Waldenström Macroglobulinemia Facts No. 20 in a series providing the latest information for patients, caregivers and healthcare professionals - PDF

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Information Speciaist: Wadenström Macrogobuinemia Facts No. 20 in a series providing the atest information for patients, caregivers and heathcare professionas Highights Wadenström

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Information Speciaist: Wadenström Macrogobuinemia Facts No. 20 in a series providing the atest information for patients, caregivers and heathcare professionas Highights Wadenström macrogobuinemia (WM) is an indoent (sow-growing) subtype of non-hodgkin ymphoma that affects sma ymphocytes (white bood ces). WM is rare, with an incidence rate of about 6 cases per miion peope per year in the United States. WM probaby begins with one or more acquired changes (mutations) to the DNA of a singe B ymphocyte. The cancer causes the overproduction of a monocona protein caed immunogobuin M (IgM), which can resut in a thickening of the bood known as hyperviscosity. This monocona IgM protein may ead to many symptoms, incuding fatigue, unexpained weight oss, enarged ymph nodes or speen, weakness and unexpained beeding. Over 90 percent of WM patients have a mutation in the MYD88 gene in their ymphoma ces. The mutation turns on pathways that sustain the growth and surviva of WM ces. Over 30 percent of WM patients have a mutation in the CXCR4 gene, which promotes the WM ces to return to the bone marrow. The exact cause of WM is unknown, athough it is beieved that genetics may pay a roe in disease deveopment. Many patients with WM have a famiy member with WM or a cosey reated ymphoma, chronic ymphocytic eukemia (CLL), or mutipe myeoma. The cancer occurs most commony in peope over age 60 years, is more frequenty found in men than women, and is found in more whites than backs. WM is aso found in a high frequency of individuas of Ashkenazi Jewish descent. Some patients with WM do not have symptoms at diagnosis and may not require treatment for years. In these cases, patients are cosey monitored for symptoms in an approach known as watchfu waiting. Active treatment is started ony when symptoms appear. There is no cure for WM, but the disease is treatabe. Therapy regimens that incude a combination of bioogica agents (treatment that stimuates the immune system to fight cancer), signaing inhibitors (drugs that bock progrowth and surviva signas), and chemotherapy have provided promising resuts. The safety and effectiveness of potentia new therapies for WM patients, incuding the use of new drugs and drug combinations, are being researched in cinica trias. Recenty ibrutinib (Imbruvica ) became the first ever drug approved for the treatment of symptomatic patients with WM. Introduction Lymphoma is the name for many different types of cancer that arise in the ymphocytes (white bood ces). There are three types of ymphocytes: B ymphocytes (B ces), T ymphocytes (T ces) and natura kier (NK) ces. B ymphocytes make antibodies to fight infection; T ymphocytes have many functions, incuding heping B ymphocytes to make the antibodies that fight infection; and natura kier ces attack cancer ces and viruses. Lymphocytes go through severa stages of deveopment. The fina stage of B-ymphocyte deveopment is a mature, immunogobuin-producing pasma ce. Lymphoma may arise in any of these types of ymphocytes. In genera, B-ce ymphomas are more common than T-ce ymphomas. Lymphoma is divided into two major categories: Hodgkin ymphoma (HL) and non-hodgkin ymphoma (NHL). Wadenström macrogobuinemia (WM) is an uncommon B-ce cancer that is cassified by the Word Heath Organization as a subtype of NHL. WM is aso referred to as a B-ce ymphoproiferative disease, and it accounts for approximatey 1 to 2 percent of hematoogic (bood) cancers. This fact sheet provides specific information about the diagnosis, treatment and expected outcomes of WM, information about new treatments being investigated in cinica trias, and support resources. For additiona information about WM, pease see the free The Leukemia & Lymphoma Society (LLS) pubication Non-Hodgkin Lymphoma. Support for this pubication provided by FS20 Wadenström Macrogobuinemia Facts I page 1 Revised May 2015 Wadenström Macrogobuinemia Facts About Wadenström Macrogobuinemia WM, aso caed ymphopasmacytic ymphoma (LPL), is a rare, indoent (sow-growing) bood cancer that is treatabe with avaiabe therapies but is not curabe. Large amounts of an abnorma monocona protein caed immunogobuin M (IgM or macrogobuin ) are produced. Immunogobuins, sometimes caed gamma gobuins, are proteins that hep the body fight infection. The major casses of immunogobuins (Ig) are IgG, IgA, IgM, IgD and IgE. Low Ig eves may cause repeated infections in some patients. WM probaby begins with one or more changes (mutations) to the DNA of a B ymphocyte (B ce), which then mutipies uncontroaby. These mutations occur during the ce s maturation stage so that it continues to reproduce more maignant (cancer) ces. The resut is the overproduction of IgM