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Non-Hodgkin Lymphoma
A Guide for Patients, Survivors and Loved Ones
Third Edition
Understanding
Non-Hodgkin Lymphoma
A Guide for Patients, Survivors and Loved Ones
3rd Edition
This guide is an educational resource compiled by the Lymphoma Research Foundation providing general information on non-Hodgkin lymphoma. Publication of this information is not intended to take the place of medical care or the advice of your doctor. Patients are strongly encouraged to talk to their physicians for complete information on how their disease should be diagnosed, treated and followed. Before starting treatment, patients should discuss the potential benefits and side effects of cancer therapy.
National Headquarters 115 Broadway, 13th Floor New York, NY 10006 (212) 349-2910 phone (212) 349-2886 fax Helpline: (800) 500-9976 Helpline@lymphoma.org Website: lymphoma.org Email: LRF@lymphoma.org
This patient guide is supported through unrestricted educational grants from:
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ACKNOWLEDGMENTS
The Lymphoma Research Foundation wishes to acknowledge those individuals listed below who have given generously of their time and expertise. We thank them for their contributions, editorial wisdom and advice, which have truly enhanced this publication. The chairman and senior advisors guided the content and development of this publication. Without their dedication and efforts this publication would not have been possible. We hope those in the lymphoma community will now be better informed and have a better understanding of their illness because of the gracious efforts of those involved in the planning and execution of this comprehensive disease guide.
Editorial Board Steering Committee Chairman Morton Coleman, MD, Weill Cornell Medical CollegeNew York Presbyterian Hospital Senior Advisors Stephanie A. Gregory, MD, Rush University Medical Center Jennifer Mills, LMSW, MPH, Lymphoma Research Foundation Owen A. OConnor, MD, PhD, New York University Cancer Institute
Review Committee Carolyn Bell, MSW, Santa MonicaUCLA Medical Center Richard Boyajian, RN, MSN, APN, Dana-Farber Cancer Institute Jennifer Brown, MD, PhD, Dana-Farber Cancer Institute Bruce D. Cheson, MD, Georgetown University Hospital Joseph Connors, MD, British Columbia Cancer Agency Richard I. Fisher, MD, University of Rochester Medical Center, James P. Wilmot Cancer Center Anna Franklin, MD, MD Anderson Cancer Center Jonathan Friedberg, MD, University of Rochester Medical Center Richard R. Furman, MD, Weill Cornell Medical CollegeNew York Presbyterian Hospital Les Gallo-Silver, ACSW, LCSW-R, LaGuardia Community College, CUNY Randy Gascoyne, MD, British Columbia Cancer Agency Irene Ghobrial, MD, Dana-Farber Cancer Institute
Review Committee (continued) Leo I. Gordon, MD, Northwestern University Andre Goy, MD, Hackensack University Medical Center Thomas M. Habermann, MD, Mayo Clinic College of Medicine John Hainsworth, MD, Sarah Cannon Research Institute Steven Horwitz, MD, Memorial Sloan-Kettering Cancer Center Elaine Jaffee, MD, National Cancer Institute Rebecca H. Johnson, MD, Seattle Childrens Judy Jones, LPC, Cutaneous Lymphoma Foundation John P. Leonard, MD, Weill Cornell Medical CollegeNew York Presbyterian Hospital Craig Lustig, MPA, Childrens Cause for Cancer Advocacy Ralph Meyer, MD, National Cancer Institute of Canada and Queens University Thomas P. Miller, MD, University of Arizona, Arizona Cancer Center Joanna Morales, Esq, Cancer Legal Resource Center John M. Pagel, MD, PhD, Fred Hutchinson Cancer Research Center Lauren Pinter-Brown, MD, UCLA Medical Center Oliver W. Press, MD, PhD, Fred Hutchinson Cancer Research Center Kanti Rai, MD, Long Island Jewish Medical Center Andrei Shustov, MD, Fred Hutchinson Cancer Research Center Sonali Smith, MD, The University of Chicago David Straus, MD, Memorial Sloan-Kettering Cancer Center James Testaverde, BS, Lymphoma Research Foundation Brian Tomlinson, MPA, BSW, Lymphoma Research Foundation Julie Vose, MD, University of Nebraska Medical Center Tim Walker, MA, National Marrow Donor Program Kathleen Wesa, MD, Memorial Sloan-Kettering Cancer Center Michael Williams, MD, University of Virginia School of Medicine Teresa Woodruff, PhD, Northwestern University Anas Younes, MD, MD Anderson Cancer Center Bradley Zebrack, PhD, MSW, MPH, University of Michigan School of Social Work Andrew Zelenetz, MD, PhD, Memorial Sloan-Kettering Cancer Center Contributing Medical Writer: Jo Cavallo
TAbLE Of CONTENTS
Part I: Learning the basics
Chapter 1 Overview of Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-Hodgkin Lymphoma Overview. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Causes of Non-Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Common Types of Non-Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2 6 7
Chapter 2 Signs and Symptoms of Non-Hodgkin Lymphoma. . . . . . . . . . . . . . . . . . . . . . . 17 When to Seek Medical Attention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 What the Doctor Looks For. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Chapter 3 Getting a Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Common Diagnositic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Grading and Staging Non-Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . Getting a Second Opinion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Choosing an Oncologist and Treatment Center . . . . . . . . . . . . . . . . . . . . . . . . . . 19 19 25 26 27
Chapter 8 fertility Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 How to Protect Fertility in Men . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 How to Protect Fertility in Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
83 83 84 84
Part
Chapter 1
Overview of Cancer
Our bodies consist of millions of cells that grow and divide in an orderly fashion and work in harmony to support thousands of biological functions. The cells divide only when it is necessary to replace worn-out or dying cells. Cancer is a group of diseases that develop as the result of the uncontrolled growth and spread of abnormal cells. Cancer cells are different from normal cells because instead of dying in an orderly fashion, they continue to grow and divide, forming new abnormal cells. Cancer cells develop when there is damage to the DNA, the hereditary material found in every cell, that is caused either by inherited DNA cell abnormalities and/or exposure to something in the environment, such as smoking. Usually the body is able to destroy these damaged cells, but when the bodys natural defense systems do not work sufficiently, these abnormal cells may grow in an uncontrollable fashion, eventually forming a cancerous tumor.
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The Immune System
Non-Hodgkin lymphoma is a cancer of the lymphocytes, which play a vital role in the immune system. The immune system is one of the bodys major defenses against disease. It is made up of highly specialized cells and a circulatory system separate from blood vessels, called the lymph system. The cells of the immune system work together to rid the body of foreign invaders, such as bacteria and viruses, before they can harm the body. These invading organisms are generally detected by the immune system through proteins called antigens that are located on the surface of all cells, including both normal and germ cells. Special receptors located on the immune cells lock onto these antigens. And just as a lock will only close with the right key, an immune cell can only lock onto an antigen if it has a specific receptor on its cell surface. When an antigen and an immune cell lock together, the immune response begins, and the body acts to destroy, remove or wall off the foreign invaders or affected cells.
Spleen
bone marrow
Bacteria
Viruses
Parasites
Fungi
Pollution
Toxins
foreign cells and act quickly to destroy them. There are two main types of lymphocytes: B-lymphocytes and T-lymphocytes. B-lymphocytes develop into cells called plasma cells, which make specific proteins called antibodies. Antibodies recognize and lock onto specific antigens. They circulate in the blood and react with toxins, bacteria and some cancer cells and act like biologic guided missiles homing in on only those antigen targets they have been programmed to attack on the surface of the cell. The body can then identify and remove these unwanted substances. However, some invaders can avoid B-lymphocytes by growing inside the bodys cells and that is where T-lymphocytes play a role. They sense when the bodys own cells have become infected and destroy them directly. T-lymphocytes help the body fight viral infections, tuberculosis and fungal infections and may play a role in destroying abnormal or cancerous cells. After an invader has been destroyed, surviving B-lymphocytes and T-lymphocytes develop into specialized memory cells that remain on watch in the lymph nodes, waiting to be reactivated if and when a particular antigen is encountered again. These memory cells act as guards that are always on the lookout to prevent specific invaders from spreading in the body. The body has a complicated system of checks and balances to keep the number of lymphocytes in balance.
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have been infected with viruses such as Epstein-Barr (which causes mononucleosis), human T-lymphotropic virus type 1 (HTLV-1), HIV/AIDS, hepatitis C or certain bacteria such as H.pylori However, it is important to note that having one or more of these risk factors does not mean you will develop NHL. In fact, most people with risk factors never develop the disease, and most of those diagnosed with lymphoma have never been exposed to clearly identifiable risk factors. While they do not know why NHL develops, they do know that it cannot be caused by injury or caught from someone who has the disease.
Follicular Lymphoma
Follicular lymphoma is a relatively common lymphoma, making up between 20 percent and 30 percent of all NHLs, and typically occurs in middle-aged and older adults, but it can affect younger people in their 30s and 40s. Follicular lymphoma is typically slow-growing and arises from B-lymphocytes, making it one of the B-cell lymphomas. Follicular lymphoma usually appears in lymph nodes throughout the body. They arise in the germinal center or follicle of the lymph node. Often, the first sign of follicular lymphoma is a painless swelling in the neck, armpit or groin caused by enlarged lymph nodes. Because follicular lymphoma is a common indolent lymphoma, it is often used as a model for the treatment of other slow-growing lymphomas. Follicular lymphoma may eventually transform into a more aggressive form of the disease, often referred to as histologic transformation. As with most indolent lymphomas, people with follicular NHL usually will present with disease in many parts of the body, including the bone marrow.
