Waldenström macroglobulinemia (WM) and cancer

ALSO KNOWN AS: Lymphoplasmacytic lymphoma, Waldenström’s macroglobulinemia

RELATED CONDITIONS: Multiple myeloma, hepatitis C

DEFINITION: Waldenström macroglobulinemia (WM) is a slow-growing form of non-Hodgkin lymphoma distinguished by a significantly elevated level of immunoglobulin-M (IgM) in the blood, often leading to hyperviscosity (thickening) of the blood. The disease was named for Jan Gosta Waldenström, a Swedish physician who, in 1944, identified “monoclonal gammopathy” in patients experiencing a thickening of their serum albumin. In a 1961 report, he described two patients with bleeding from the gums and nose, high platelet count, low red blood cell count (anemia), high sedimentation rate, and swollen lymph nodes. He ruled out multiple myeloma based on bone marrow biopsy tests and a lack of bone pain. He found a large amount of a single, unknown globulin (protein) in the serum with an extremely high molecular weight (macroglobulin). This macroglobulin is now known as IgM.

Risk factors: Researchers have found few risk factors for WM. At least some cases of WM (up to 20 percent) are familial, being passed between generations. Gene mutations associated with the disease include MYD88, which occurs in around 90 percent of cases, and in around 40 percent of cases, changes in the CXCR4 gene are observed. For others, the cause is unknown. Infection of the hepatitis C virus increases the incidence of WM in some individuals, as does prior diagnosis with monoclonal gammopathy of undetermined significance (MGUS), Sjögren's syndrome, and acquired immunodeficiency syndrome (AIDS). Being older, white, and a man are known risk factors. None of these risk factors are controllable, so prevention remains elusive.

Etiology and the disease process: B cells are an important part of the human body's immune system. They are the antibody-secreting cells that are a principal part of the adaptive immune system (which creates immunity for specific invaders, such as bacteria, viruses, and so on). There are five antibodies (immunoglobulin or Ig) secreted by B cells: IgA, IgD, IgE, IgG, and IgM. IgM is by far the largest, hence the name “macroglobulin.” Some B cells circulate throughout the blood, while others reside in the body's lymph nodes. Immature B cells are found in the bone marrow.

The lymph nodes are small, pea-sized collections of immune system cells (B cells, T cells, and macrophages) found in recognizable locations throughout the body. The predominant nodes are in the underarm area, the groin, both sides of the neck, the chest, and the abdomen. Small amounts of lymphoid tissue are also found in the digestive tract and the respiratory system.

For unknown reasons, early B cells, predominantly in the bone marrow, can multiply out of control. As they do this, they can crowd out the normal red blood cell production, leading to a low blood cell count. As they mature and circulate, these B cells secrete much larger amounts of IgM than normal. This leads to hyperviscosity (thickening of the serum) as more large protein is secreted and trapped in the bloodstream. Other symptoms, such as swelling of the lymph nodes and other parts of the immune system, are also related to the overpopulation of B cells and the overproduction of this macroglobulin.

The cancerous cells found in individuals with WM are similar to those found in people suffering from multiple myeloma (cancer of plasma cells) and non-Hodgkin lymphomas (cancer of lymphocytes, including B cells). The cancer cells of WM are lymphoplasmacytic, similar to both plasma cells and lymphocytes. These cells secrete large amounts of IgM and create the various symptoms of the disease.

Incidence: Between 1,000 and 1,500 new cases are confirmed annually in the United States. The incidence is higher in Whites than in Black or Latinx individuals and higher in men than in women. The chance of developing this disease increases with age (mostly because of its slow nature), with the median age of diagnosis at seventy-one. It is very rare in people under sixty-five.

