QUESTIONS & ANSWERSszpiczak.org/.../makroglobulinemia_waldenstroma/... · Waldenstrom’s macroglobulinemia (WM) is a rare white blood cell cancer defined by the World Health Organization

International Waldenstrom’s Macroglobulinemia Foundation: Hope, Outreach, Support, Research

QUESTIONS & ANSWERS

Mission Statement:

To offer mutual support and encouragement to the Waldenstrom’s macroglobulinemia community and others with an interest in the disease.

To provide information and educational programs that address patients’ concerns. To promote and support research leading

to better treatments, and ultimately, a cure.

Published by the International Waldenstrom’s Macroglobulinemia Foundation This information has been provided by IWMF at no cost to you. Please consider

joining and/or contributing to IWMF to enable us to continue to provide materials like these to support research toward better treatments and a cure for

Waldenstrom’s macroglobulinemia. You may join and/or contribute at our website, www.iwmf.com or you may mail your contribution to:

IWMF Business Office 6144 Clark Center Ave.

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FOREWORD

Questions and Answers is published by the International Waldenstrom’s Macroglobulinemia Foundation (IWMF), a nonprofit organization founded in 1994 by Arnold Smokler. The IWMF was established to promote medical research on Waldenstrom’s macroglobulinemia and to provide support to patients, their families, and caregivers. Tax-deductible contributions are welcome and appreciated. Information on how to contact the IWMF is provided on the back of this booklet.

Questions and Answers was initially published in August 2003. Mary Ann Foote, PhD, assisted with the writing of the original manuscript. The IWMF gratefully acknowledges David Agus, MD, Morie Gertz, MD, Robert Kyle, MD, and Alan Saven, MD, for their thoughtful review of the original manuscript. The booklet was revised in 2010 by Suzanne Herms and Guy Sherwood, MD, and reviewed by Robert Kyle, MD. Copyright 2003 IWMF

1 ~ Waldenstrom’s Macroglobulinemia - Questions and Answers

TABLE OF CONTENTS

Introduction .........................................................................2

What Is Waldenstrom’s Macroglobulinemia? ..................2

What Are Blood Cells? How Do They Change InWaldenstrom’s Macroglobulinemia? .................................3

What Is The Prevalence Of Waldenstrom’sMacroglobulinemia? ...........................................................5

What Is The Prognosis For Waldenstrom’sMacroglobulinemia? ...........................................................6

Are There Any Known Risk Factors For DevelopingWaldenstrom’s Macroglobulinemia? .................................7

What Are The Signs And Symptoms? ...............................8

How Is Waldenstrom’s MacroglobulinemiaDiagnosed And Monitored? ............................................12

How Is Waldenstrom’s Macroglobulinemia Treated? ...............................................................................14

What Are Clinical Trials? Are There Any ForWaldenstrom’s Macroglobulinemia? ...............................25

What Are Some Of The Emerging Therapies? .............. 27

What Other Resources Are Available? ...........................29

Glossary ..............................................................................35

References...........................................................................42

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INTRODUCTION

Questions and Answers is designed to address common questions about Waldenstrom’s macroglobulinemia (WM) for people with the disease, their families, friends, and others. Those who are newly diagnosed may want to read the booklet from beginning to end, whereas those who are more familiar with the disease may focus on a specific question.

Answering questions about this disease requires the use of terms that may not be familiar to some readers. Terms related to WM are italicized the first time they are used and defined in the glossary found at the end of this booklet. Should readers have other questions not found in this booklet or seek further explanation on a particular topic, they should direct their inquiries to a healthcare professional.

WHAT IS WALDENSTROM’S MACRO-

GLOBULINEMIA?

Waldenstrom’s macroglobulinemia (WM) is a rare white blood cell cancer defined by the World Health Organization (WHO) and the Revised European American Lymphoma (REAL) classification as a lymphoplasmacytic lymphoma, a type of non-Hodgkin’s lymphoma. It is often compared with other white blood cell cancers, especially chronic lymphocytic leukemia and multiple myeloma. A defining characteristic of the disease is the presence of an elevated IgM immunoglobulin protein, also referred to as an IgM paraprotein or monoclonal IgM.

Dr. Jan Gosta Waldenström first described the disease that bears his name in 1944. He described two patients who experienced bleeding from the mouth, nose, and retina of the eye. They also


had enlarged lymph nodes and several abnormal laboratory values including low hemoglobin, low platelet counts, and an increase in an unknown protein which was later identified as the large (macro) immunoglobulin IgM.

WHAT ARE BLOOD CELLS? HOW DO THEY

CHANGE IN WALDENSTROM’S

MACROGLOBULINEMIA?In order to understand this rare disease, one needs to understand blood components, which are summarized briefly in this section. More information on blood, blood components, and blood tests can be found in the papers “Blood Tests” by Barb Hauser and “Immunoglobulins” by Guy Sherwood, MD, available from the IWMF at the foundation’s website www.iwmf.com.

Blood has both a liquid portion and a solid portion. The liquid (plasma) portion of the blood contains proteins such as immunoglobulins, clotting factors, hormones, and albumin, as well as electrolytes such as sodium, chloride, potassium, calcium, and magnesium. When clotting factors are removed from plasma, the remaining liquid is called serum. The solid portion of the blood contains blood cells such as red blood cells (erythrocytes), white blood cells (leukocytes), and platelets (thrombocytes).

The different types of blood cells perform different functions. Red blood cells deliver oxygen from the lungs to other areas of the body. Hemoglobin is a large iron-containing protein found in red blood cells and is the carrier molecule for oxygen. Platelets help blood to clot. When a blood vessel is broken, platelets bind to the broken blood vessel surface, clump together, and stop the bleeding. Both red blood cells and platelets are found primarily in the blood,

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whereas some white blood cells are found not only in the blood but also in other body tissues. The primary function of all white blood cells is to eliminate foreign substances such as bacteria and fungi from the body. Neutrophils, eosinophils, basophils, monocytes, macrophages, T-lymphocytes, natural killer cells, and B-lymphocytes are all different types of white blood cells.

Red blood cells, platelets, and white blood cells develop from a primitive blood cell called the hematopoietic stem cell. These stem cells are unique because they are also able to produce other blood stem cells. The process of blood cell development, called hematopoiesis, is illustrated in Figure 1.

Hematopoiesis occurs primarily in the bone marrow, a spongy tissue located inside the bones. Hematopoiesis occurs in all bones at birth. By adulthood, however, it occurs only in the backbone (vertebrae), ribs, skull, hip, shoulder, breastbone (sternum), and the long bones (femur and humerus).

Figure 1. Hematopoiesis, the process of blood cell differentiation.