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known as a lymphocyte, is involved in both CLL and SLL. The only difference between the two diseases is where the cancer primarily occurs. When the cancer cells are located mostly in the lymph nodes, the disease is called SLL. When most of the cancer cells are located in the bloodstream and the bone marrow, the disease is referred to as CLL, although the lymph nodes and spleen are often involved as well. Thinking of CLL/SLL as a lymphoma and not a form of leukemia is important because CLL has a clinical course and treatment regimen that is similar to other indolent lymphomas. Chronic lymphocytic leukemia tends to be a slow-growing cancer. However, over time, it can progress to a more aggressive type of lymphoma. The staging system for CLL is different from the staging system applied to other NHLs. For a more detailed description of CLL, visit cllinfogroup. org or request a copy of the Lymphoma Research Foundations publication entitled Understanding CLL/SLL: A Guide for Patients, Survivors and Loved Ones.
chronic inflammation is associated with Helicobacter pylori (H. pylori), a microbial pathogen linked to chronic gastritis sometimes, MALT lymphomas can be treated with antibiotics Different infections have also been implicated in other forms of MALT lymphoma. Hepatitis C has been associated with splenic marginal zone lymphoma. Nodal marginal zone B-cell lymphomas are uncommon and are sometimes called monocytoid B-cell lymphomas.
Waldenstroms Macroglobulinemia
Waldenstroms macroglobulinemia (also known as lymphoplasmacytic lymphoma or immunocytoma) is a rare B-cell lymphoma that occurs in less than two percent of people with NHL. There are about 1,500 new cases of Waldenstroms each year. The disease usually affects older adults and is primarily found in the bone marrow, although lymph nodes may sometimes be involved. Waldenstroms is characterized by a high level of a protein called immunoglobulin M (IgM) in the blood. These high levels of IgM can cause a thickening of the blood, resulting in symptoms such as nosebleeds, headaches, dizziness and blurring or loss of vision. For more information, visit the International Waldenstroms Macroglobulinemia Foundation (iwmf.com).
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fusion proteins, interferon, systemic chemotherapy and histone deacetylase inhibitors). A common topical retinoid used to treat cutaneous lymphomas is bexarotene (Targretin). Denileukin diftitox (Ontak) is a commonly used fusion protein. Within recent years, new treatment options have emerged specifically for T-cell lymphomas, including romidepsin (Istodax) and vorinostat (Zolinza). Numerous other agents are being investigated in clinical trials, as well as more effective ways to deliver current treatments. Patients with cutaneous lymphoma may be treated by dermatologists, radiation oncologists, medical oncologists or a combination. For more detailed information on cutaneous lymphoma disease-specific biology and treatment options, please contact the Cutaneous Lymphoma Foundation (clfoundation.org).
lymphoma may initially follow an indolent, or slow-growing, course but may transform early into an aggressive disease and is, therefore, often treated as an aggressive lymphoma. In general, it is currently incurable with standard approved therapies.
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Anaplastic Large-Cell Lymphoma
Anaplastic large-cell lymphoma (ALCL) is a rare type of aggressive T-cell lymphoma comprising about 3 percent of all lymphomas in adults and between 10 percent and 30 percent of all lymphomas in children. It can present either systemically (meaning in organs throughout the body) or cutaneously (on the surface of the skin). Systemic anaplastic large-cell lymphoma may respond well to chemotherapy treatment and is potentially curable. When ALCL is confined to the skin, it follows a less aggressive course and is associated with a rare condition called lymphomatoid papulosis (LyP), which, though not classified as a lymphoma, is often a precursor to development of cutaneous anaplastic large-cell lymphoma. Patients with systemic ALCL are divided into two groups, depending on the expression of a protein called anaplastic lymphoma kinase (ALK). The prognosis for ALCL depends on whether a patient is ALK positive (expresses the protein) or ALK negative (does not express the protein). ALK positive disease responds well to chemotherapy, putting most patients in long-term remission or cure. A majority of ALK negative patients will relapse within five years and are treated more aggressively, often with transplant.
Angioimmunoblastic Lymphoma
Angioimmunoblastic lymphoma (AILD) is a fast-growing T-cell lymphoma that accounts for between one percent and two percent of all cases of NHL in the United States. Symptoms include high fever, night sweats, skin rash and some types of autoimmune disorders, such as autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP), in which the body does not recognize its own cells. As a result, the body makes antibodies against and destroys its own cells or tissues, such as platelets (ITP) and red blood cells (AIHA). Angioimmunoblastic lymphoma may be treated first with steroids, although it often progresses and requires chemotherapy and other medications. In advanced cases, transplantation may be used.
Other Lymphomas
AIDS-Related Lymphomas
Lymphomas occurring in HIV-positive patients are usually aggressive. It is estimated that as many as ten percent of people who are HIV-positive will ultimately develop lymphoma. Although both Hodgkin and non-Hodgkin lymphomas may occur in AIDS patients, non-Hodgkin lymphomas are more common and include diffuse large B-cell, Burkitts/Burkitt-like and primary central nervous system lymphoma.
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Pediatric Lymphoma
Childhood NHL comprises about five percent of all NHL cases diagnosed in the United States. The most common types are lymphoblastic lymphoma, Burkitts lymphoma, diffuse large B-cell lymphoma and anaplastic large-cell lymphoma. Lymphoblastic lymphoma is closely related to childhood acute lymphoblastic leukemia. The number of children with NHL continues to increase. (See Children and Young Adults With Non-Hodgkin Lymphoma, beginning on page 79.)
Lymphoblastic Lymphoma
Lymphoblastic lymphoma can appear in both B-cells and T-cells but is much more common in T-cells, comprising 80 percent of all lymphoblastic lymphomas. This lymphoma is most often diagnosed in children. With
intensive chemotherapy the complete remission rate can be very high. The disease is often treated similarly to acute lymphoblastic leukemia.
T-Cell Leukemias
T-cell leukemias are also derived from T-cells and can act like T-cell lymphoma. These cancers include T-cell promyelocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK-cell leukemia and adult T-cell lymphoma/leukemia.
lymphoma.org
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Chapter 2
see whether any internal organs are enlarged. Patients will be asked about pain and examined for any weakness or paralysis that could be caused by an enlarged lymph node pressing against nerves or the spinal cord. If the doctor suspects lymphoma after reviewing the signs and symptoms, he or she may order other tests to help confirm the diagnosis. These tests should include a biopsy and may also include blood tests, X-rays and other imaging tests, scans and a bone marrow evaluation.
lymphoma.org
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Chapter 3
Getting a Diagnosis
An accurate assessment of NHL requires a number of diagnostic tests. First, a hematopathologist (a doctor specializing in the identification of hematologic malignancies) will examine the tumor tissue under a microscope and confirm the diagnosis. Examinations will then be performed to determine how far the disease has spread (staging) and how well the body is functioning.
biopsies
A biopsy is a procedure in which a piece of tissue from an area of suspected disease is removed from the body and examined under a microscope. The information provided by this tissue sample is crucial to diagnosing and treating NHL.
Learning the Basics 19
Excisional Biopsy
The preferred type of biopsy to establish an initial diagnosis of lymphoma is called an open excisional biopsy in which an entire lymph node or a generous wedge of tissue is surgically removed. Because there are many types of lymphoma, the precise subtype of lymphoma must be exactly determined to select the best therapy. This generally requires a microscopic review of the lymph node tissue extracted, preferably from a generous sample. Trying to make a diagnosis from a small tissue specimen can lead to errors in diagnosis and suboptimal therapy. Laparoscopy (inserting a tube into the abdomen) or abdominal surgery may be necessary to obtain a sufficient sample of the tumor for examination.
Needle Biopsy
When lymph nodes are in locations that are difficult to biopsy, for example, deep in the chest or abdomen, a more limited needle biopsy may suffice, especially if a bore needle is used to perform a core biopsy. In this type of biopsy, a needle is inserted into a lymph node suspected of being cancerous and a small tissue sample is removed. A core biopsy can be done under local anesthesia and stitches are usually not required.
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blood Tests
Blood tests are performed to determine whether different types of blood cells, including red blood cells, white blood cells and platelets, are normal in number and appearance when viewed under the microscope. Abnormalities in these blood cells may sometimes be the first sign of lymphoma. Certain blood tests can be used to determine whether lymphoma is affecting the liver, kidneys or other parts of the body. Blood abnormalities can also help doctors determine potential treatment choices and predict outcomes. For example, in patients with NHL, levels of the enzyme lactate dehydrogenase (LDH) and/or the protein beta (2) microglobulin (B2M) are commonly measured because higher levels of either or both suggest that the lymphoma may be more aggressive and that more intensive treatment may be needed. If the lymphoma is circulating in the blood, tests can also be used to classify the tumors according to molecular markers (or antigens) on the surface of cancer cells. This process is called immunophenotyping and is also performed on tissue samples removed by biopsy or bone marrow extraction. This information can help distinguish different types of lymphoma.
Imaging Tests
Physicians will often order imaging tests that provide pictures of the inside of the body. Most of these tests are painless, and no anesthetic is required. Several types of imaging procedures may be needed to help best evaluate lymphoma, including the following:
X-rays
X-rays use radiation to take pictures of areas inside the body. The amount of radiation used in most diagnostic tests is so small that it poses little risk to the patient.
