infiltrate should express a typical immunophenotype (e.g., surface IgM+, CD5-/+, CD10-, CD11c-, CD19+, CD20+, CD22+, CD23-, CD25+, FMC7+, CD103-, CD138-). The plasmacytic component will be CD138+, CD38+, and CD45- or less prominent.

The differential diagnosis includes chronic lymphocytic leukemia, marginal zone and mantle cell lymphoma.

Not every VM patient requires treatment. For asymptomatic patients, follow-up without treatment every 3-6 months is recommended.

Treatment is indicated for patients with symptomatic WM if any of the following are attributable to WM:

• Systemic symptoms: B symptoms such as recurrent fever, severe night sweats, fatigue and/or unintentional weight loss

• Cytopenias: Hemoglobin ≤10 g/dL or platelet count <100,000/microL; cold agglutinin anemia, immune hemolytic anemia, and/or thrombocytopenia

• Symptomatic or large (≥5 cm) lymphadenopathy, symptomatic splenomegaly and/or tissue infiltration

• End-organ damage: Hyperviscosity, peripheral neuropathy, immunoglobulin light chain (AL) amyloidosis with organ dysfunction, symptomatic cryoglobulinemia, pleural effusions or nephropathy due to WM

Symptomatic hyperviscosity in a patient with an indication for treatment requires urgent plasmapheresis. Signs and symptoms associated with hyperviscosity include oronasal hemorrhage, blurred vision, headache, dizziness, paresthesia, retinal vein occlusion, papilledema, stupor, and coma.

In patients with treatment indications but without symptoms of hyperviscosity, options include rituximab plus bendamustine or Bruton&apos;s tyrosine kinase inhibitors (such as ibrutinib, zanubrutinib, or acalabrutinib). Treatment of relapsed or refractory disease may include Bruton&apos;s tyrosine kinase inhibitors, bendamustine plus rituximab, nucleosome analog-based regimens, and venetoclax, if not previously used. High-dose chemotherapy and autologous or allogeneic hematopoietic cell transplantation (HCT) are rarely used in the treatment of WM.