Normally, B-lymphocytes develop into plasma cells as shown in Figure 2. The role of plasma cells is to secrete immunoglobulins, which are proteins also referred to as antibodies, that are produced when a foreign substance or antigen is detected in the body. The immunoglobulins coat the foreign substance, such as a bacterium, so that other types of white blood cells can eliminate it. Five classes of immunoglobulins have been identified, IgA, IgD, IgE, IgG, and IgM.

Figure 2. Plasma cell development.

In WM, the cancerous B-lymphocytes do not develop properly into normal plasma cells but into a type of cancer cell referred to as a lymphoplasmacytic cell. These cells invade the bone marrow and other lymphoid organs, such as the spleen and lymph nodes, and make and release increased amounts of IgM into the blood. This increased release of IgM may result in thickening of the blood (hyperviscosity).

WHAT IS THE PREVALENCE OF

WALDENSTROM’S MACROGLOBULINEMIA?WM is a rare cancer. Analyses of new cancers reported in the United States show that blood cell or hematologic cancers such as leukemias, lymphomas, and multiple myeloma account for about 10% of all new cancers, and WM accounts for only 1.4% of hematologic cancers or 0.1% of all cancers.1,2 These numbers mean that approximately 1,500 people in the United States are diagnosed

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with this disease each year.2 In comparison, lung cancer accounts for 15%, breast cancer 13%, prostate cancer 13%, and colon and rectal cancer 10% of all newly diagnosed cancers.1

WHAT IS THE PROGNOSIS FOR

WALDENSTROM’S MACROGLOBULINEMIA?The prognosis is variable. Although the median survival was reported as 5-7 years in the older literature,2 the survival time has been increasing steadily because of better treatments, and many patients live for more than 20 years.

Several studies have attempted to determine characteristics or prognostic factors that affect disease severity. The most recent was an international study that developed the International Prognostic Scoring System for Waldenstrom’s Macroglobulinemia (ISSWM) for WM. This study did not include asymptomatic patients who had not yet received treatment. Five adverse survival factors were identified: advanced age (>65 years), hemoglobin level less than or equal to 11.5 g/dL, platelet count less than or equal to 100 x 109/L, beta-2 microglobulin more than 3 mg/L, and serum monoclonal IgM concentration more than 7.0 g/dL. Based on these factors, patients were categorized into three groups. Low risk patients at treatment presented with not more than one adverse factor and age less than or equal to 65 years – these patients had a 5-year survival rate of 87%. Intermediate risk patients had two adverse factors or age older than 65 years and had a 5-year survival rate of 68%. High risk patients had three or more adverse factors and had a 5-year survival rate of 36%.3


ARE THERE ANY KNOWN RISK FACTORS

FOR DEVELOPING WALDENSTROM’S

MACROGLOBULINEMIA?A risk factor is anything that increases the chances of developing a disease. The only risk factors that have been identified in WM are male sex, increasing age, white race, and a diagnosis of monoclonal gammopathy of undetermined significance (MGUS) of IgM class.4

The risk is higher in men than in women, with the annual age-adjusted incidence approximately twice as high in men as in women.4,5,6 The incidence of the disease is also higher in older people. The median age at diagnosis is 62 although patients as young as 18 have been reported. The annual incidence increases dramatically as age increases.6 Race appears to be a risk factor, as the incidence is higher in whites than in blacks.4,5 Reliable figures for other races are not available.

People with IgM MGUS have an increased risk of developing WM. In one long-term study of IgM MGUS, the incidence of progression to WM and other lymphoid malignancies was 10% at 5 years, 18% at 10 years, and 24% at 15 years.7

Several reports suggest a link between WM and genetic, environmental, and viral factors. Research findings report an element of familial susceptibility that is more significant than with other B-lymphocyte cancers.8 Some evidence links the disease to a deletion in part of chromosome 6, although this abnormality is not present in all cases of WM.9 Environmental factors such as radiation exposure and occupational exposure to leather, rubber, paints, and dyes have also been implicated in some studies, as have viral factors such as hepatitis C and human herpes virus 8.2,10,11,12 However, none of these factors has consistently been determined to increase the risk.

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WHAT ARE THE SIGNS AND SYMPTOMS?People with WM can have a wide variety of signs and symptoms, the most common of which is fatigue, although many patients present with no symptoms at all. Other signs and symptoms are listed in Table 1. Most of these are attributable to cancer cells that replace normal cells in the bone marrow and secrete increased amounts of IgM.

Abnormal bleeding from gums and nose

Increased concentration of IgM

Decreased red blood cell count Neurological symptomsEnlarged liver Visual impairmentEnlarged lymph nodes WeaknessEnlarged spleen Weight lossFatigue Night sweats

Table 1. Common signs and symptoms of Waldenstrom’s macroglobulinemia

There are several distinguishing features of WM, found in some, but not all patients. These include hyperviscosity syndrome, peripheral neuropathy, cryoglobulinemia, cold agglutinin disease, and amyloidosis.

Hyperviscosity syndrome occurs in approximately 10-30% of patients2 as a result of the increased IgM concentration, which also ultimately results in an increased plasma volume. IgM molecules are also large and contribute to the increase in serum viscosity. Signs and symptoms of hyperviscosity include chronic bleeding from the nose, gums, and, less commonly, the gastrointestinal tract; headache; ringing in the ears (tinnitus); dizziness (vertigo); impaired hearing; blurring or loss of vision; distended, sausage-


shaped veins in the retina; and swelling of the optic disk at the back of the eye (papilledema). In severe cases, heart failure, sleepiness (somnolence), stupor, and coma can develop. Symptoms of hyperviscosity occur most commonly at IgM concentrations greater than 5,000 mg/dL; however, such concentrations are not always associated with hyperviscosity.

Peripheral neuropathy (PN) is a commonly reported complication of WM – the reported incidence varies but is generally about 20-30%. The clinical features of PN are predominantly sensory, with abnormal sensations (paresthesias) such as burning, prickling, itching, tingling, or numbness that are usually first noticed in the feet. The paresthesias are symmetric, affecting both feet equally, and slowly progress to the upper legs, hands, and arms. Strength is often normal. The PN in WM is usually caused by the targeting of specific antigens on the nerve coating (myelin) by the circulating IgM, leading to nerve dysfunction.13 Symptoms can be reduced with gabapentin (Neurontin), pregabalin (Lyrica), amitriptyline (Elavil), opiate drugs, and others. These medications mask the symptoms but do not slow the progression of PN. The treatment of IgM-related neuropathy is directed toward the reduction of circulating IgM, usually by either plasmapheresis or rituximab-based therapy, both of which are further explained in the section of this booklet entitled “How Is Waldenstrom’s Macroglobulinemia Treated?”

Cryoglobulinemia (often referred to as cryo) literally means “cold antibody in the blood” and refers to the physical and chemical properties of the antibodies involved. Cryoglobulins precipitate at temperatures below body temperature and then re-dissolve upon warming. Cryo is most often due to unknown causes but may in some cases be associated with an underlying disease such as WM.