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PET (positron emission tomography) Scan
PET scans have largely replaced gallium scans (in which radioactive gallium was injected into the body) in many cancer centers, because the technique is more convenient and more sensitive. This test evaluates NHL activity in all parts of the body. To perform the test, a radioactive glucose (sugar) tracer substance is first injected into the body. A positron camera is then used to detect the radioactivity and produce cross-sectional images of the body. Unlike gallium scans, which are used primarily to detect response to treatment, PET scans are useful for both determining how much disease is present (staging) and how well it is responding to treatment. While CT scans show the size of a lymph node, gallium and PET scans show if the lymph node is active (still has disease). Today, CT and PET scans are often being combined into one test (CT/PET).
of immunological techniques that detect the expression of specific proteins (antigens) on the surface of tumor cells. Using these tests, doctors can sometimes detect cancer earlier, and they can more accurately classify tumor types. This information may help the physician choose the most appropriate treatment for the disease. Immunologic and genetic tests can find evidence of cancer unseen by a pathologists microscope. An advantage of molecular diagnostic tests is that they are usually very sensitive and require only tiny amounts of tissue obtained from biopsies, fine-needle aspirates or sometimes blood. Researchers are currently developing ways to measure the activity of genes within the cells of a lymphoma sample. This technique is called microarray analysis, which may lead to even more accurate diagnoses based on a tumors individual genetic characteristics and behavior. Because it is too complex to be performed routinely, the method is currently being used in an experimental setting for assessing NHL tumors. INTERPRETING DIAGNOSTIC REPORTS
It is important to be aware that no one test is definitive. Tests can be reported as normal even though lymphoma may be present. Tests may also be reported as abnormal even though no lymphoma is present. Other conditions may mimic lymphoma. The interpretation of tests, such as imaging scans, can be difficult in some situations and needs to be made in the context of the disease and the patient. Oftentimes, follow-up tests are needed to determine the true significance of previous results. In fact, biopsies occasionally are needed to clarify the results. Some patients like to review their written scan reports. When doing so, it is important to review the findings with the physician.
Other Tests
In addition to these tests, doctors may also order tests to evaluate the health of organs that could be affected by treatments. Examples of some tests include echocardiograms or radionuclide tests to evaluate the heart and pulmonary function tests to evaluate the lungs.
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Grading and Staging Non-Hodgkin Lymphoma
Although people often confuse the terms grade and stage in a lymphoma diagnosis, their meanings are very different.
The A category is used to designate a person with no symptoms. The B category is used to designate a person with symptoms that affect their entire body (called systemic symptoms). Examples of these include fever, night sweats and weight loss. The E category is used when the disease spreads directly from a lymph node into an organ. Category E can also be used when the disease involves a single organ outside the lymphatic system with no other local lymphatic involvement. THE fOUR STAGES Of NON-HODGKIN LYMPHOMA
Stage I (early disease): The cancer is found only in a single lymph node region OR in one organ or area outside the lymph node. Stage II (locally advanced disease): The cancer is found in two or more lymph node regions on one side of the diaphragm (the breathing muscle that separates the abdomen from the chest). Stage III (advanced disease): The disease involves lymph nodes both above and below the diaphragm. Stage Iv (widespread disease): The lymphoma cells are found in several parts of one or more organs or tissues (in addition to the lymph nodes). Or, it is in the liver, blood, or bone marrow.
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records. A second opinion is not considered adequate unless another pathologist, preferably one well versed in lymphoma, reviews the tissue and blood samples. A patients physician or healthcare team can often recommend an oncologist for a second opinion.
lymphoma.org
Chapter 4
always accurately predict what will happen to a particular patient. The doctor most familiar with your situation is in the best position to help interpret these statistics and determine how they apply to you.
Although family members are often very concerned about their loved one and want information concerning his or her care, growing confidentiality rules prohibit physicians from giving out information to anyone without the patients expressed permission. For efficiency, it is suggested that one family member be designated as the family contact to the physician. However, the patient must inform their physician who this individual will be in advance.
Specific instructions on the medical care, including the types of special treatment a patient wants or does not want, such as cardiopulmonary resuscitation (CPR), artificial respiration, drugs to make the heart function, kidney dialysis, artificial feeding and certain surgical procedures. A patients choice of healthcare proxy.
How to be a Self-Advocate
Being a self-advocate and an active participant in healthcare can be a positive experience and may help restore a sense of control that was lost following diagnosis. It is important for patients to remember that they are a partner in their treatment plan and many patients feel better when they actively participate in their care. The first steps in participating in treatment are to ask questions, learn about options and work closely with the physician. Patients must be comfortable with their physician and the approach that they take. If not, patients should openly discuss their concerns. Confidence in the medical team often leads to confidence in treatment. If the patient does not feel that the team is a good match, they should ask for a referral. Questions will likely vary depending on the purpose of the meeting with the oncologist (e.g., the initial visit to discuss the diagnosis as opposed to a routine visit to monitor a remission). Ask for the timing of office visits, treatments and tests. The physician can help explain what the tests will look for and define the possible responses and the options for further care depending on treatment response. Although each person is different and each response to therapy is unique, knowing someone who has been through the same treatment and who may have had similar concerns can be a source of great comfort for patients. If a patient is interested in talking to and learning from people who have had similar experiences, they should ask their oncologist, hematologist, oncology nurse or the oncology social worker about any support groups in their area. The Lymphoma Support Network, a nationwide buddy program that matches patients or caregivers, offers the opportunity to share experiences and information, and offers support and encouragement. For more information about this program, call (800) 500-9976 or e-mail support@lymphoma.org.
32 Understanding Non-Hodgkin Lymphoma
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TIPS ON SELf-ADvOCACY
Do not be afraid to ask your doctor or nurses questions about your care. Learn more about your lymphoma from reliable websites, such as the Lymphoma Research Foundation at lymphoma.org. Or ask your doctor for information specific to your type of lymphoma. Take advantage of other services offered at your doctors office, cancer center or hospital, such as counseling, support groups, nutritional counseling and fitness classes. Consider joining the Lymphoma Support Network, a nationwide buddy program that matches patients and/or caregivers. For more information about the program, call (800) 500-9976 or e-mail support@lymphoma.org.
Before any tests are performed, a patient should check with their healthcare team to determine which costs are covered by insurance and which are not. A patient should not be afraid to broach nonmedical issues, such as transportation, finances, insurance and childcare, with the healthcare team.
Age
People under the age of 60 generally have better treatment outcomes than those who are older. Younger patients may be better able to tolerate the effects of therapy because they generally have fewer health problems, such as heart or lung disease, that could limit the type or dose of therapy.
Prior Therapy
The greater the number of prior therapies, the less likely treatment will be successful, which is why it is important to attack the tumor initially with the most effective therapy available.
Performance Status
Performance status is used to describe a persons ability to follow a typical lifestyle. Those with good performance status (people who are active) tend to respond better than those with poor performance status (people with chronic health problems or those so ill that they are confined to bed) because they can tolerate more intensive therapy. Performance status is ranked on a scale from 0 to 4, with a number of 2, 3 or 4 indicating progressively sicker patients.
Stage of Disease
Stages I and II are used to describe localized disease, and stages III and IV refer to more widespread or advanced disease. Patients with stage III or IV disease may have a lower cure rate compared with individuals with stage I or II disease. Based on many of these and other factors, physicians have developed indices, such as the International Prognostic Indicator (IPI) or FLIPI (for follicular lymphoma), to predict the success of the therapy. By referring to these indices, physicians will make treatment choices as to how to approach an individuals particular lymphoma.
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QUESTIONS TO ASK bEfORE TREATMENT bEGINS
hat is my exact diagnosis? W hat is the stage and grade of my disease? W hat are my treatment choices? Which do you recommend for me? W Why? hat are the risks and possible side effects of each treatment? W hat side effects should I report to you? W re there any late- or long-term side effects I should be aware of? A ow long will the treatment last? H hat are the chances that the treatment will be successful? W ow will the treatment affect my normal activities? H re new treatments being studied? Would a clinical trial be appropriate A for me? hat is the treatment likely to cost? Does my insurance cover it? W
lymphoma.org
Chapter 5
Watchful Waiting
Understanding Watchful Waiting
Watchful waiting or watch-and-wait refers to an approach wherein the patient has regular visits and follow-up evaluation procedures, such as laboratory and imaging tests, but no specific anti-lymphoma treatment is given. The patient pursues a normal life as long as symptoms of NHL are not present and the disease is clinically stable. Watchful waiting may be appropriate either at the time of initial diagnosis or following treatment for selected indolent lymphoma patients. When the patient begins to develop lymphoma-related symptoms, or when there are signs that the disease is progressing, watchful waiting will be abandoned in favor of active treatment. Watchful waiting is not a treatment option for aggressive lymphomas, as treatment is almost always needed shortly following diagnosis.
Bendamustine
Treanda
Carboplatin Carmustine Chlorambucil Cisplatin Cyclophosphamide Dacarbazine Ifosfamide Mechlorethamine Melphalan Procarbazine
Paraplatin BCNU BiCNU Leukeran Platinol CDDP Cytoxan CTX DTIC Ifex Nitrogen mustard Mustargen Alkeran L-PAM Matulane
ICE Stem cell transplantation Single agent DHAP CHOP, EPOCH, CEEP HyperCVAD ABVD ICE MOPP Stem cell transplantation MOPP
Bleomycin Doxorubicin
Mitoxantrone
Novantrone
FND, GNP
Antimetabolites
These drugs interfere with normal cell growth by inhibiting synthesis of DNA. Chemical Name Brand or Other Name Examples of Use in Combination Chemotherapy
Single Agent
Cytosine arabinoside DHAP Ara-C Cytosar DepoCyt FCR, FND-R, R-Flu HyperCVAD, Single agent PCR ICE, CHOEP, LPOCH
Fludarabine phosphate Fludara Methotrexate Pentostatin Etoposide Rheumatrex Trexall Nipent VP-16 Etopophos Toposar VePesid Gemzar Folotyn
Gemcitabine Pralatrexate
Hormones
These drugs also affect cell growth.
