Waldenström Macroglobulinemia Facts No. 20 in a series providing the latest information for patients, caregivers and healthcare professionals www.LLS.org • Information Specialist: 800.955.4572 Highlights l There is no cure for WM, but the disease is treatable. Therapy regimens that include a combination of l Waldenström macroglobulinemia (WM) is an biological agents (treatment that stimulates the indolent (slow-growing) subtype of non-Hodgkin immune system to fight cancer), signaling inhibitors lymphoma that affects small lymphocytes (white (drugs that block progrowth and survival signals), blood cells). WM is rare, with an incidence rate and chemotherapy have provided promising results. of about 6 cases per million people per year in the The safety and effectiveness of potential new United States. therapies for WM patients, including the use of new l WM probably begins with one or more acquired drugs and drug combinations, are being researched changes (mutations) to the DNA of a single in clinical trials. Recently ibrutinib (Imbruvica®) B lymphocyte. The cancer causes the overproduction became the first ever drug approved for the of a monoclonal protein called “immunoglobulin M” treatment of symptomatic patients with WM. (IgM), which can result in a thickening of the blood known as “hyperviscosity.” This monoclonal IgM protein may lead to many symptoms, including fatigue, unexplained weight loss, enlarged lymph Introduction nodes or spleen, weakness and unexplained bleeding. “Lymphoma” is the name for many different types of l Over 90 percent of WM patients have a mutation cancer that arise in the lymphocytes (white blood cells). in the MYD88 gene in their lymphoma cells. The There are three types of lymphocytes: B lymphocytes mutation turns on pathways that sustain the growth (B cells), T lymphocytes (T cells) and natural killer (NK) and survival of WM cells. cells. B lymphocytes make antibodies to fight infection; T lymphocytes have many functions, including helping l Over 30 percent of WM patients have a mutation in B lymphocytes to make the antibodies that fight infection; the CXCR4 gene, which promotes the WM cells to and natural killer cells attack cancer cells and viruses. return to the bone marrow. Lymphocytes go through several stages of development. l The exact cause of WM is unknown, although it The final stage of B-lymphocyte development is a mature, is believed that genetics may play a role in disease immunoglobulin-producing plasma cell. Lymphoma may development. Many patients with WM have a family arise in any of these types of lymphocytes. In general, member with WM or a closely related lymphoma, B-cell lymphomas are more common than T-cell lymphomas. chronic lymphocytic leukemia (CLL), or multiple Lymphoma is divided into two major categories: Hodgkin myeloma. The cancer occurs most commonly in lymphoma (HL) and non-Hodgkin lymphoma (NHL). people over age 60 years, is more frequently found in Waldenström macroglobulinemia (WM) is an uncommon men than women, and is found in more whites than B-cell cancer that is classified by the World Health blacks. WM is also found in a high frequency of Organization as a subtype of NHL. WM is also referred to individuals of Ashkenazi Jewish descent. as a “B-cell lymphoproliferative disease,” and it accounts for approximately 1 to 2 percent of hematologic (blood) cancers. l Some patients with WM do not have symptoms at diagnosis and may not require treatment for This fact sheet provides specific information about the years. In these cases, patients are closely monitored diagnosis, treatment and expected outcomes of WM, for symptoms in an approach known as “watchful information about new treatments being investigated waiting.” Active treatment is started only when in clinical trials, and support resources. For additional symptoms appear. information about WM, please see the free The Leukemia & Lymphoma Society (LLS) publication Non-Hodgkin Lymphoma. Support for this publication provided by FS20 Waldenström Macroglobulinemia Facts I page 1 Revised May 2015 Waldenström Macroglobulinemia Facts About Waldenström Macroglobulinemia LPL. WM accounts for approximately 1 to 2 percent of all hematologic (blood) cancers. WM, also called “lymphoplasmacytic lymphoma (LPL),” is a rare, indolent (slow-growing) blood cancer that is treatable Certain risk factors may play a role in the development of with available therapies but is not curable. Large amounts of WM. A risk factor is anything that increases a person’s chance an abnormal monoclonal protein called “immunoglobulin M” of developing a disease. Currently, there is no known way to (IgM or “macroglobulin”) are produced. Immunoglobulins, prevent this cancer, nor are the exact causes known. sometimes called “gamma globulins,” are proteins that help the body fight infection. The major classes of immunoglobulins The following factors may raise a person’s risk of developing (Ig) are IgG, IgA, IgM, IgD and IgE. Low Ig levels