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Frequently, the type of cryo associated with WM does not cause symptoms until the concentration of antibody reaches high levels, at which point it can produce a variety of symptoms because the precipitated antibody physically obstructs smaller blood vessels. When present, symptoms can include blueness of hands and feet from the cold, Raynaud’s phenomenon (whiteness and numbness of the fingers and toes from the cold), purpura (purple skin marks), bleeding, ulcers, and gangrene of the fingers and toes. WM patients should be tested for cryoglobulinemia at diagnosis, since it can not only complicate treatment but can also affect the results of other laboratory testing.

Cold agglutinin disease (CAD) is sometimes confused with cryoglobulinemia because both conditions involve antibodies (usually of the IgM-type) that react at lower temperatures. However, the antibodies responsible for cold agglutinin disease are specifically directed against proteins (antigens) found on one’s own red blood cells. It is this characteristic that is responsible for one of CAD’s primary manifestations: hemolytic anemia. Cold agglutinins occur naturally in nearly everyone, but at low levels that seldom cause problems. High concentrations can cause anemia because red blood cells are destroyed faster than the bone marrow can replace them. Clinical signs and symptoms of CAD vary according to the severity of the disease. These may include Raynaud’s phenomenon, painful fingers and toes, anemia, fatigue, shortness of breath, jaundice, and dark urine caused by the presence of hemoglobin. A few of these symptoms, such as Raynaud’s, are similar to those of cryoglobulinemia because both conditions can affect the circulation. Hemolytic anemia is not, however, a consequence of cryoglobulinemia.


Amyloidosis is a group of diseases caused by the buildup of an abnormal protein, called amyloid, in various tissues and organs of the body. The amyloid protein forms abnormal fibers that may injure certain tissues and organs or interfere with their normal function. The protein may be deposited in a localized area or systemically (throughout the body). The most common tissues and organs involved are the kidneys, heart, gastrointestinal tract, peripheral nerves, and liver. Symptoms can vary widely, based on which tissues and organs have the abnormal protein deposits. Clinical signs and symptoms of amyloidosis may be vague, such as weakness, fatigue, weight loss, shortness of breath, abnormal sensations in the feet, enlarged liver and/or spleen, bleeding under the skin, and anemia. More specific signs and symptoms might include swelling of the extremities, an enlarged tongue, carpal tunnel syndrome, food malabsorption, skin thickening, unexplained congestive heart failure, and unexplained kidney failure.

Patients may also have kidney, gastrointestinal, eye, or skin involvement. Bone lesions are uncommon and reported in less than 5% of cases.2 Rarely, tumors with WM-like cells have been reported in the spine, breast, extremities, palate, etc. Another unusual complication of WM is Bing-Neel syndrome, which involves infiltration of the central nervous system (brain and spinal cord) by WM cells and/or IgM deposition, as well as hyperviscosity. Complications of Bing-Neel syndrome may include mental deterioration, confusion, visual disturbances, irritability, personality changes, convulsions, and coma.

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HOW IS WALDENSTROM’S

MACROGLOBULINEMIA DIAGNOSED

AND MONITORED?The diagnosis of WM is made upon demonstration of bone marrow infiltration with lymphoplasmacytic lymphoma cells, the presence of an IgM monoclonal protein regardless of its concentration, and supporting immunophenotypic analysis (flow cytometry or immunohistochemistry) that looks for specific surface proteins, called cluster differentiation (CD) markers, on the lymphoplasmacytic cells of the bone marrow.4 Each type of cancer, including B-lymphocyte cancers such as WM, has its own identifying pattern of CD markers, and this pattern helps to confirm the diagnosis. The typical CD pattern for WM is CD19+, CD20+, CD5-, CD10-, CD22+, CD23-, and CD79+ (+ means the marker is present on the cell, whereas – means it is absent), although some variation from this typical pattern can occur. Laboratory tests of blood, serum, and urine and a bone marrow aspiration and biopsy are used for these determinations. Imaging studies (X-rays, CT scans, and PET scans) of the chest, abdomen, pelvis, and other areas may show evidence of enlarged lymph nodes, enlarged spleen, or soft tissue tumors.

In Table 2 common laboratory tests that may be used to diagnose or monitor WM are listed, as well as normal reference values. Other laboratory tests, such as metabolic panels and liver function studies may also be performed.

It is important to realize that laboratory reference ranges are not nationally standardized and therefore may vary slightly from laboratory to laboratory. Units of measurement used for reporting laboratory values may also vary. Generally speaking, patients should follow the trends of their laboratory test results over time.


All laboratory tests have an inherent degree of imprecision, some more than others, and depend on proper specimen collection, handling, and interpretation for accurate results. If a laboratory test result is in doubt, it should be repeated.

More information on laboratory tests can be obtained from the paper titled “Blood Tests” by Barb Hauser14 and from the IWMF booklet, Medical Tests in Waldenstrom’s Macroglobulinemia Including Glossary of Medical Terms Relating to Tests by Guy Sherwood, MD.15

Blood Test Normal Value WM AbnormalityWhite blood cell (WBC) count

3.5-6.1 million/ mL May be decreased

WBC differential Neutrophils 50%-70% of WBC count May be decreased Bands 0%-4% of WBC count May be decreased Eosinophils 0%-7% of WBC count May be decreased Basophils

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As mentioned above, a bone marrow aspiration and biopsy are absolute requirements to confirm the diagnosis of WM. These procedures typically involve inserting a needle into a bone and removing a piece of bone and some bone marrow, usually from the back of the pelvis (iliac crest). Evaluation of this material under a microscope will demonstrate the lymphoplasmacytic cells characteristic of WM. While a bone marrow aspiration and biopsy are essential for diagnosis, they are generally not used for monitoring because of their invasive nature, except in special circumstances such as a clinical trials protocol.

HOW IS WALDENSTROM’S

MACROGLOBULINEMIA TREATED?There is no known cure for WM. Initiating treatment early in the course of the disease in an asymptomatic patient does not prolong survival; therefore, treatment is delayed until the onset of symptomatic disease. Some patients with increased amounts of IgM or increased numbers of lymphoplasmacytic cells in the bone marrow (measured as % of bone marrow infiltration) may remain stable and continue to be asymptomatic for a long time. Such patients are considered to be on “watch and wait,” which means that their disease status and their health are monitored regularly for changes, sometimes for years, before any treatment is initiated.

Signs and symptoms that may require the initiation of treatment include the following: weakness, fatigue, fever, night sweats, weight loss, bleeding from the nose or gums, blurred vision, bulky (enlarged) lymph nodes, greatly enlarged liver or spleen, hemoglobin less than 10 g/dL, platelets less than 100,000/µL, hyperviscosity, severe peripheral neuropathy, amyloidosis, and symptomatic cryoglobulinemia or cold agglutinin disease.