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Brand or Other Name Diprolene Temovate Lidex Decadron Deltasone
Dexamethasone Prednisone
Drugs That Prevent Cells from Dividing by blocking Cell Duplication (Mitosis)
Chemical Name Vinblastine Vincristine Vinorelbine Brand or Other Name Velban Oncovin Vincasar Navelbine
Chemotherapy Cycles
Chemotherapy is usually given in cycles in which each treatment is followed by a period of rest and recovery. Together, each period of treatment and non-treatment is called a chemotherapy cycle. Clinical trials have determined how often chemotherapy should be given to kill the most tumor cells while minimizing side effects. However, timing may vary depending on the specific treatment. For NHL, a chemotherapy cycle is typically given every one, two, three or four weeks. Chemotherapy for NHL may require as few as three or as many as eight or more cycles of treatment, depending on factors such as the stage of the disease, the type of lymphoma, the kind of drugs used, the level of response achieved and the nature and severity of the side effects.
Regimen Abbreviation Drugs CP CVP (COP) Chlorambucil (Leukeran) Prednisone (Deltasone) Cyclophosphamide (Cytoxan) Vincristine (Oncovin) Prednisone (Deltasone) Cyclophosphamide (Cytoxan) Doxorubicin or Hydroxydaunorubicin (Adriamycin, Rubex) Vincristine (Oncovin) Prednisone (Deltasone) Etoposide (VP-16, VePesid) Prednisone (Deltasone) Vincristine (Oncovin) Cyclophosphamide (Cytoxan) Doxorubicin or Hydroxydaunorubicin (Adriamycin, Rubex) Fludarabine (Fludara) Mitoxantrone (Novantrone) Dexamethasone (Decadron, Dexasone) Cyclophosphamide (Cytoxan) Vincristine (Oncovin) Doxorubicin (Andriamycin) Dexamethasone (Decadron) Methotrexate (Rheumatrex) Cytarabine (Ara-C, Cytosar)
CHOP-R
EPOCH
FND
HyperCVAD/MTX-Ara-C
Regimen Abbreviation Drugs ICE Ifosfamide (Ifex) Carboplatin (Paraplatin) Etoposide (VP-16, VePesid) Dexamethasone (Decadron) Cisplatin (Platinol, CDDP) Cytarabine (Ara-C, Cytosar) Dexamethasone (Decadron) Cisplatin (Platinol, CDDP) Cytarabine (Ara-C, Cytosar) Etoposide (VP-16, VePesid)
DHAP
ESHAP
flushing). However, it also has disadvantages. Each time this type of device is used, an injection through the skin is required, and it may not always be convenient to draw blood samples. These devices may also occasionally clot. Another type of intravenous catheter is a peripherally inserted central catheter or PICC line, which uses a thin, soft plastic tube to deliver medicines and fluids through a large vein in the arm. While the PICC line is a more temporary device, it can be kept in place for a number of months, and is a good option for patients who need to have many short infusions or continuous infusions given in a hospital or at home with a portable pump. Patients in need of a catheter should discuss the pros and cons of the different types with their physician.
Radiation Therapy
Radiation therapy (also called radiotherapy) uses high-energy x-rays to kill cancer cells and shrink tumors. Radiation is a most often localized, which means it only affects cancer cells in the treated area. The term radiation field is used to describe the part of the body selected to receive radiation therapy. Radiation is generally confined to lymph nodes, the areas immediately surrounding lymphoma nodes or the area
of origin if the lymphoma arose from an extranodal site. These fields are determined on a case-by-case basis and depend on the type of tumor and the extent of disease. Radiation may be given to a limited or involved field (a small area) or may be given more broadly to larger common areas (extended field). To prepare for radiation therapy, the skin is marked with tiny ink dots (called tattoos) so the exact area will be treated every time. Before the first treatment, the healthcare team devotes a substantial amount of time marking the body to make sure that only the targeted areas receive radiation. Normal tissues around the radiation field are shielded by lead, which blocks the path of stray radiation beams. Patients lie still on a table beneath a large machine that delivers the radiation painlessly. Props and supports with plastic forms, pillows and rolled blankets help keep patients in the proper position. Once the preparations have been made, it takes only a few minutes to deliver the prescribed dose. The total dose of radiation is usually divided and given over one to six weeks. The site must carefully be guarded from the sun during and after radiation therapy.There are many different types of radiation as well as different ways to deliver radiation. Some of the more common types of radiation and delivery methods used in the treatment of NHL include:
Radioimmunotherapy
Radioimmunotherapy is a form of liquid radiation whereby a radioactive molecule is attached to a monoclonal antibody to target specific cancer cells. (See Radioimmunotherapy, on page 53.)
First, a three-dimensional image of the tumor is collected using CT, MRI or PET scans. A special computer program is then used to analyze the three-dimensional image and design radiation beams that conform to the specific shape of the tumor. This technique allows physicians to target the tumor with radiation, while sparing the healthy tissue surrounding it.
A transplant using any one of these cells can replace a patients damaged marrow with healthy blood-forming cells, resulting in a new blood and immune system. With these new cells working in the patients bone marrow (the spongy material found inside our bones) the marrow can once again form healthy: Red blood cells, which carry oxygen to all parts of the body White blood cells, which fight infections Platelets, which control bleeding by helping blood to clot To get the patients body ready for a transplant, he/she will receive chemotherapy and/or radiation. This will destroy or suppress the immune system. Physicians call this a preparative regimen, or conditioning. The new stem cells grow in the body, and take over the blood-forming machinery in the marrow. Because a transplant places great strain on a patients body, it is not an option for everyone. Among the things to consider are age, medical history, cancer stage and response to previous therapy. In some patients, a reduced-intensity conditioning regimen can be used, which lowers the strain on the body (see below). There are two types of stem cell transplants: allogeneic, in which patients receive stem cells from another person, and autologous, in which patients receive their own cells.
Autologous Transplantation
In this procedure, a patients own stem cells are removedpreferably while the patient is in remissionand frozen. When it is time for the transplant, the patient will receive very high-dose chemotherapy and/or radiation, after which the thawed stem cells are re-infused back into the patients body. The cells go into the bloodstream, where they make their way to the bone marrow where they belong. The advantage to this type of transplant is that the patients body cannot reject the stem cells, and there is no risk of graft versus host disease (GVHD), which may occur with allogeneic transplantation. A disadvantage is that autologous transplantation has a higher risk of relapse than allogeneic transplantation. Autologous transplants use primarily marrow or PBSCs; cord blood has only been used in rare instances.
Allogeneic Transplantation
In allogeneic transplantation, a donors stem cells are used. Finding a compatible donor is important because the body will reject stem cells if they are too unlike the patients own cells. The new cells may also react against the patients body, a condition called graft-versus-host disease (GVHD). However, allogeneic transplants also have one important potential advantage: the donors immune cells can destroy any lymphoma cells in the body not killed by the conditioning regimen. Very sensitive tests are used to see if someone is a suitable transplant donor. The best candidates are siblings, but there is only a one in four chance that a sibling will be a close enough match for a transplant. If no family members are a match, a search for an unrelated donor (or a cord blood unit) in a large registry of volunteers can be initiated.
Peripheral Blood Stem Cells (PBSC) - The second, and now more common way to collect stem cells from an adult, is by harvesting PBSCs from the blood. In this case, the donor takes a drug called a growth factor that causes the stem cells in the marrow to move into the peripheral blood. The stem cells are then removed from the donors blood using a process called apheresis. Blood is taken from a vein in one of the donors arms and passes through an apheresis machine, which separates out the stem cells. The rest of the blood, minus the stem cells, is returned to the donor through a different vein. Cord Blood - Cord blood is collected at birth from a newborns umbilical cord. After the delivery is complete, trained technicians pierce the base of the cord with a sterile needle and drain the blood into a collection bag. The cord blood cells are then processed, tested and frozen until needed for a patient. Step 2: Processing or preserving stem cells In autologous transplants, marrow and PBSC collections are frozen for later re-infusion. In allogeneic transplants, cells undergo minimal processing and are given to the waiting patient as soon as possible. Cord blood cells (almost exclusively used in allogeneic transplants) are shipped frozen to the patients hospital, where they are kept until the patient is conditioned and ready to receive them. Step 3: Pre-transplant conditioning Before receiving the cells, patients are conditioned with chemotherapy and/or radiation. High-dose conditioning is always used in autologous transplants. In allogeneic transplants, the type and dose of the conditioning depends on the stage and type of disease, whether it is a recurrence and the condition of the patient. Step 4: Infusing the stem cells When the patient is ready, the stem cells are infused into the patients bloodstream through a needle inserted into a vein in one arm. The infused cells travel through the bloodstream, pass through the bones and implant themselves in the marrow. There, they slowly begin to make healthy new cells. Over time, the marrow produces enough healthy cells to completely
restore the patients blood and immune system. Until these new cells are created, patients are more susceptible to infections. For more information on transplantation, please visit the National Marrow Donor Programs website at marrow.org.
