WALDENSTRÖM MACROGLOBULINEMIA

WALDENSTRÖM MACROGLOBULINEMIA

Waldenström macroglobulinemia

Waldenström macroglobulinemia is a syndrome of IgM hypergammaglobulinemia that 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. These cells characteristically secrete the IgM paraprotein, and many clinical manifestations of the disease are related to this macroglobulin. Another name for WM is lymphoplasmacytic lymphoma. This condition used to be called Waldenstrom’s macroglobulinemia, so some people refer to it as Waldenstrom’s.

WM is a cancer that starts in B cells. The cancer cells in people with WM are similar to those of 2 other types of cancer: multiple myeloma and non-Hodgkin lymphoma. Multiple myeloma is considered a cancer of plasma cells, and non-Hodgkin lymphoma is a cancer of lymphocytes. WM cells have features of both plasma cells and lymphocytes and are called lymphoplasmacytoid.

WM cells make large amounts of a certain type of antibody (immunoglobulin M, or IgM), which is known as a macroglobulin. Each antibody (protein) made by the WM cells is the same, so it is called a monoclonal protein, or just an M protein. The buildup of this M protein in the body can lead to many of the symptoms of WM, including excess bleeding, problems with vision, and nervous system problems.

The WM cells grow mainly in the bone marrow, where they can crowd out the normal cells that make the different types of blood cells. This can lead to low levels of red blood cells (called anemia), which can make people feel tired and weak. It can also cause low numbers of white blood cells, which makes it hard for the body to fight infection. The numbers of platelets in the blood can also drop, leading to increased bleeding and bruising.

Lymphoma cells can also grow in organs like the liver and spleen, causing these organs to swell and leading to abdominal pain.

Signs and symptoms

This disease characteristically develops insidiously in patients in their 60s or 70s. Patients usually present with fatigue related to anemia.

Hyperviscosity of serum may be manifested in a number of ways.

Mucosal and gastrointes­tinal bleeding is related to engorged blood vessels and platelet dysfunction.

Other complaints include nausea, vertigo, and visual disturbances.

Alter ations in conscious­ness vary from mild lethargy to stupor and coma.

The IgM paraprotein may also cause symptoms of cold agglutinin disease (hemolysis) or chronic demyelinating peripheral neuropathy.

On examination, there may be hepatosplenomegaly or lymphadenopathy.

The retinal veins are engorged. Purpura may be present. There should be no bone tenderness.

Diagnosis

Anemia is nearly universal, and rouleaux formation is common, although the red blood cells are agglutinated when the blood smear is prepared at room temperature.

The anemia is related in part to expansion of the plasma volume by 50–100% due to the presence of the paraprotein. Other blood counts are usually normal. The abnormal plasmacytic lymphocytes may appear in small numbers on the peripheral blood smear. The bone marrow is character­istically infiltrated by the plasmacytic lymphocytes.

The hallmark of macroglobulinemia is the presence of a monoclonal IgM spike seen on serum PEP in the beta-globulin region. The serum viscosity is usually increased above the normal of 1.4–1.8 times that of water. Symptoms of hyperviscosity usually develop when the serum viscosity is over four times that of water, and marked symptoms usu­ally arise when the viscosity is over six times that of water. Because paraproteins vary in their physicochemical prop­erties, there is no strict correlation between the concentra­tion of paraprotein and serum viscosity.

The IgM paraprotein may cause a positive antiglobulin (Coombs) test for complement and have cold agglutinin or cryoglobulin properties. If macroglobulinemia is suspected but the serum PEP shows only hypogammaglobulinemia, the test should be repeated while taking special measures to maintain the blood at 37°C, since the paraprotein may precipitate out at room temperature. Bone radiographs are normal, and there is no evidence of kidney injury.

Differential diagnosis

Waldenström macroglobulinemia is differentiated from MGUS by the finding of bone marrow infiltration with monoclonal malignant cells. It is distinguished from CLL by bone marrow morphology, the absence of CD5 expression and the absence of lymphocytosis and from plasma cell myeloma by bone marrow morphology, the finding of the characteristic IgM paraprotein, and the absence of bone disease.

Treatment

Patients with marked hyperviscosity syndrome (stupor, coma, pulmonary edema) should be treated on an emer­gency basis with plasmapheresis. On a chronic basis, some patients can be managed with periodic plasmapheresis alone. As with other indolent malignant lymphoid diseases, rituximab (375 mg/m2 intravenously weekly for 4–8 weeks) has significant activity.

However, a word of caution: the IgM often rises first after rituximab therapy before it falls. Com­bination therapy is recommended for advanced disease. MYD88 is commonly mutated in Waldenström macroglobulinemia, and in patients with relapsed or refrac­tory disease, the BTK inhibitor ibrutinib, at a dose of 420 mg daily, has shown significant activity with a 90% response rate and a 73% major response rate that can result in dura­ble remissions.

Bortezomib, lenalidomide, and bendamus­tine have also been shown to have activity in this disease. Autologous hematopoietic stem cell transplantation is reserved for relapsed or refractory patients.

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