Available treatment options include chemotherapy; corticosteroids; biologic therapy; immunomodulatory drugs; proteasome inhibitors; radiation; surgical and other procedures such as plasmapheresis, splenectomy, or stem cell transplantation; and newer emerging therapies. The booklet Treatment Options16, written primarily for patients, is available through the IWMF. The booklet Review of Therapy17, written for doctors and scientists by Morie A. Gertz, MD, and also available from the IWMF, includes a complete review of therapy options.

The success of a selected treatment is measured by the degree of disease response to the therapy. “Progressive disease” is characterized by an increase in serum monoclonal IgM of 25% or more and confirmed by a second measurement, or by progression of clinically significant signs or symptoms. “Stable disease” is defined as either less than 25% reduction or a less than 25% increase in serum monoclonal IgM without progression of lymph node or organ enlargement or other clinically significant signs or symptoms. A “minor response” is a reduction in serum monoclonal IgM equal to or greater than 25%, but less than 50%, and no new signs or symptoms of active disease. A “partial response” is a reduction in serum monoclonal IgM equal to or greater than 50%, a 50% decrease in lymph node or organ enlargement on physical examination or on CT scan, and no new signs or symptoms of active disease. A “complete response” is categorized by a disappearance of serum and urine monoclonal IgM, absence of malignant cells in the bone marrow, resolution of enlarged lymph nodes or organs confirmed by CT scan, and no signs or symptoms of disease. Reconfirmation of complete response is required six weeks later.18

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Chemotherapy

One of the most common options used in the treatment of WM is chemotherapy. In Table 3 selected drugs currently used in the treatment of WM are listed. The two main classes of chemotherapy are alkylating agents and nucleoside analogs. Alkylating agents include chlorambucil, cyclophosphamide, and melphalan. Nucleoside analogs include fludarabine, cladribine (also referred to as 2CdA), and pentostatin.

Chlorambucil was historically the most common alkylating agent used in treating WM. Chlorambucil has produced minor and partial responses in 60-70% of patients; however, complete responses are rare. Response to chlorambucil therapy occurs slowly and may take from several months to more than one year. The drug is administered orally either as low-dose, daily therapy or as pulse therapy, which consists of a higher dose administered daily for 7 days and repeated every 6 weeks. The optimal length of chlorambucil therapy is unknown. Treatment is usually administered until the reduction of IgM is maximal and at a stable (plateau) concentration. Treatment is restarted as symptoms warrant. Maintenance therapy with chlorambucil is not recommended because prolonged administration is associated with an increased risk of developing complications such as abnormal or defective formation of bone marrow cells (myelodysplasia) or a secondary leukemia.

Alkylating agents have been used in varying combinations with other drugs, such as nucleoside analogs, vincristine, doxorubicin, corticosteroids, and/or rituximab.


Generic Name (Brand Name)

Dosage Form Possible Side effects

Alkylating AgentsChlorambucil (Leukeran) Tablet Nausea, vomiting, decreased

white blood cell and/or plate-let count, skin rashes

Cyclophosphamide(Cytoxan)

Infusion or tablet

Nausea, vomiting, decreased white blood cell and/or plate-let count

Melphalan (Alkeran) Infusion or tablet

Decreased white blood cell and/or platelet count

Nucleoside AnaloguesFludarabine (Fludara) Infusion or

tabletDecreased white blood cell and/or platelet count, fatigue, neurotoxicity, hemolytic anemia

Cladribine (Leustatin) Infusion Decreased white blood cell and/or platelet count, fatigue, neurotoxicity

Pentostatin(Nipent)

Infusion Nausea, vomiting, skin rashes, decreased white blood cell and/or platelet count, fatigue

Table 3. Selected chemotherapy agents used in the treatment of Waldenstrom’s macroglobulinemia

The nucleoside analogs include fludarabine, cladribine, and pentostatin. Compared with alkylating agents, nucleoside analogs provide patients with response rates of 40-80%,2 but with a more rapid onset of response. Therefore, fludarabine, cladribine, and pentostatin may be the treatment of choice for people who have serious complications and require rapid response. The nucleoside analogs have also been effective in approximately 40% of people who had disease progression on chlorambucil therapy.19 One of the most common side effects with nucleoside analog therapy is suppression of blood cell production by the bone marrow. This

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side effect increases one’s chance of developing an infection. When treatment ceases, blood cell production usually resumes. There is a risk of developing myelodysplasia or secondary leukemia in WM patients treated with nucleoside analogs. There may also be an increased incidence of transformation to a more aggressive lymphoma following treatment with these drugs. If autologous stem cell transplantation is being considered, prior exposure to purine nucleoside analogs is not advisable because of their effect on the ability to procure hematopoietic stem cells.

Nucleoside analogs are often used in varying combinations with other drugs, such as alkylating agents, corticosteroids, and/or rituximab.

Corticosteroids

Although corticosteroids such as prednisone or dexamethasone are rarely used alone in treating WM, they have been administered in combination with other therapies. Corticosteroids or combination alkylating agent-corticosteroid therapy may be beneficial in people who also have or who develop selected hematologic complications that are associated with WM (cryoglobulinemia, cold agglutinin disease, thrombocytopenia).

Biologic Therapy

Biologic therapy is a treatment that causes activation of the body’s own disease fighting systems. Biologic therapies for WM include interferon, alemtuzumab, and rituximab and are listed in Table 4.

Interferon, a hormone-like protein produced by white blood cells to help the immune system fight infections, has been successful in


treating a small number of patients,2 although it is seldom used at present. Studies reported that responses occurred 3-6 months after the start of therapy. Typical side effects included fever, lethargy, anorexia (poor appetite), muscle and joint aches, and bone marrow suppression. Low doses of interferon were better tolerated.

Alemtuzumab (Campath) is a monoclonal antibody therapy that targets the CD-52 antigen that is expressed on WM cells and on mast cells, which are frequently found in association with WM cells in the bone marrow. Initial results indicate that this treatment can be helpful in WM, although toxicity is a problem. More studies are needed.

Rituximab (Rituxan) is a monoclonal antibody therapy targeted against the CD-20 antigen located on many lymphoid cancer cells, as well as on normal B-lymphocytes, and is effective in treating several types of lymphoma. Responses to rituximab therapy alone have been reported in 40-75% of patients with WM, including those who were previously treated with an alkylating or nucleoside analog agent.20 Rituximab is now commonly used as a first-line treatment in WM because it is less toxic than either alkylating agents or nucleoside analogs; it has also been evaluated in combination with these drugs, as well as with some of the emerging therapies. The most typical side effects of rituximab occur during the first infusion of the drug, when patients may experience chills or fever. Subsequent infusions usually cause fewer side effects. If a WM patient with high IgM and/or hyperviscosity elects to undergo rituximab treatment, his physician needs to be aware of a phenomenon known as rituximab “flare,” which causes a rapid but temporary increase in IgM, potentially resulting in increased serum viscosity or other IgM-associated complications.