Rituximab (Rituxan)
Rituximab (Rituxan) was the first monoclonal antibody approved for cancer therapy by the US Food and Drug Administration (FDA) as a single agent in the treatment of relapsed or refractory lymphoma patients with CD20 positive, B-cell non-Hodgkin lymphoma. This drug targets the CD20 antigen found on the surface of almost all B-cells. Rituximab (Rituxan) is now FDA approved for the treatment of patients with the following:
relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after first-line CVP chemotherapy previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens Rituximab (Rituxan) is currently approved in Europe for the frontline treatment of CLL. However, the US FDA approval to use rituximab (Rituxan) in CLL is pending review. Ongoing research is exploring the effectiveness of using rituximab (Rituxan) in combination with chemotherapeutic agents, such as fludarabine (Fludara), in the treatment of CLL. Because rituximab (Rituxan) has been found to have a very favorable toxicity profile, it has been found to not enhance the toxicity of existing chemotherapy regimens. For this reason, rituximab (Rituxan) is now being integrated into virtually every chemotherapy regimen and new drug for the treatment of B-cell malignancies. For example, the addition of rituximab (Rituxan) to CHOP chemotherapy was found to markedly enhance the overall cure rate of CHOP chemo in patients with diffuse large B-cell lymphoma. Similarly, the addition of rituximab (Rituxan) to fludarabine (Fludara) has been found to markedly improve the effectiveness of fludarabine (Fludara) alone in indolent lymphomas, such as follicular lymphoma and CLL. As additional new drugs are approved by the FDA, one common strategy to improve these new found therapies is to evaluate them over time in combination with r to improve the efficacy of these new agents (e.g., bendamustine-rituxan). Ongoing clinical trials will continue to evaluate the safety profile of adding rituximab (Rituxan) to both FDA approved as well new agents yet to be approved by the FDA.
Alemtuzumab (Campath)
Alemtuzumab (Campath), which targets the antigen CD52, was the first US Food and Drug Administration (FDA) specifically approved for the treatment of chronic lymphocytic leukemia (CLL). It works very well in patients in whom the CLL cells are confined to blood and bone marrow. It does not appear to work alone very well in patients with bulky lymph nodes or spleen. However, in these situations, it has been used successfully in combination with other MAbs like rituximab (Rituxan) or with chemotherapy. Alemtuzumab (Campath) may increase susceptibility to certain viral (e.g., cytomegalovirus reactivation; CMV), fungal and bacterial infections, and it is mandatory to use medications to prevent these infections while on this drug. Alemtuzumab (Campath) is also being tested in T-cell lymphoma.
Ofatumumab (Arzerra)
Ofatumumab (Arzerra) is another monoclonal antibody that targets the CD20 antigen, which is found on the surface of chronic lymphocytic leukemia (CLL) cells. The Food and Drug Administration (FDA) granted the accelerated approval of ofatumumab (Arzerra) for the treatment of patients with CLL whose disease is refractory to fludarabine (Fludara) and alemtuzumab (Campath) in fall 2009. Unlike other monoclonal antibodies, ofatumumab (Arzerra) binds to a specific part of the CD20 protein on the surface of cells called the small loop epitope. This drug kills cells by recruiting proteins called complement, that lead to tumor cell death. It also induces antibody dependent cellular cytoxicity (ADCC) by recruiting the bodys immune system to kill the CLL cells. This drug is presently being studied in patients with other B-cell malignancies.
Immunoconjugates
The ability to link potentially toxic drugs or radioactive agent to MAbs offers a unique opportunity to target an otherwise toxic agent specifically to tumor cells. This strategy involves the development of immonoconjugates which have the added benefit of sparing normal tissues from exposure to these otherwise very toxic therapeutic agents. To date, a variety of immunoconjugates have been developed, including
radioimmunoconjugates, which involve the linking of a radioisotope to the backbone of a MAb (i.e., Bexxar and Zevalin) and immunotoxin conjugates that conjugate specific proteins or other small molecules to a MAb which bring the toxic drug in close proximity to the tumor cell and allow for high efficiency killing of the tumor without the significant toxicity that would be seen if the small molecule was given by itself.. Examples include denileukin diftitox (Ontak) and inotuzumab ozogamicin (CMC-544).
Radioimmunotherapy
Radioimmunotherapy involves the attachment of a radioactive molecule to a monoclonal antibody. This therapy delivers radiation directly to lymphoma cells that express the CD20 antigen on their surface. Currently, two radioimmunotherapy drugs are commercially available and continue to be further examined in clinical trials. These include ibritumomab tiuxetan (Zevalin) and tositumomab (Bexxar). Researchers agree these therapies have high activity in patients with indolent and some transformed lymphomas, including those with relapsed disease. Ongoing studies are examining the effectiveness of using combination chemotherapy with a monoclonal antibody versus a radioimmunotherapy agent. There are also other agents (which are directed against targets other than CD20) in clinical trials. The two currently available therapies are more similar than different. Both therapies require specific imaging tests and the administration of a dosimetric dose before giving the therapeutic dose that actually treats the lymphoma. Treatment for both drugs is completed in approximately one week. While some scheduling and side effect differences exist between the two products, the basic premise of this treatment includes imaging tests, two injections of the radioimmunotherapy agent and a close monitoring of blood counts for some time thereafter. Patients receiving radioimmunotherapy should speak with their physician about the specific safety precautions associated with this treatment. Because small amounts of radiation may be present in body fluids, such as blood and urine, it may be recommended that for a few days after treatment patients slightly modify their activities with respect to contact with others.
Ibritumomab tiuxetan (Zevalin): Ibritumomab tiuxetan (Zevalin) combines the cell targeting ability of the monoclonal antibody rituximab (Rituxan) with the additional killing ability of the radioisotope yttrium-90. This drug was originally approved in 2002 by the US Food and Drug Administration for the treatment of patients with relapsed (disease returns after treatment) or refractory (disease does not respond to treatment), low-grade or follicular B-cell non-Hodgkin lymphoma. In fall 2009, ibritumomab tiuxetan (Zevalin) received expanded label approval from the FDA for the treatment of patients with previously untreated follicular non-Hodgkin lymphoma (NHL), who achieve a partial or complete response to first-line chemotherapy. Tositumomab (Bexxar): Tositumomab (Bexxar) uses a radioisotope called Iodine-131 attached to a monoclonal antibody called tositumomab. This drug is FDA approved for the treatment of patients with relapsed or refractory, low-grade or follicular B-cell non-Hodgkin lymphoma.
Proteasome Inhibitors
Nearly all cells in the body continually break down their own protein components to remove improperly made or damaged proteins and to control cell growth and other vital processes. The cellular disposal system which handles these proteins is called the proteasome. In this form of cellular housekeeping, the proteasome cuts up protein molecules that are no longer needed by the cell. Recently, physicians and scientists have learned that certain cancer cells are particularly vulnerable to a new class of molecules called proteasome inhibitors.
Bortezomib (Velcade)
Bortezomib (Velcade), a therapy first approved for a type of blood cancer called multiple myeloma, was the first drug of this type approved to treat cancer. Bortezomib is a relatively selective and reversible inhibitor of the proteasome, which means that exposure to the drug is necessary for its activity. This drug has been approved for relapsed mantle cell lymphoma and is currently being tested as a therapy for follicular lymphoma. The major side effect of the drug that limits its use in many patients is neurotoxicity. (For a listing of other proteasome inhibitors currently under investigation, see page 98.)Recent studies with bortezomib (Velcade) have also demonstrated that inhibiting the proteasome appears to complement many conventional chemotherapy agents to treat lymphoma in a synergistic fashion. These data have now led to the development of novel chemotherapy platforms (e.g., R-CHOP-Velcade, RC-Velade-P; RCHVelcade-P) for the treatment of both aggressive and indolent lymphomas. Presently available data seems to suggest that the integration of bortezomib (Velcade) into these combination chemotherapy regimens may be very active in patients whose disease has become resistant to otherwise conventional chemotherapy agents. Clearly the future use of proteasome inhibitors, including bortezomib (Velcade) and other agents with more favorable toxicity profiles, will be dependent upon their activity in combination with other conventional chemotherapy active drugs.
Vorinostat (Zolinza)
Vorinostat (Zolinza) is the first treatment in this category to be approved for lymphoma. Vorinostat (Zolinza) was approved for the treatment of cutaneous T-cell lymphoma and is now being investigated in many other forms of NHL. Some recent exciting developments with vorinostat (Velcade) have shown that it potently synergizes with proteasome inhibitors, such as bortezomib (Velcade), and is now being studied in large international randomized studies with patients with multiple myeloma, mantle cell lymphoma and the T-cell lymphomas.
Romidepsin (Istodax)
Romidepsin (Istodax) was approved in the fall of 2009 for the treatment of cutaneous T-cell lymphoma in patients who have received at least one prior systemic therapy. Romidepsin (Istodax) is now under review for the treatment of peripheral T-cell lymphoma. Like vorinostat (Zolinza), romidepsin (Istodax) has also been found to synergize with proteasome inhibitors and combination chemotherapy regimens and is now being studied in many phase I and phase II settings in combination with other drugs known to be active in the treatment of lymphoma.
Bendamustine (Treanda)
Bendamustine (Treanda) is a novel alkylating agent that damages the DNA in tumor cells, thereby disrupting the cell cycle and causing cell death. Approved originally for clinical use in Germany for cancer, the US FDA approved bendamustine (Treanda) in 2008 for the treatment of indolent B-cell NHL that has progressed during or within six months of receiving rituximab (Rituxan) or a rituximab-containing regimen. It has also been approved to treat chronic lymphocytic leukemia (CLL), both in front-line as well as for previously treated patients. Data from randomized controlled trials in Europe suggest that a combination of rituximab
(Rituxan) and bendamustine (Treanda) may have a more favorable toxicity profile and equivalent or better efficacy in patients with indolent and mantle cell lymphoma who have been treated with other combination chemotherapy regimens such as R-CVP and R-CHOP. The implications of this data indicate that this two drug combination regimen may find a solid place among the available choices for treatment of NHL and CLL. Future clinical trials will continue to study bendamustine (Treanda) in combination with many of the new exciting drugs as discussed in Chapter 14.