may cause WM, although most people with these risk factors will never repeated infections in some patients. develop the disease: WM probably begins with one or more changes (mutations) l Age—The risk of WM increases with age. The median age to the DNA of a B lymphocyte (B cell), which then multiplies at diagnosis is 63 years. uncontrollably. These mutations occur during the cell’s maturation stage so that it continues to reproduce more l Gender—Men are more likely than women to develop malignant (cancer) cells. The result is the overproduction of IgM the cancer. antibody by the malignant B cells. l Race—WM incidence is highest among Caucasians and is The abnormal WM cells grow mainly in the bone marrow. rare in other population groups. As a result, the healthy red blood cells, which carry oxygen; the white blood cells, which fight infection; and the platelets, l Monoclonal gammopathy of undetermined significance which help with blood clotting, are crowded out and normal (MGUS)—MGUS is an abnormality of antibody blood production is disrupted. Low levels of red blood cells producing cells that is related to WM and another B-cell can lead to anemia, making people feel tired and weak; low blood cancer called “myeloma.” In most cases, MGUS numbers of white blood cells make it hard for the body to does not cause health problems, but up to 25 percent of fight infection; and a low platelet count can result in increased people with MGUS, especially those with a monoclonal bleeding and bruising. IgM protein, will develop WM, another type of NHL At the time of diagnosis, WM most commonly involves the or myeloma. See the free LLS publications Monoclonal blood and bone marrow; however, WM can start almost Gammopathy of Undetermined Significance (MGUS) Facts anywhere and spread to almost any part of the body, affecting and Myeloma at www.LLS.org/booklets. the lymph nodes, liver or spleen as well as the stomach, intestines l Heredity—Genetic factors appear to play a role in WM or lungs. WM rarely involves the skin or thyroid gland. onset, with studies showing a degree of familial clustering of WM or another type of lymphoma in about 20 percent Lymphoplasmacytic Lymphoma (LPL) of the cases examined. LPL and WM are closely related, slow-growing types of l Environmental factors—The role of the environment lymphoma that originate in a B-lymphocyte precursor. in WM onset is unknown. However, the United States In LPL, the lymph nodes are typically more involved than Department of Veterans Affairs has listed non-Hodgkin in WM. Both disorders show malignant lymphoplasmacytic lymphoma as a cancer associated with Agent Orange. For cells. LPL is usually diagnosed by lymph node biopsy more information, see the We’re Here to Help section on and often does not have a measurable level of serum IgM page 9. monoclonal protein; if the protein is present, it is present in low quantities. WM is diagnosed by marrow examination, Additional risk factors being studied: and an IgM protein is almost always present and usually at higher levels. l Scientists have recently made progress in the understanding of how certain changes in DNA can cause Incidence, Causes and Risk Factors normal lymphocytes to become lymphoma cells. Scientists are also beginning to understand how changes in the DNA WM is rare, with an incidence rate of about 6 cases per of some lymphoma cells cause them to produce high levels million people per year in the United States. About 1,000 of IgM, a key reason for many symptoms of WM. to 1,500 people are diagnosed with WM each year in the United States. WM results from the accumulation, mainly in l In WM, the most common mutation occurs in MYD88 the bone marrow, of clonal lymphocytes, lymphoplasmacytic gene. Over 90 percent of patients carry this mutation in cells and plasma cells that secrete a monoclonal IgM protein. the WM cells. MYD88 L265P mutation turns on growth Most cases of LPL are WM, with less than 5 percent of cases and survival pathways including Bruton tyrosine kinase made up of IgA-secreting, IgG-secreting or non-secreting (BTK), the target of ibrutinib. FS20 Waldenström Macroglobulinemia Facts I page 2 Waldenström Macroglobulinemia Facts l About a third of WM patients also carry a mutation in the with IgM serum levels greater than 50 grams per liter (g/L) gene CXCR4 that turns on growth and survival pathways. are considered to be at an increased risk for hyperviscosity Over thirty different types on mutations occur in WM syndrome. Untreated, long-standing hyperviscosity syndrome patients, and the particular type of mutation of the can cause life-threatening complications. Symptoms of CXCR4 gene can impact disease presentation at diagnosis. hyperviscosity syndrome typically do not develop unless the Patients with nonsense mutations of CXCR4 can patient’s serum viscosity is especially elevated. Therefore, present with higher serum IgM levels and bone marrow patients need to be tested periodically for evidence of involvement.