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Some studies have suggested that maintenance rituximab may prolong response times and even overall survival in patients with certain B-lymphocyte lymphomas. Although protocols vary, typical maintenance consists of a single rituximab infusion every two or three months for up to two years or more following the end of the primary chemotherapy regimen. At present there are no studies that confirm increased response times or overall survival for WM patients.

There are several second and third generation monoclonal antibodies similar to rituximab that also target the CD-20 antigen on B-lymphocytes. As of 2010, a few of these, including ofatumumab (Arzerra), are either still in clinical trials or have been recently approved for some B-lymphocyte cancers; it remains to be seen whether they will be more effective than rituximab or will have fewer infusion-related side effects.

Generic Name (Brand Name)

Dosage Form

Possible Side effects

Interferon alfa (Roferon,Intron)

Injection Flu like symptoms, fever, nausea, vomiting, decreased appetite, diar-rhea, dizziness, decreased blood counts

Alemtuzumab (Cam-path)

Infusion or Injection

Shortness of breath, chills, facial flushing, fatigue, fever, headache, decreased blood pressure, nausea, vomiting, itching, decreased blood counts

Rituximab (Rituxan) Infusion Shortness of breath, chills, facial flushing, fatigue, fever, headache, decreased blood pressure, nausea, vomiting, itching

Table 4. Selected biologic agents used in the treatment of Waldenstrom’s macroglobulinemia


Immunomodulatory Drugs

Immunomodulatory drugs kill tumor cells by four described mechanisms of action: they starve the tumor cells by inhibiting the development of blood vessels that feed them (anti-angiogenic effect); they enhance the tumor killing properties of T-lymphocytes and natural killer cells; they block some of the interactions between tumor cells and other cells in the bone marrow environment; and finally they appear to directly kill tumor cells by a mechanism not yet fully understood. The best known immunomodulatory drug is thalidomide (Thalomid) which was originally developed in the 1950s as a sedative but was removed from the market when it was discovered to be responsible for birth defects. It was subsequently found to be effective in the treatment of multiple myeloma, a disease closely related to WM. It has shown promise when used in combination with other drugs, but its major side effects are constipation and peripheral neuropathy. Several newer thalidomide-type drugs have been developed, such as lenalidomide (Revlimid) and pomalidomide (Actimid). These are expected to be as effective as thalidomide but with fewer side effects.

Proteasome Inhibitors

Bortezomib (Velcade) is the first of a new class of drugs called proteasome inhibitors. Proteasomes are large protein complexes present in all cells that help regulate cell growth and death. When proteasomes are inhibited with bortezomib, many types of cancer cells, including those common to lymphoma and multiple myeloma, undergo apoptosis (cell death). Normal non-cancerous cells appear better able to tolerate the drug without significant difficulties. Side effects such as peripheral neuropathy, temporary bone marrow

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suppression, and constipation have occurred with bortezomib. Clinical trials using modified dosing schedules have greatly reduced the incidence of peripheral neuropathy. Bortezomib has also been combined with other therapies such as rituximab, leading to better responses. Carfilzomib is a newer proteasome inhibitor currently being evaluated in clinical trials, and oral proteasome inhibitors are also being developed.

Radiation Therapy

Radiation therapy has been used in WM, primarily for the selective and targeted reduction of enlarged lymph nodes and in the uncommon instances of tumors developing in other sites such as the spine. Total body irradiation is not used in the management of WM.

Surgical and Other Procedures

Procedures that have been used include plasmapheresis, splenectomy, and stem cell transplantation.

Plasmapheresis involves removal of blood from the body, separation of the liquid (plasma) portion from blood, replacement of plasma (usually with albumin and sodium chloride solutions), and return of the remaining blood components to the body. Plasmapheresis can be thought of as a form of dialysis where the primary aim is the “filtering out” or removal of IgM from the circulation. Plasmapheresis is widely used to reduce the symptoms associated with hyperviscosity syndrome. In general, plasmapheresis is initiated just prior to or concurrent with chemotherapy; however, some patients have been treated successfully with only


plasmapheresis, particularly if they cannot tolerate more toxic therapies. If performed alone, plasmapheresis must be repeated frequently to maintain acceptable IgM levels because the procedure has no effect on the growth and survival of WM cells.

Surgical removal of the spleen (splenectomy) has been effective in reducing the IgM concentration for select cases after failure of chemotherapy because the spleen is a major source of IgM-producing cells. Splenectomy is usually considered only to relieve symptoms of a significantly enlarged spleen and certain blood count abnormalities, particularly the case of low platelets (thrombocytopenia).

Stem cell transplants are feasible in WM. Preliminary data suggest that a larger number of complete responses have been obtained with stem cell transplant than with standard chemotherapy, although there are serious side effects associated with transplantation.

Autologous stem cell transplantation reinfuses a patient’s own stem cells collected before he has undergone high-dose chemotherapy to destroy the tumor cells in the bone marrow. Allogeneic stem cell transplantation uses donor stem cells from either a family member (usually) or an unrelated individual. A newer type of allogeneic stem cell transplant, called non-myeloablative or “mini-allo” transplant does not completely clear the recipient’s bone marrow before infusion of the stem cells; it is believed that the donor stem cells will recognize any remaining tumor cells in the marrow as foreign and destroy them. Mini-allo transplant is less toxic than a regular allogeneic transplant and recovery time tends to be less.

The major toxicities of stem cell transplantation occur because the patient’s immune system is severely depressed during the procedure and for some time afterward. Because an allogeneic transplant

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uses donor stem cells, there is also a risk of serious complications from graft vs. host disease (GVHD), which occurs when the donor’s immune cells see the host’s cells as foreign and attack them. Graft vs. host disease can be acute or chronic. Both forms bring with them an increased risk of infections, either because of the process itself or its treatment with immunosuppressive drugs.

While autologous stem cell transplantation is used more frequently in WM, allogeneic stem cell transplantation for WM is usually recommended only in the context of a clinical trial or in cases where aggressive disease is not responding to other treatment.

Approach to Therapy

Initiation of therapy should not be based on IgM levels alone, and asymptomatic patients should be monitored on a regular basis.

Individual patient considerations need to be considered when deciding on a first-line treatment – these include the presence of low blood counts, need for rapid disease control, age, overall general health, and possibility for future autologous stem cell transplantation. Single-agent rituximab therapy may be the preferred initial treatment for most patients with WM. Certain patients with low-risk disease may be candidates either for single-agent rituximab or for single-agent chlorambucil therapy because of associated health problems. The presence of low blood counts and relatively low levels of IgM may favor rituximab, whereas slow progression and older age may favor the use of chlorambucil. When rapid disease control is needed, the addition of cyclophosphamide to rituximab or the combination of rituximab with a nucleoside analog, with or without cyclophosphamide, may also be appropriate.