Pralatrexate (Folotyn)
In fall 2009, the US Food and Drug Administration approved pralatrexate (Folotyn) for the treatment of patients with relapsed (disease returns after treatment) or refractory (disease does not respond to treatment) peripheral T-cell lymphoma. Pralatrexate (Folotyn) belongs to a class of chemotherapy drugs called anti-folates. It is different than other anti-folates, like methotrexate, in that pralatrexate (Folotyn) selectively accumulates in certain tumor cells. Given that this is the first drug approved for peripheral T-cell lymphomas, there is a lot of interest in combining pralatrexate (Folotyn) with other drugs to treat people with various types of lymphoma. Studies that are ongoing or planned include combinations with gemcitabine (Gemzar), HDAC inhibitors and proteasome inhibitors.
Interferon
Interferon alfa (Intron A, Roferon-A) is a protein produced naturally by the body to help fight infection and cancer cells. Interferon alfa (Intron A, Roferon-A) and is approved for the treatment of certain forms of NHL. Scientists and physicians believe that interferon alfa (Intron A, Roferon-A) probably kills tumor cells directly and may also stimulate the normal host immune system to eradicate malignant cells. Some oncologists recommend administration of interferon alfa (Intron A, Roferon-A) as maintenance therapy for patients who are in remission after treatment with chemotherapy and for patients with cutaneous T-cell lymphoma. Most studies to date show some improvement in the length of remission with minimal improvement in survival. The most common side effects of interferon alfa (Intron A, Roferon-A) therapy are flu-like symptoms, including fever,
weakness, tiredness and muscle and joint aches. These side effects have limited the drugs use by physicians in the United States. To reduce the impact of these flu-like symptoms, physicians may recommend injecting interferon alfa (Intron A, Roferon-A) shortly before bed, drinking a lot of nonalcoholic and non-caffeinated fluids to stay well hydrated and, if your physician recommends, taking nonprescription pain relievers such as acetaminophen or ibuprofen. Interferon alfa (Intron A, Roferon-A) can sometimes cause depression, which may be severe. Patients should speak with their physician if they become depressed while taking interferon alfa (Intron A, Roferon-A). Uncommon side effects include a diminished appetite, an aversion to food (anorexia) or a decrease in thyroid function. QUESTIONS TO ASK bEfORE UNDERGOING RADIATION THERAPY
What is the goal of my radiation? How will radiation be given? When will treatments begin? When will treatments end? How will I feel during therapy? What can I do to take care of myself during and after therapy? How will we know whether the radiation is working? How will radiation treatment affect my normal activities? What are the side effects of radiation?
Complementary therapy, also known as integrative medicine, includes a vast array of mind/body therapies, such as meditation, guided imagery, self-hypnosis, tai chi and yoga; touch therapies such as massage, reflexology and Reiki; acupuncture; and nutrition. However, because even some complementary practices, such as ingesting certain herbs or botanicals, may negatively impact cancer treatment, NHL patients should consult with their healthcare team before embarking on any integrative medicine plan.
What to Avoid
Dietary supplements such as multivitamins; high doses of vitamins like C, E and folic acid; and antioxidant-rich drinks like green tea, cranberry and pomegranate juice can interfere with cancer treatment and may actually increase the growth of cancer cells in some patients. Botanicals and herbs like ginkgo biloba may in some instances increase bleeding disorders and either increase or reduce the effectiveness of chemotherapy drugs.
Chapter 6
gastrointestinal tract and the bone marrow. Some chemotherapy drugs may also damage heart cells. Side effects of chemotherapy can vary widely depending on the types of drugs that are given and an individual patients response. Side effects can be mild or serious. Some of the most common side effects caused by chemotherapy include the following: SOME COMMON SIDE EffECTS CAUSED bY CHEMOTHERAPY
Cardiotoxicity Changes in taste Decreased blood cell production Risk of infections Diarrhea Fatigue Hair loss Mouth sores Nausea/vomiting Sexual dysfunction Sterility
Cardiotoxicity
Cardiotoxicity (damage to the heart or heart muscle) from standard chemotherapy drugs has been well documented in the treatment of solid tumor cancers. However, less is known about the late effects of chemotherapy on non-Hodgkin lymphoma patients because there are so many different subtypes of the disease and treatment cycles are not the same. For example, the majority of patients with diffuse large B-cell lymphoma may only need to be treated with chemotherapy once, therefore, their risk for developing chemotherapy-related cardiovascular disease is small. Conversely, NHL patients with indolent, or slow-growing, lymphoma may need multiple treatments over the course of many years, raising their risk for developing cardiotoxicity. In general, cardiac drugs used in NHL regimens are kept within the safe or acceptable range, where cardiac toxicity is usually not encountered. Lifestyle can also impact a patients risk for cardiotoxicity. For example, previous heart disease, smoking, obesity, lack of exercise, high cholesterol and high blood pressure may all contribute to chemotherapy-related or radiation-related cardiotoxicity. Careful monitoring by your healthcare team can reduce your chances for developing cardiotoxicity. Most doctors will prescribe either an
62 Understanding Non-Hodgkin Lymphoma
echocardiogram or a MUGA (multiple gated acquisition) scan, which measures cardiac function, before cardiac toxic chemotherapy begins. This will ensure that the chemotherapy dose is well within the range considered heart safe.
Changes in Taste
Some patients will experience a change in the way foods or beverages taste. Familiar foods sometimes taste differently (called dysgeusia) or the flavors of foods are not as strong (called hypogeusia). Some patients may also feel that foods have a metallic taste. These side effects are temporary and typically disappear after chemotherapy is completed.
cycle. When neutropenia threatens a patients ability to receive the planned dose of chemotherapy, drugs such as filgrastim (Neupogen), pegfilgrastim (Neulasta) or sargramostim (Leukine) can be given after chemotherapy to reduce the duration and severity of neutropenia. These drugs can sometimes cause bone pain and, if in the chest, may make patients think they are having a heart attack. Nonsteroids may relieve this pain rapidly. By keeping the white blood count from dipping too low, these medications can help keep chemotherapy doses on schedule. Occasionally, oral antibiotics are given to help prevent infection when neutrophil counts are low. Thrombocytopenia is the term used when myelosuppression depletes the number of platelets in the blood. Platelets help start the clotting process when bleeding occurs. If platelet counts are low, patients may bruise easily. A low platelet count may also cause prolonged or excessive bleeding from cuts, nose bleeds, bleeding from the gums or bleeding without a previous injury. A platelet transfusion may be needed in some cases.
Risk of Infections
A normal white blood cell count ranges from 4,000 to 10,000. Physicians regularly monitor the absolute neurtophil count (ANC), the number of neutrophils in the peripheral blood. When the ANC drops below 1,500, patients are at high risk for contracting infections. If a fever of 100.5F or greater develops, patients should immediately contact their physician or go to the emergency room.
Diarrhea
Diarrhea can be a side effect of chemotherapy. While most patients do not experience severe diarrhea, the most important thing to remember is to avoid dehydration (a loss of body fluids). Patients should report bloody diarrhea or fever with diarrhea to their healthcare team.
fatigue
Fatigue is a common side effect of many types of chemotherapy. Fatigue should go away after treatments are over, but it can take weeks or months until it is completely gone.
Hair Loss
One side effect of chemotherapy is hair loss (also called alopecia). Thinning or loss of hair can occur at any place on the body, including the scalp, eyebrows, eyelashes, arms, legs and pelvis. The hair loss may be variable. It is important to note that hair loss does not occur with all drugs. Remember that hair loss due to chemotherapy is usually temporary. At first, the new hair growing in may be a slightly different texture or color than it was before treatment, but it oftens returns to normal. TIPS fOR AvOIDING DEHYDRATION fROM DIARRHEA OR vOMITING
Drink plenty of liquids (eight glasses a day) of not just water, but electrolyte replacement drinks as well (e.g., Gatorade, Powerade). Look for signs of dehydration, including dry mouth or skin, decreased urine and dizziness or lightheadedness when you stand up. Avoid milk products, which can worsen diarrhea. Avoid hard-to-digest foods, such as those with high fiber, which can worsen diarrhea. Eat plenty of bananas and other high-potassium foods (check with your physician or dietitian to make sure these foods will not interfere with your chemotherapy or other medications you are taking). Take the medicines that your doctor recommends to control diarrhea (notify your healthcare team if diarrhea occurs).
Mouth Sores
The membranes of the mouth may become red, sore or irritated during chemotherapy, which is referred to as mucositis. Infections of the mouth and throat caused by viruses or fungi may also occur. If throat soreness
occurs, the healthcare team will examine the throat and may do a swab (called a culture) to check for infection, particularly herpes, fungus and bacterial infections. If an infection is present, several medications are available to treat it. To help reduce the risk of mouth infections, a physician may request a complete dental checkup and cleaning before receiving chemotherapy.
Nausea or vomiting
Chemotherapy can cause nausea or vomiting. Drugs that prevent vomiting (called antiemetics) include aprepitant (Emend), ondansetron (Zofran), granisetron (Kytril), metoclopramide (Reglan), prochlorperazine (Compazine) and dolasetron (Anzemet), and a variety of
corticosteroids, such as Deltasone (prednisone). Nausea most frequently occurs on the day chemotherapy is administered, but it can also start several days later. Physicians may prescribe an antiemetic before chemotherapy to prevent nausea. In most cases, antiemetics can partially or completely prevent nausea and vomiting.
Sexual Dysfunction
Chemotherapy can cause a drop in libido (sex drive). Usually, a normal libido returns after treatment is finished. (See Chapter 7.)
Sterility
Chemotherapy (and radiation) can sometimes cause either temporary or permanent sterility (the ability to have children) in both men and women, because the treatment may damage sperm and egg cells. The specific dose of treatment, whether the patient has received one or several therapies and the patients age at the time of treatment are all contributing factors to infertility side effects. Patients should speak with their physicians about fertility presevation before starting treatment. (See Chapter 8.)
fatigue
The likelihood that patients will experience fatigue depends on their disease and the specific radiation plan. (See page 66 for tips on overcoming fatigue.)