antibody by the maignant B ces. The abnorma WM ces grow mainy in the bone marrow. As a resut, the heathy red bood ces, which carry oxygen; the white bood ces, which fight infection; and the pateets, which hep with bood cotting, are crowded out and norma bood production is disrupted. Low eves of red bood ces can ead to anemia, making peope fee tired and weak; ow numbers of white bood ces make it hard for the body to fight infection; and a ow pateet count can resut in increased beeding and bruising. At the time of diagnosis, WM most commony invoves the bood and bone marrow; however, WM can start amost anywhere and spread to amost any part of the body, affecting the ymph nodes, iver or speen as we as the stomach, intestines or ungs. WM rarey invoves the skin or thyroid gand. Lymphopasmacytic Lymphoma (LPL) LPL and WM are cosey reated, sow-growing types of ymphoma that originate in a B-ymphocyte precursor. In LPL, the ymph nodes are typicay more invoved than in WM. Both disorders show maignant ymphopasmacytic ces. LPL is usuay diagnosed by ymph node biopsy and often does not have a measurabe eve of serum IgM monocona protein; if the protein is present, it is present in ow quantities. WM is diagnosed by marrow examination, and an IgM protein is amost aways present and usuay at higher eves. Incidence, Causes and Risk Factors WM is rare, with an incidence rate of about 6 cases per miion peope per year in the United States. About 1,000 to 1,500 peope are diagnosed with WM each year in the United States. WM resuts from the accumuation, mainy in the bone marrow, of cona ymphocytes, ymphopasmacytic ces and pasma ces that secrete a monocona IgM protein. Most cases of LPL are WM, with ess than 5 percent of cases made up of IgA-secreting, IgG-secreting or non-secreting LPL. WM accounts for approximatey 1 to 2 percent of a hematoogic (bood) cancers. Certain risk factors may pay a roe in the deveopment of WM. A risk factor is anything that increases a person s chance of deveoping a disease. Currenty, there is no known way to prevent this cancer, nor are the exact causes known. The foowing factors may raise a person s risk of deveoping WM, athough most peope with these risk factors wi never deveop the disease: Age The risk of WM increases with age. The median age at diagnosis is 63 years. Gender Men are more ikey than women to deveop the cancer. Race WM incidence is highest among Caucasians and is rare in other popuation groups. Monocona gammopathy of undetermined significance (MGUS) MGUS is an abnormaity of antibody producing ces that is reated to WM and another B-ce bood cancer caed myeoma. In most cases, MGUS does not cause heath probems, but up to 25 percent of peope with MGUS, especiay those with a monocona IgM protein, wi deveop WM, another type of NHL or myeoma. See the free LLS pubications Monocona Gammopathy of Undetermined Significance (MGUS) Facts and Myeoma at Heredity Genetic factors appear to pay a roe in WM onset, with studies showing a degree of famiia custering of WM or another type of ymphoma in about 20 percent of the cases examined. Environmenta factors The roe of the environment in WM onset is unknown. However, the United States Department of Veterans Affairs has isted non-hodgkin ymphoma as a cancer associated with Agent Orange. For more information, see the We re Here to Hep section on page 9. Additiona risk factors being studied: Scientists have recenty made progress in the understanding of how certain changes in DNA can cause norma ymphocytes to become ymphoma ces. Scientists are aso beginning to understand how changes in the DNA of some ymphoma ces cause them to produce high eves of IgM, a key reason for many symptoms of WM. In WM, the most common mutation occurs in MYD88 gene. Over 90 percent of patients carry this mutation in the WM ces. MYD88 L265P mutation turns on growth and surviva pathways incuding Bruton tyrosine kinase (BTK), the target of ibrutinib. FS20 Wadenström Macrogobuinemia Facts I page 2 Wadenström Macrogobuinemia Facts About a third of WM patients aso carry a mutation in the gene CXCR4 that turns on growth and surviva pathways. Over thirty different types on mutations occur in WM patients, and the particuar type of mutation of the CXCR4 gene can impact disease presentation at diagnosis. Patients with nonsense mutations of CXCR4 can present with higher serum IgM eves and bone marrow invovement. ( Nonsense mutations are mutations that cause part of the CXCR4 protein to be cut off, thereby a shorter protein exists which acks the segment that aows it to be shut off.) WM ces with mutations of the CXCR4 gene aso show resistance to ibrutinib. Symptoms and Compications At east 25 percent of peope with WM are asymptomatic (have no symptoms), and the cancer is diagnosed because of abnorma resuts from bood tests that were ordered, usuay during a routine physica exam. Some patients are symptomatic (have signs and symptoms). The signs and symptoms may be simiar to those of peope with other types of NHL. WM symptoms are mosty associated with the effects of WM ces in the marrow Monocona IgM in the bood. The most