The choice of therapy after relapse is also dependent on several factors. Reuse of a first-line single agent therapy or combination is reasonable if a patient achieved a response that lasted for 12 months or more; otherwise, use of an alternate single agent or combination is recommended. It is clear, however, that combination therapies using two or more agents are more effective than single-agent therapies.

The use of stem cell transplantation in WM requires a more extensive evaluation and selection of individual patients, focusing primarily on patients with high-risk disease or on young patients with aggressive disease.21

WHAT ARE CLINICAL TRIALS? ARE THERE

ANY FOR WALDENSTROM’S MACRO-

GLOBULINEMIA?Clinical trials are research studies designed to answer questions about diseases and new ways to treat diseases. Several different types of clinical trials for cancer are available, including treatment, prevention, screening, and quality-of-life or supportive care trials. Treatment trials are designed to evaluate new treatments such as new drugs or new combinations of drugs. Prevention trials are designed to evaluate ways of lowering the risk of developing cancer. Screening trials find the best way of diagnosing cancer. Finally, quality-of-life and supportive care trials identify ways of improving the comfort and quality of life of cancer patients.

Clinical trials for cancer treatment are conducted in four phases. Phase I trials are the first step in testing a new treatment in humans. Researchers evaluate what dosages are safe, how new agents

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should be administered (by mouth, infusion into a vein, injection subcutaneously or into a muscle) and how often the drugs are to be given to the patient. Researchers primarily monitor harmful side effects. The dose of the new therapy or technique is increased a little at a time. The highest dose with an acceptable level of side effects is determined to be appropriate for further testing. Phase I trials usually include only a limited number of patients and are often carried out at a few large academic medical centers.

Phase II trials attempt to determine whether the new agent or technique works for a specific type of cancer and continue to study its safety and effectiveness.

Phase III trials compare the treatment outcomes of patients taking the new therapy with results of people taking standard treatment. Participants are randomly assigned to the standard (also called control) group or to the new treatment group. This method, called randomization, helps to avoid bias and ensures that human choices or other factors do not affect the study’s results. In most cases, studies move into Phase III testing only after they have shown promise in Phases I and II. Phase III trials often include large numbers of participants.

Phase IV trials occur after a treatment has been approved and is being marketed. The drug’s maker may study it further to evaluate the side effects, risks, and benefits over a longer period of time and in a larger number of people than in Phase III clinical trials. Because of the small WM patient population, Phase III and Phase IV trials for the disease are very uncommon.

Placebos or “sugar pills” are not normally used in cancer trials. The details of the clinical trial, including the advantages, disadvantages, and possible treatment-related side effects, must be understood by


the participant before he or she enrolls in a clinical trial. A person enrolled in a clinical trial can withdraw from the trial at any time without penalty.

Cancer clinical trials change frequently. A trial will be stopped after enough people are enrolled to answer the research question. The results of one trial may lead to a new question that necessitates a new trial. For example, a new drug may show promise in one condition and merit testing in a related condition. Therefore, it is important to obtain the most current information from resources that are routinely updated. General information on clinical trials and specific information on clinical trials enrolling people with WM can be found on the IWMF website at www.iwmf.com, at the National Cancer Institute’s Cancer Trials website at www.cancer.gov/clinical_trials, or from the National Institutes of Health website at www.clinicaltrials.gov.

WHAT ARE SOME OF THE EMERGING

THERAPIES?A number of new regimens and therapies are currently being studied, a few of which will be covered here. It remains to be seen how these will become part of the treatment protocol for WM in the future.

Radioimmunotherapy combines a monoclonal antibody, such as rituximab or similar agent, with a radioactive particle, called a radioisotope. This radioisotope-antibody targets and binds to the CD-20 antigen present on B-lymphocytes, delivering a dose of radiation to the targeted cells. Two such radioimmunotherapy treatments are called Zevalin and Bexxar. Very good results have been achieved from using these treatments in certain lymphomas,

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including a significant number of complete responses. The difficulty in using these agents is that patients who have extensive bone marrow involvement may not be able to receive them without resulting in significant suppression of the bone marrow – the radioactive particles also destroy surrounding normal bone marrow cells.

Bendamustine (Treanda) shares characteristics of both an alkylating agent and a nucleoside analog. Although it was developed in Germany in the 1960s, it has only recently been approved for use in chronic lymphocytic leukemia and in follicular lymphoma that is resistant to treatment with rituximab. It is being used for WM by some investigators, primarily in Europe.

There are several molecular signaling pathways in B-lymphocytes that can influence cell growth and survival. Some of these may be over- or under-expressed in malignant cells, and this abnormal expression can impact the development and growth of malignant cells. Several new agents that alter these signaling pathways, among them enzastaurin, Everolimus (RAD001), perifosine, oblimersen sodium (Genasense), and certain histone deacetylase inhibitors (HDACs), are in the process of being tested in WM patients.

Vaccine therapy is currently in development for other types of B-lymphocyte lymphomas. These lymphomas develop on their surfaces certain molecules that distinguish them from healthy cells. A vaccine is created specifically for an individual patient from the patient’s own tumor cells and is designed to mobilize the patient’s immune system to attack the malignant cells. A vaccine is typically administered following treatment designed to minimize the disease. After a rest period the vaccine is administered. The goal is to prevent recurrence or at least to extend the response time.


WHAT OTHER RESOURCES ARE

AVAILABLE?In addition to this booklet, information on living with cancer (and more specifically with WM) can be obtained from several organizations and on the Internet. The following list is a sampling of available resources. Information can also be obtained from cancer treatment facilities and healthcare professionals.

Organizations

International Waldenstrom’s Macroglobulinemia Foundation

The International Waldenstrom’s Macroglobulinemia Foundation (IWMF) is a nonprofit organization founded in 1994 by Arnold Smokler. The IWMF provides numerous services for people with WM including patient and caregiver support groups, dissemination of information, and promotion of research. The IWMF distributes information to members through newsletters, handbooks, annual conferences, conference tapes, and the Internet. Membership in the IWMF is based on voluntary contributions that support the administration, outreach, and education programs of the Foundation.

International Waldenstrom’s Macroglobulinemia Foundation 6144 Clark Center Avenue Sarasota, FL 34238 Telephone number: 941-927-4963 Email address: [email protected] Internet address: www.iwmf.com

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Waldenstrom’s Macroglobulinemia Foundation of Canada

The Waldenstrom’s Macroglobulinemia Foundation of Canada (WMF Canada) is the Canadian chapter of the IWMF. Members of WMF Canada are automatically also members of the IWMF. The group was formed in order to support WM research, to provide support to patients and caregivers, and to issue tax receipts for contributions that are deductible for income tax purposes by Canadian taxpayers.