Nausea
Nausea may occur after radiation treatment, especially in patients who have radiation to the abdomen. Some people can avoid nausea if they eliminate eating (especially sweet, spicy or fatty foods) a few hours before radiation treatment. Taking a medication that prevents nausea (an antiemetic) before each radiation therapy session may be recommended. (See page 67 for additional tips regarding coping with nausea and vomiting.)
Skin Reactions
Radiation can cause a slight to moderate reddening of the skin and is often accompanied by discomfort, itching and flaking. These skin changes usually diminish and disappear over a few weeks. During radiation treatment, patients can protect their skin by: Avoiding exposing areas of the skin that are receiving radiation to the sun. These areas will always need extra protection, even after treatment is completed. Wearing a T-shirt and using plenty of sunscreen (with a high SPF) when out in the sun.
WHEN TO CALL OR SEE YOUR PHYSICIAN Your physician or a member of your healthcare team will discuss possible treatment side effects with you prior to initiating therapy. If you experience a side effect that is not expected or if your complications are prolonged, see your physician. If you experience a medical problem that cannot wait for a regularly scheduled appointment, such as high fever, shortness of breath, unremitting nausea and vomiting, chest pains and dizziness, call your physician, who will evaluate your situation and decide your next course of action. If you cannot reach your physician or a member of your medical team, go to your hospital emergency room for a medical assessment and place another call to your physician.
(sharp, throbbing, etc.), how strong it is and how long it lasts will help physicians develop the most appropriate pain management plan. For more information on managing pain, visit the American Pain Foundations website at painfoundation.org.
Exercise
Regular physical activity helps keep the cardiovascular system strong and body muscles flexible. Exercise can also help alleviate breathing problems, constipation, poor appetite and mild depression. It also helps reduce stress and fatigue. Several types of exercise are particularly helpful: General physical activity, such as swimming, dancing, mowing the lawn Aerobic activity to improve cardiovascular fitness, such as walking, jogging, bicycling Resistance training to strengthen muscles, protect joints and help remedy osteoporosis by building bone mass, such as lifting weights or using resistance-training equipment, push-ups, carrying and lifting Flexibility practices to improve range of motion, balance and stability, such as stretching and yoga Patients should consult their physician before starting an exercise program.
Diet
Eating a healthy diet is important during NHL treatment. Nutritionists specializing in oncology care can be helpful in developing individualized nutrition plans. Patients should consult their physician before taking dietary supplements such as multivitamins or individual vitamin supplements because they may interfere with treatments.
lymphoma.org
Chapter 7
Sexuality
Sexual function During Treatment
The causes of sexual dysfunction experienced by men and women during and after a cancer diagnosis are varied. Psychological factors, such as fear about illness, altered body image due to hair loss and depression, and the physical side effects of treatment, can all conspire to reduce sexual desire (libido) and function. Besides fatigue, some chemotherapy treatments can interfere with testosterone levels in men, resulting in low libido. In women, decreased estrogen production may cause vaginal dryness, hot flashes and other menopausal symptoms. In women, radiation therapy to the pelvis can cause a narrowing of the vagina, painful intercourse and ovarian failure, resulting in infertility. (See Fertility Risks, on page 77.) Some antidepressants and over-the-counter medications also lower sexual desire, as do certain lifestyle choices, such as smoking and drinking. Be assured that the lack of sexual desire and function due to treatment is usually temporary. Although many people are often too embarrassed to raise the issue of sexual function with their physician, it is important to recognize that sexuality is an integral part of life and patients should discuss this with their physician. Physicians may order tests to track hormone levels and make recommendations to see a specialist and/or prescribe medications to restore erectile function in men and hormone therapy to alleviate vaginal dryness and other menopausal symptoms in women.
(Thalomid) and lenalidomide (Revlimid), a derivative of thalidomide, which may cause birth defects in developing fetuses. Avoiding pregnancy while on chemotherapy is necessary since chemotherapy drugs may affect the fetus. Women should alert their physician if they suspect they have become pregnant. It is also recommended that people who have undergone stem cell transplants use condoms to reduce their risk for contracting cytomegalovirus and other infections, due to a compromised immune system. To further reduce risk of infection, patients should avoid sexual intercourse if their blood counts (hemoglobin, white blood cells and platelets) are low. Patients should ask their physician when it is safe to engage in sexual intimacy.
Chapter 8
fertility Risks
Treatment for NHL, such as certain types of chemotherapy, especially alkylating agents, and radiation therapy to the pelvic area, can interfere with fertility in several ways. In addition to killing cancer cells, these treatments can also affect healthy cells and reproductive organs like the ovaries and testes, which produce the eggs and sperm crucial to fertility. Whether the infertility is temporary or permanent depends on a number of factors, including the patients sex, age at the time of treatment, the specific type and dose of radiation therapy and/or chemotherapy and treatment duration. Patients considering having children in the future should consult their physician before treatment begins. A fertility specialist may also be consulted. The doctor will be able to recommend a counselor or fertility specialist.
Chapter 9
General Information
Despite the rarity of childhood cancers, scientific investigators have made tremendous advances in its treatment. In 2009, nearly 11,000 new cases of cancer were expected to occur in children between the ages of 0 and 14 years. According to the International Classification of Childhood Cancer, NHL makes up only 4.3 percent of all childhood cancers. The most common types of childhood lymphoma include: Hodgkin lymphoma Burkitts and Burkitt-like lymphoma Diffuse large B-cell lymphoma Lymphoblastic lymphoma Anaplastic lymphoma While the causes of NHL are unknown, the following may increase the risk of childhood or adolescent NHL: Family history (although no hereditary pattern has been established) Autoimmune disease Receipt of an organ transplant
Children and Young Adults With Non-Hodgkin Lymphoma 79
Exposure to chemicals, such as pesticides, fertilizers or solvents Infection with viruses, such as Epstein-Barr virus, human T-lymphotropic virus type 1, HIV, hepatitis C or certain bacteria (e.g., H. pylori)
Survival
The past three decades have seen a tremendous improvement in the survival rates of childhood cancers, including lymphoma. This upward trend is due to the continuous development of new and improved treatments resulting from successful clinical trial investigations. According to the most recent statistics, the five-year survival rate for children diagnosed with NHL is 86 percent.
Detection
The symptoms of NHL are often nonspecific and may mimic the symptoms of other common illnesses. Therefore, parents should ensure that children receive regular medical check ups and report any unusual or persistent symptoms to their childs physician. Some symptoms of NHL in children include: Shortness of breath Trouble breathing Wheezing Swelling of the head or neck Trouble swallowing Painless swelling of the lymph nodes in the neck, armpit, stomach or groin Fever for no apparent reason Weight loss Night sweats Children suspected of having NHL will undergo similar tests and procedures as adults, which may include a physical exam, blood work, biopsy, X-ray, and CT or PET scan.
Treatment Options
Because childhood cancers are so rare, oncologists specializing in these diseases are often located at academic medical centers and affiliated with clinical trials. The majority of children with cancer are treated in clinical trials. High clinical trial enrollment has led to rapid increases in the survival rates of children and teens with cancer over the past several decades. Therefore, patients that are eligible should consider participating in a clinical trial. Common treatment options include chemotherapy, radiation and stem cell transplant. However, compared to adults, children with NHL are often treated with different therapeutic regimens as well as lower doses of chemotherapy. The treatment that is selected depends largely on the type of NHL and the stage of disease.
Coping
Getting an NHL diagnosis can be difficult for the child as well as the family. Psychosocial problems, such as social withdrawal, depression and anxiety, may develop, straining relationships with friends and family. Many resources exist to help children, siblings and family members cope with the diagnosis. Some helpful resources include: National Childrens Cancer Society (nationalchildrenscancersociety.com) Candlelighters Childhood Cancer Foundation (candlelighters.org) SuperSibs! (supersibs.org)
The Childrens Oncology Group (COG) has developed guidelines for screening and managing the late effects of cancer treatment in childhood cancer survivors. To view the guidelines, please visit survivorshipguidelines.org. Patients should discuss these guidelines with their physician to create an individualized care plan based on their personal disease and treatment history.
lymphoma.org
Chapter 10
,,,
those diagnosed in older adulthood, because of better functioning of their liver, kidneys and blood systems. Further research is exploring the unique biology of young adults with cancer to determine specific care considerations for this age group.
resources for young adults diagnosed with cancer. For a complete listing of young adult cancer organizations, visit livestrong.org/yaa. Young adults diagnosed with NHL should also be aware of their employment and career rights, such as what to disclose, insurance issues and more. The Cancer Legal Resource Center (cancerlegalresourcecenter.org) provides free and confidential information and resources on cancer-related legal issues to cancer survivors, their families, friends, employers, health care professionals, and others coping with cancer. Cancer and Careers (cancerandcareers.org) provides support and resources to those living with a cancer diagnosis who work.
lymphoma.org
Chapter 11
Coping
Communicating
It is important that patients communicate their fears and concerns about having NHL with their loved ones, friends, physicians, nurses or social workers. Writing down their fears in a journal may also help.
Overcoming Depression
It is not unusual for people living with cancer to feel sad or depressed. Being diagnosed with NHL and undergoing treatment can be challenging both physically and emotionally. Signs of sadness or depression include sleeping more or less than usual, lack of energy, crying and an inability to concentrate. In addition to challenging life circumstances, depression may
Living With Non-Hodgkin Lymphoma 87
also be caused by certain medications. Patients who experience any symptoms of depression that last longer than two weeks should contact a psychiatrist, social worker, psychologist or counselor.
follow-Up Care
Most people with NHL will have a favorable response to initial treatment, enabling them to achieve either a complete remission or a partial remission. However, regardless of the type of remission achieved, it is important that each patient adhere to a schedule of regular follow-up office visits established by his or her physician. Follow-up visits can range in frequency from every few months to once a year depending on the patients disease progression, age, general health and time from last treatment.