common eary symptoms of WM are fatigue and weakness due to anemia. Other common symptoms incude Fever Night sweats Weight oss Enarged ymph nodes Enarged speen and iver Periphera neuropathy (numbness or a painfu pins and needes sensation in the feet, egs and hands). Sow and progressive reduction in kidney function may occur with WM. However, acute kidney faiure is rare. The foowing are severa distinguishing features of WM found in some but not a patients. Hyperviscosity syndrome is the arge accumuation of IgM proteins in the bood. These proteins thicken the bood and impair bood fow. When the bood gets too thick, it has troube traveing through the smaest bood vesses. This causes poor circuation to the brain, which can ead to probems simiar to a stroke, incuding surred speech and weakness on one side of the body. It can aso strain the heart, causing congestive heart faiure. Hyperviscosity syndrome occurs in about 10 to 30 percent of WM patients. Patients with IgM serum eves greater than 50 grams per iter (g/l) are considered to be at an increased risk for hyperviscosity syndrome. Untreated, ong-standing hyperviscosity syndrome can cause ife-threatening compications. Symptoms of hyperviscosity syndrome typicay do not deveop uness the patient s serum viscosity is especiay eevated. Therefore, patients need to be tested periodicay for evidence of hyperviscosity syndrome progression. Probems associated with hyperviscosity syndrome incude Cotting and beeding abnormaities that may resut from the interaction of IgM with coaguation factors in the bood Beeding that may resut when monocona IgM coats the pateets, interfering with their function. Some of the most common symptoms associated with hyperviscosity syndrome incude Abnorma beeding, especiay from the nose, gums and the ining of the gastrointestina tract Fatigue Headache Infections Vertigo Visua impairment (burred vision) Changes in menta status (ranging from impaired thinking to dementia) Shortness of breath. Symptomatic hyperviscosity syndrome is considered a medica emergency and requires treatment with pasmapheresis, which rapidy reduces the concentration of IgM proteins in the bood. Appropriate treatment for WM may aso be required to reduce the number of ces making these abnorma proteins. If the syndrome is not treated, the proteins wi accumuate at high eves again and the symptoms wi recur. Cod aggutinin disease is when monocona IgM destroys red ces when a patient is in an environment with a ow temperature. About 10 percent of WM patients have this acquired hemoytic anemia. Cryogobuinemia is when monocona IgM in the bood becomes thick and ge-ike when exposed to cod temperatures, causing circuatory probems in areas exposed directy to the cod, such as fingertips, ears and nose; joint pain; kidney probems; skin esions; and purpura (purpish or red-brown discooration of the skin). Up to 20 percent of patients with WM may deveop this condition athough fewer than 5 percent of patients have symptoms. FS20 Wadenström Macrogobuinemia Facts I page 3 Wadenström Macrogobuinemia Facts Raynaud s syndrome (aso caed Raynaud phenomenon ) is associated with both cod aggutinin disease and cryogobuinemia. This syndrome is characterized by signs of poor red ce circuation in the bood vesses near the nose, ears, fingers and toes in response to cod temperatures. Features of Raynaud s syndrome incude feeings of cod, numbness, tinging, discooration of the affected areas and pain in the hands and feet in coo temperatures. The foowing are supportive therapy options that may be used to hep manage WM: Pasmapheresis is used when IgM eves get very high and the bood becomes very thick. Pasmapheresis reduces the viscosity (thickness) of the bood using a machine that separates the pasma (the iquid part of the bood) that contains the abnorma protein from the bood ces. The ces are returned to the person undergoing treatment, whie the pasma, which contains the antibodies, is discarded and repaced with other fuids. Medication to keep the bood from cotting (an anticoaguant) is given through a vein during the procedure. Treatment with pasmapheresis aone may be indicated if hyperviscosity is the patient s ony symptom. Impaired kidney function can generay be reversed and hyperviscosity symptoms can be aeviated by remova of the abnorma protein through pasmapheresis. In some cases, pasmapheresis is used when a patient s WM is not controed by chemotherapy, bioogica therapy or other treatments. Red bood ce transfusions to treat anemia may benefit patients with WM. However, patients may aso have reduced capiary bood fow foowing transfusions because of hyperviscosity. Therefore, patients shoud not be transfused uness treatment for hyperviscosity has been impemented first to reduce serum IgM eves. Spenectomy, the surgica remova of the speen, may be needed in WM patients, but it is uncommon. However, this procedure is indicated in some patients with WM who have painfu enargement of the speen and for whom drug therapy was not hepfu. Moreover, spenectomy may aso benefit individuas with enarged speens who deveop severe bood count