Waldenstrom’s Macroglobulinemia Foundation of Canada 260 Dalewood Drive Oakville, ON L6J 4P3 Canada Telephone number: 905-337-2455 Internet address: www.WMFC.ca

Lymphoma Research Foundation

The mission of the Lymphoma Research Foundation (LRF) is to eradicate lymphoma and serve those touched by the disease.

Lymphoma Research Foundation 8800 Venice Blvd., Suite 207 Los Angeles, CA 90034; and 115 Broadway, 13th Floor New York, NY 10006 Telephone numbers: CA 800-500-9976; and NY 800-235-6848 Internet address: www.lymphoma.org


The Leukemia & Lymphoma Society

The mission of The Leukemia & Lymphoma Society (LLS) is to cure leukemia, lymphoma, and myeloma and improve the lives of patients and their families.

The Leukemia & Lymphoma Society 1311 Mamaroneck Avenue, Suite 310 White Plains, NY 10605 Telephone number: 800-955-4572 Internet address: www.leukemia-lymphoma.org

American Cancer Society

The American Cancer Society (ACS) is a nationwide community-based organization. The American Cancer Society provides information on specific cancers and general information on coping with a cancer diagnosis. Information is available both for people with cancer and for their families and friends.

American Cancer Society 1599 Clifton Road NE Atlanta, GA 30329 Telephone number: 800-ACS-2345 Internet address: www.cancer.org

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National Coalition for Cancer Survivorship

The National Coalition for Cancer Survivorship (NCCS) is a patient-led organization dedicated to assuring quality cancer care for all Americans. The NCCS works for people with all types of cancer and their families. The NCCS provides information on living with and surviving a cancer diagnosis.

National Coalition for Cancer Survivorship 1010 Wayne Avenue, Suite 770 Silver Spring, MD 20910 Telephone number: 888-650-9127 Email address: [email protected] Internet address: www.canceradvocacy.org

National Cancer Institute

The National Cancer Institute (NCI) is one part of the National Institutes of Health. The National Cancer Institute is the federal government’s principal agency for cancer research and training. The National Cancer Institute provides information on many topics, including specific types of cancer, prevention of cancer, genetic predisposition to cancer, and coping with cancer.

NCI Public Inquiries Office 6116 Executive Boulevard Room 3036A, MSC8322 Bethesda, MD 20892-8322 Telephone number: 800-422-6237 Internet address: www.cancer.gov


Canadian Cancer Society

The Canadian Cancer Society is a community-based organization of volunteers whose mission is the eradication of cancer and enhancement of the quality of life of Canadians living with cancer.

Canadian Cancer Society National Office Suite 200, 10 Alcorn Ave. Toronto, Ontario M4V 3B1 Telephone number: 416-961-7223 Internet address: www.cancer.ca

European CanCer Organization

The European CanCer Organization (ECCO) is an umbrella organization campaigning on political issues such as equitable access to treatment and organizes a biennial series of congresses for cancer researchers and healthcare professionals.

ECCO – the European CanCer Organisation Avenue E. Mounier 83 B-1200 Brussels Belgium Telephone number: +32 2 775 02 01 Internet address: www.ecco-org.eu

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The Cancer Council Australia

The Cancer Council Australia is a national, non-profit organization which aims to promote cancer-control policies and to reduce the illness caused by cancer in Australia.

Cancer Council Australia GPO Box 4708, Sydney NSW 2001 Level 1, 120 Chalmers St. Surry Hills NSW 2010 Telephone number: +61 2 8063 4100 Internet address: www.cancer.org.au

Internet Websites

www.cancerindex.org – This site was established in 1996 and provides a directory of key websites for people with cancer and their families and caregivers. Information is also provided for healthcare professionals, scientists, and others interested in learning about cancer.

www.nlm.nih.gov – The National Library of Medicine website provides access to various types of health information for both healthcare professionals and consumers. PubMed contains references and abstracts from biomedical journals that can be searched for information on specific diseases and treatments. Medline Plus has excellent health information for consumers.

www.cancer.gov/clinical_trials and www.clinicaltrials.gov – These two websites provide general and specific information on clinical trials. Both sites can be searched for clinical trials currently enrolling people with WM.


GLOSSARYAlbumin – the most abundant plasma protein, it is produced in the liver and is important in regulating blood volume and carrying molecules such as hormones, fatty acids, calcium, and certain drugs.

Alkylating agent – a chemotherapeutic compound such as chlorambucil or cyclophosphamide that damages DNA and blocks cell division.

Amyloidosis – a group of diseases caused by the buildup of an abnormal protein, called amyloid, in various tissues and organs of the body. The amyloid protein forms abnormal fibers that may injure certain tissues and organs or interfere with their normal function.

Antibody – another name for immunoglobulin.

B-lymphocyte – a type of white blood cell that manufactures immunoglobulin and develops into a plasma cell when a foreign substance is detected.

Basophil – a type of white blood cell that is involved in allergic reactions.

Beta-2 microglobulin – a protein found on all cells with a nucleus; it is frequently elevated in people with multiple myeloma and lymphoma.

Bing-Neel syndrome – a condition that involves infiltration of the central nervous system (brain and spinal cord) by WM cells and/or IgM deposition, as well as hyperviscosity; complications of Bing-Neel syndrome may include mental deterioration, confusion, visual disturbances, irritability, personality changes, convulsions, and coma.

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Chronic lymphocytic leukemia – the most common type of leukemia, this is a cancer of B-lymphocytes that usually occurs in adults and is characterized by increased numbers of B-lymphocytes in the blood.

Cold agglutinin disease – a condition resulting from antibodies (usually of the IgM-type) that react at lower temperatures; these antibodies are specifically directed against proteins (antigens) found on one’s own red blood cells and can cause anemia, among other symptoms.

Cryoglobulinemia – a condition characterized by antibodies that precipitate at temperatures below body temperature and then re-dissolve upon warming; it is most often due to unknown causes but may in some cases be associated with an underlying disease such as WM; signs and symptoms are due to obstruction of small blood vessels in the extremities and include whiteness, numbness, bleeding, ulcers, and gangrene.

Doxorubicin – a drug used in cancer chemotherapy that blocks cell division; it is known by the trade name Adriamycin.

Eosinophil – a type of white blood cell that is involved in allergic reactions and is responsible for combating parasites.

Flow cytometry – a process in which an instrument uses a laser beam to scatter light from cells as they pass through a liquid in the instrument’s chamber; the laser beam light bounces off each cell, is picked up by detectors, and provides information about the cell’s characteristics, such as size and inner structure; flow cytometers can also use antibodies tagged with fluorescent stains that bind to specific antigens on the cell surfaces - in the case of leukemias and lymphomas, these fluorescent-tagged antibodies bind with and identify protein surface markers on the immune cells.