Symptoms: Many patients are asymptomatic. In others, symptoms vary widely. The most common symptoms of WM are weakness, swollen lymph nodes, swollen liver or spleen, severe fatigue (often the result of severe anemia), low appetite and weight loss, and bleeding from the gums and nose (often the first signs of increased platelet activity). In addition, many patients experience visual problems (most likely due to bleeding of the small blood vessels inside the eyes) or neurological problems (dizziness, headache, vertigo), probably caused by slowed blood circulation to the brain.

Pain or numbness in the extremities may also be noted, a sign of early nerve damage. Heart problems often arise due to damage caused to the heart muscle by the high levels of IgM and because the heart has to work extra hard to pump the very thick blood through the body. Symptoms can vary widely depending on the severity of the disease and the amount of IgM being secreted. None of these symptoms alone are diagnostic of WM since they also occur in many other cancers and noncancerous diseases.

Screening and diagnosis: No tests are available to screen for early WM. When signs and symptoms first appear, diagnosis can generally be made based on blood and urine tests along with a bone marrow biopsy or fine needle aspiration biopsy. Blood viscosity tests are extremely important, as are measurements of the amount of IgM and other immunoglobulins in the serum.

There is no standard staging system for WM (as for most other cancers). The amount of lymphoplasmacytic cells in the bone marrow, the degree of anemia, the degree of viscosity, and the patient's age are all used to determine prognosis.

Treatment and therapy: Although there is no cure for WM, several treatments can help control the symptoms. Since this is a slow-growing type of cancer, there is no rush to start treatment immediately upon diagnosis. Treatments generally aim to relieve symptoms, which vary tremendously from one individual to another. The decision about which treatment to use typically depends on the results of viscosity tests and bone marrow biopsies.

Patients with high viscosity may undergo plasmapheresis. Blood from the patient is removed through a machine that separates the cellular part of the blood from the plasma (the liquid fraction containing the IgM). The cellular portion is returned to the patient along with a plasma substitute. Since this treatment removes only the IgM currently in the system and does not stop the body from producing more, it is only a temporary solution, but it does relieve symptoms, especially in newly diagnosed individuals.

Most patients also undergo either chemotherapy (anticancer drugs) or biological therapy to destroy the IgM-producing cells and stimulate the immune system into attacking the cancer. The most often used regimen has been chlorambucil and prednisone in combination. Other anticancer drugs being used include cyclophosphamide, doxorubicin, fludarabine, and cladribine. Most treatments are given during outpatient therapy over several days. Blood tests of IgM levels, physical examination of lymph nodes, and scans of lymph nodes help determine whether a particular drug works for the patient. These drugs have side effects that may include nausea, vomiting, loss of appetite, hair loss, lowered resistance to infection, and easy bruising. Careful monitoring is important.

Biological therapies may include interferon (a protein produced by lymphocytes to help fight infections) and monoclonal antibodies designed to attack lymphoma cells (rituximab).

A few other treatments have been tested with varying successes. These include splenectomy (removal of an enlarged spleen, where much IgM may be produced) and high-dose chemotherapy followed by stem cell transplantation (cells that will migrate to the bone marrow and replace those blood-forming and immune system cells destroyed by the chemotherapy). Additionally, drugs such as thalidomide and bortezomib, which have been used to treat multiple myeloma (a related type of cancer), have been tried in some patients. Researchers continue to look for new drugs, combinations of drugs, and new biological therapies.

Prognosis, prevention, and outcomes: The prognosis for WM is extremely variable. Many describe a life span of five to seven years after diagnosis, but since the average age of diagnosis is relatively late, there is a great likelihood of dying from other causes. The American Cancer Society lists an overall relative five-year survival rate of 78 percent. According to the International Waldenström’s Macroglobulinemia Foundation, patients have been known to live for twenty-five or more years after diagnosis.

Bibliography

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Treon, Steven P., et al. "Genomic Landscape of Waldenström Macroglobulinemia and Its Impact on Treatment Strategies." Journal of Clinical Oncology, vol. 38, no. 11, 2020, pp. 1198-1208. doi.org/10.1200/JCO.19.0231.

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