depetions. Diagnosis A diagnosis of WM may be suspected if bood test resuts show ow bood counts or unusuay high protein eves. To determine the presence and amount of IgM monocona proteins, an additiona test caed serum protein eectrophoresis (SPEP) wi be performed. SPEP is used to identify the presence of abnorma proteins, to identify the absence of norma proteins and to determine increases and decreases of different groups of proteins in serum. This test is typicay ordered to detect and identify excessive production of specific proteins (immunogobuins). A five types of immunogobuin (IgG, IgA, IgM, IgE, or IgD) are measured by this test. An excessive production of a monocona immunogobuin may be shown on ab resuts as a spike on a graph. Generay, IgM protein eves greater than 3 grams per deciiter (g/dl) are an indication of WM. Other typica findings from bood tests may incude Red bood ces Anemia (ow eves of red ces) is present in most patients at diagnosis. Hemogobin and hematocrit eves (measures of the concentration of red ces in the bood) are often ow, athough the absoute quantities may be norma or near-norma, because there is an increase in pasma (the fuid portion of the bood). White bood ces. A reduction in the tota white ce count (eukopenia) may be present at diagnosis. However, the number of ymphocytes (a type of white ce) is usuay increased. Beta 2 -microgobuin (B 2 M). Many patients have eevated serum B 2 M at diagnosis. B 2 M is a protein found on the surface of many ces incuding ymphocytes and is a marker of tumor burden. Its eve is aso increased in patients with abnorma kidney function. Immunogobuins. There may be a decrease in the number of uninvoved immunogobuins (IgG, IgA, IgD and IgE). Because the symptoms of WM can aso be caused by noncancerous probems, such as infections, or by other kinds of cancer, a diagnosis of WM can ony be confirmed by performing a bone marrow aspiration and bone marrow biopsy, in which a sma amount of bone and marrow are removed and examined under a microscope by a pathoogist (a doctor speciaizing in evauating ces, tissues and organs to diagnose disease) to see if ymphoma ces are present. A bone marrow biopsy can be done at the doctor s office or at the hospita, and the patient can usuay go home soon after the procedure. Rarey, a ymph node biopsy, in which tissue is removed from a ymph node, may be used to diagnose WM, athough this method is more usefu for other types of ymphoma. Other aboratory tests used in the diagnosis of WM incude Immunophenotyping This is a method used to identify a specific type of ce in a sampe of bood or marrow ces to determine if the abnorma ymphocytes are B ces or T ces. Abnorma B ymphocytes are associated with WM and are characterized by the ce markers CD19, CD20, CD22, CD79 and FMC7. CD stands for custer of differentiation, which is used to identify an antigen on the surface of the ce. Expressions of CD5, CD10 and CD23 may be found in 10 to 20 percent of WM cases. FS20 Wadenström Macrogobuinemia Facts I page 4 Wadenström Macrogobuinemia Facts Fow cytometry In this test, ce properties are measured using a ight-sensitive dye and a aser beam or other type of ight. The test is often used to ook at markers on the surface of ces or inside the ymphocytes. Fow cytometry has become increasingy important in heping doctors to determine a patient s exact type of ymphoma. An anaysis of urine coected over 24 hours This test is used to detect eevated eves of protein in the urine. Imaging Tests Imaging tests may incude computed tomography (CT or CAT) scan, which may evauate the chest, abdomen and pevis to detect sweing of the ymph nodes and the enargement of the iver and/or speen. A skeeta survey (x-rays of the skeeton) can hep distinguish between WM and a simiar pasma ce cancer caed myeoma. In contrast to myeoma, in WM no ytic bone esions are seen. Magnetic resonance imaging (MRI) and/or positron emission tomography (PET) may be usefu in determining where the ymphoma is ocated throughout the body. For additiona information about aboratory and imaging tests, pease see the free LLS pubication Understanding Lab and Imaging Tests. Treatment Panning Every patient s medica situation is different and shoud be evauated individuay by a hematoogist-oncoogist who speciaizes in treating NHL. It is important for you and members of your medica team to discuss a treatment options, incuding treatments being studied in cinica trias. Treatment pans for WM are deveoped for each individua patient based on severa factors, incuding The nature and extent of symptoms The need for more rapid disease contro The patient s age and eigibiity for stem ce transpantation (typicay, a stem ce transpant is reserved for patients younger than 70 years) The patient s overa heath and quaity of ife The potentia need for a stem ce transpant in the future. For more information about choosing a doctor or a treatment center, see the free LLS pubication Choosing a Bood Cancer Speciaist or Treatment Center. Treatment There are severa treatment options avaiabe to pr
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