Follicular lymphoma – one of the most common indolent (slow-growing) non-Hodgkin’s lymphomas, characterized by enlarged lymph nodes.

Graft vs. host disease – a complication that can occur following allogeneic stem cell transplant (using stem cells from a donor); the donor’s immune cells see the recipient’s cells as foreign and can make antibodies against them, causing a variety of symptoms.

Hematopoiesis – the process of blood cell development.

Hemolytic anemia – anemia due to hemolysis, which is the abnormal breakdown of red blood cells either in the blood vessels or elsewhere in the body.

Hyperviscosity syndrome – occurs as a result of increased IgM concentration; signs and symptoms include chronic bleeding from the nose, gums, gastrointestinal tract, headache, ringing in the ears (tinnitus), dizziness (vertigo), impaired hearing, blurring or loss of vision, sausage-shaped veins in the retina, and swelling of the optic disk at the back of the eye (papilledema).

IgM - an antibody that is produced by B-lymphocytes; it is the largest antibody and the first one to appear in response to initial exposure to antigen.

Immunoglobulin – a protein produced by B-lymphocytes and plasma cells in response to a foreign substance or antigen; the classes of immunoglobulins are IgA, IgD, IgE, IgG, and IgM; these are also referred to as antibodies.

Immunohistochemistry – refers to the use of special stains to identify antigens (eg. proteins) in the cells of a tissue section for purposes of identification, exploiting the principle that (labeled) antibodies bind specifically to antigens; immunohistochemical staining is widely used in the diagnosis of abnormal cells such as those found in cancerous tumors.

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Immunophenotypic analysis – a method for dividing lymphomas and leukemias into subgroups on the basis of differences in cell surfaces and antigens. These differences are detected with monoclonal antibodies and flow cytometry.

Leukemia – a cancer of the blood or bone marrow, characterized by an abnormal number of circulating blood cells, usually white blood cells; it is a broad term covering a spectrum of such diseases.

Lymphocyte – a type of white blood cell, either B-lymphocyte, T-lymphocyte, or natural killer cell.

Lymphoma – a cancer of the lymphocytes.

Lymphoplasmacytic – cancer cells which have characteristics of both B-lymphocytes and plasma cells.

Macrophage – a type of white blood cell, found in the tissues, that engulfs foreign substances and helps to stimulate the immune response.

Maintenance therapy – a treatment given at regular intervals after a disease has responded to previous treatment; maintenance therapy is given in order to help prevent spread or recurrence of the tumor.

Monoclonal – a group of cells, produced from a single ancestral cell by repeated reproduction, that share the characteristics of the original cell.

Monoclonal antibody therapy – the use of antibodies that specifically bind to a target on cells in order to stimulate the patient’s immune system to attack those cells.

Monoclonal gammopathy of undetermined significance (MGUS) – an overproduction of one clone of B-lymphocytes or plasma cells that produce an immunoglobulin; IgM MGUS is associated with an increased risk of developing WM.


Monocyte – a type of white blood cell that circulates in the blood and can develop into a macrophage when it moves into tissues.

Multiple myeloma – cancer of the plasma cells; most commonly the cancerous clone produces immunoglobulin IgG, IgA, or only light chains (kappa or lambda) of these immunoglobulins.

Myelodysplasia – a group of related disorders of the bone marrow characterized by low numbers of abnormally developed blood cells; myelodysplasia can precede the development of acute leukemia.

Natural killer cell – a type of lymphocyte that directly kills tumor cells and virus-infected cells by enzymes contained in granules found in its cytoplasm.

Neutrophil – the most abundant type of white blood cell and one of the first responders to infection; it is the predominant cell in pus.

Nucleoside analog – part of a larger class of anti-cancer drugs termed antimetabolites, which act specifically on proliferating cells; also known as purine analogs.

Paraprotein – another term for monoclonal immunoglobulin.

Peripheral neuropathy – a fairly common manifestation of WM, usually caused by the targeting of antigens on the nerve coating (myelin) by the circulating IgM; clinical features are predominantly sensory, with abnormal sensations (paresthesias) such as burning, prickling, itching, tingling, or numbness that are symmetric and usually first noticed in the feet but can progress to the hands and arms.

Plasma cell – a cell that develops from B-lymphocytes upon recognition of a foreign substance or antigen; plasma cells secrete antibodies to eliminate the foreign substance or antigen.

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Plasmapheresis – a procedure that involves removal of blood from the body, separation of the liquid (plasma) portion from blood, replacement usually with albumin and sodium chloride solutions, and return of the remaining blood components to the body.

Platelet – a type of blood cell that helps stop bleeding.

Prognosis – a prediction of the course of a disease and its outcome.

Proteasome inhibitor – binds to the core of a cell structure called a proteasome and blocks its enzyme activity, thus interfering with its ability to degrade proteins; disruption of this normal protein breakdown process allows certain proteins in the cell to accumulate to the point where they can interfere with cell reproduction and other functions and lead to cell death.

Red blood cell (RBC) – a type of blood cell that contains hemoglobin and carries oxygen from the lungs to other areas of the body.

Splenectomy – surgical removal of the spleen.

Stem cell transplantation – a procedure used to restore properly functioning bone marrow by intentionally destroying the patient’s diseased bone marrow through chemotherapy and/or radiation and replacing it with stem cells derived from the patient or a donor.

T-lymphocyte – a type of white blood cell that matures in the thymus gland.

Thrombocytopenia – decrease in the number of platelets.

Transformation – the development of a more aggressive lymphoma in a patient with an indolent or slow growing lymphoma; this may occur over time as the cancerous B-lymphocytes acquire additional mutations that cause the disease characteristics to change; some studies suggest that certain chemotherapy treatments can also cause transformation.


Vincristine – a drug used in cancer chemotherapy that blocks cell division; it is known by the trade name Oncovin.

White blood cell (WBC) – a type of blood cell that eliminates foreign substances or antigens from the body; B-lymphocytes, basophils, eosinophils, macrophages, monocytes, neutrophils, natural killer cells, and T-lymphocytes are types of white blood cells.

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18. Kimby E, Treon SP, Anagnostopoulos A, Dimopoulos M, Garcia-Sanz R, Gertz MA, Johnson S, LeBlond V, Fermand J-P, Maloney DG, Merlini G, Morel P, Morra E, Nichols G, Ocio EM, Owen R, Stone M, Blade Joan. Update on recommendations for assessing response from the Third International Workshop on Waldenstrom’s Macroglobulinemia. Clinical Lymphoma & Myeloma 2006; 6(5):380-383.

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QUESTIONS & ANSWERSszpiczak.org/.../makroglobulinemia_waldenstroma/... · Waldenstrom’s macroglobulinemia (WM) is a rare white blood cell cancer defined by the World Health Organization