Upong completing treatment, the healthcare team will develop a follow-up care schedule. This will include appointments with the hematologist/ oncologist as well as regular visits with the general practitioner, OB-Gyns, etc. The hematologist/oncologist will monitor the status of the NHL through physical examination and various tests (e.g., blood, imaging, etc.).
STAY PROACTIvE To stay proactive in your healthcare, be sure to get the following information from your medical team: opies of your medical records and a written summary of C your treatment in case you switch oncologists or need to see a primary care physician for routine medical care list of signs of disease recurrence and late side effects A from treatment At your follow-up care appointments, be sure to tell your doctor about: ny new symptoms A ain P hysical problems that disrupt your daily life, such as fatigue, P insomnia, sexual dysfunction, weight gain or loss ny new health problems, such as heart disease, diabetes or high A blood pressure ny new medications or vitamins you are taking A motional problems, such as anxiety or depression E
lymphoma.org
Chapter 12
Detailed below are common chemotherapy regimens used once patients relapse. Lymphoma research continually evolves as physicians and scientists discover new therapies and more effective ways of giving existing treatments. Chapter 14 describes some of the options currently under investigation.
Drugs Dexamethasone (Decadron) Cytarabine (Ara-C, Cytosar) Cisplatin (Platinol) Dexamethasone (Decadron) Ifosfamide (Ifex) Cisplatin (Platinol) Etoposide (VP-l6, VePesid) Etoposide (VP- 16, VePesid) Cisplatin (Platinol) Cytarabine (Ara-C, Cytosar) Methylprednisolone (Medrol) Ifosfamide (Ifex) Carboplatin (Paraplatin) Etoposide (VP- 16, VePesid) Carmustine (BCNU) Etoposide (VP- 16, VePesid) Cytarabine (Ara-C, Cytosar) Meiphalan (Alkeran) Methotrexate (Rheumatrex) Prednisone (Deltasone) Etoposide (VP- 16, VePesid) Procarbazine (Matulane) Cyclophosphamide (Cytoxan)
DICE
ESHAP
ICE
Mini-BEAM
PEP-C (oral)
Chapter 13
New drugs must pass through a rigorous approval process governed by the Food and Drug Administration (FDA) before it becomes a standard therapy for use in hospitals and clinics. The trials used to assess these drugs are typically divided into three types, called phases, each of which is designed to answer certain questions. Phase I tries to determine whether a potential treatment is well tolerated; phase II tests the drugs effectiveness in a small group of patients; and phase III tests the drugs effectiveness compared to standard therapies or other available treatments in a large, varied group of patients with a specific cancer. Patients may be eligible to take part in different stages depending on their condition, type and stage of lymphoma and the type of treatment, if any, previously given.
Phase I
Phase I studies (first in human studies) are designed to assess the maximum tolerated dose (MTD), frequency of treatment and overall safety of the drug in a small number of patients.
Phase II
Once the therapy dose is determined and shown to be safe in a phase I trial, it is then ready to be tested in a phase II study. Phase II studies aim to establish whether the therapies have any evidence of effectiveness in a larger group of patients with a particular type of cancer (e.g., follicular lymphoma). Phase II studies might be used to generate preliminary data on a drug or to confirm data to obtain FDA approval. Phase II studies also investigate whether a therapy already approved for one type of disease is effective treatment for another.
Phase III
Phase III trials are performed to determine whether the treatments developed in phase I and II studies are better than what is currently considered the standard of care for a specific disease. Phase III studies often require a large number of patients. Once a patient elects to enroll in a phase III study, he or she is assigned to one of two groups in a process called randomization. In randomization, a computer assigns the treatment the patient is to receive. One group receives the standard therapy and the
94 Understanding Non-Hodgkin Lymphoma
other group receives the experimental treatment. It is important to remember that this randomization process is done so that each treatment arm will have patients with similar characteristics and be free of bias. The randomization in phase III trials allows researchers to determine whether or not the new treatment is any more effective or less toxic than the standard of care.
Informed Consent
During the informed consent process, the healthcare team will review the design of the study, possible risks and benefits and what will be expected of the participant. The healthcare team will answer any questions and ask the patient to sign a consent form, indicating their desire to particpate in the study.
while others may define clinical trials as experimental or investigational and not cover some of the routine costs, such as physician visits, tests or treatments. The costs vary depending on the study and the health plan. Medicare provides coverage for patient care associated with governmentsponsored clinical trials. If a patient is taking part in a National Cancer Institute (NCI) trial being conducted at the National Institutes of Health (NIH) in Bethesda, Maryland, the NCI will pay for the study drug and the costs related to the study. A stipend for travel, food and lodging is also provided. Some cancer centers provide financial assistance or discounted rates for room and board and have special research units that will pay for study-related costs. Some organizations, including the Lymphoma Research Foundation, provide financial assistance for treatment-related expenses. (See Drug Costs: What to Do If Your Insurance Does Not Pay, on page 60.) Patients should ask their physician what clinical trials may be most appropriate for them. Here are some additional ways to find information: ontact the Lymphoma Helpline at the Lymphoma Research C Foundation at (800) 500-9976 to request a clinical trial search. ancer centers in your area may also have information about trials. C oalition of Cancer Cooperative Groups (CancerTrialsHelp.org). C NIH websites (Cancer.gov and Clinicaltrials.gov). QUESTIONS TO ASK YOUR DOCTOR
What is the purpose of this clinical trial? Who is sponsoring the trial (National Cancer Institute, a cancer center, a pharmaceutical company)? How long does the study last? What are the risks involved? Will I be in any discomfort or pain? What kinds of tests, procedures or treatments will be performed; how many and how often? Will I be able to see my own doctor during the trial? What costs will I be responsible for?
Chapter 14
Clinical Trials 97
To date, a variety of new proteasome inhibitors which meet some of these criteria have been successfully developed. One of these agents, carfilzomib, is being studied in randomized clinical trials against bortezomib (Velcade) in patients with multiple myeloma. To date, carfilzomib has not been associated with significant neurotoxicity while appearing to produce marked activity in patients with multiple myeloma who have relapsed following bortezomib (Velcade) treatment. Many of the developments in regard to new versions of proteasome inhibitors are oriented toward improving efficacy, decreasing toxicity and improving the convenience of administration. Other proteasome inhibitors in development with improved features include MLN-9708, which is an orally available proteasome inhibitor. This drug affords patients more convenient dosing and allows patients to take the drug at home.
Agent
Carfilzomib (PR-171)
Comments
Similar to bortezomib; known to be an irreversible proteasome inhibitor; no neurotoxicity Relapsed or refractory lymphoma NHL and HL; orally available
NPI-0052
Proteasome inhibitor
MLN-9708
Proteasome inhibitor
are known as CDK inhibitors and include drugs such as flavopiridol. Flavopiridol has been discovered to be potently active in patients with CLL and other slow-growing versions of leukemia and lymphoma. In addition to those drugs targeting the specific proteins involved in cell cycle regulation and control are a host of new drugs that are targeting other aspects of this biology, including those involved in the growth and mitosis (cell separation process that results in two identical cells) of tumor cells. Among these are drugs targeting aurora kinase (e.g., MLN-8237) purine nucleoside phosphorylases (e.g., BCX-1777) and novel approaches affecting tubulin biology (e.g., ixabepilone; kinesin spindle protein inhibitors).
Agent
Flavopiridol
Comments
Activity seen in CLL and mantle cell lymphoma Relapsed NHL NHL
MLN-8237 AT-9283
Aurora A kinase inhibitor Aurora A kinase and aurora B kinase inhibitor Purine nucleoside phosphorylase inhibitor Tubulin polymerization
Tubulin polymerization
HL
Clinical Trials 99
induce cell death while anti-apoptotic proteins resist cell death. Clearly, tumor cells contain an overabundance of those anti-apoptotic proteins which help the tumor cells survive even despite very toxic environments, including those imposed by chemotherapy. One of the first of these drugs is oblimersen (Genasense). Since the development of oblimersen (Genasense), a variety of new small molecules, many of which are orally available, have been developed. These drugs appear to inhibit the anti-apoptotic influence of many different proteins within the tumor cell, thereby increasing the sensitivity of the tumor cell to the induction of cell death by chemotherapy. Though these agents are now in very early development, they have so far demonstrated very promising activity in early phase clinical trials across a whole range of lymphomas. The future development of these agents will be oriented toward studying them in combination and lowering the threshold required to induce cell death. These agents have the value that they target biology that is selectively overrepresented in tumor cells and therefore are not associated with the same toxicity seen with combination chemotherapy. To date, these agents have been found to be very tolerable in early phase I and II clinical trials in patients with lymphoma.
Agent
Oblimersen (Genasense)
Comments
Being studied in melanoma and CLL Active in CLL; may make chemotherapy more effective; broad applicability Similar to ABT-263 above; orally available; being combined now with chemotherapy Being studied in solid tumors and blood cancers, including follicular NHL, CLL and other forms of lymphoma NHL and other solid tumors Relapsed HL and NHL
ABT-263
Bcl-2, Bcl-XL
AT-101
Bcl-2
YM-155 AMG-655
Comments
NHL Relapsed B-cell NHL CLL FDA indication in B-cell CLL Relapsed HL NHL, including CLL continued
CD30 CD40
Agent
TRU-016 HCD122 Galiximab Anti-CTLA-4
Comments
CLL and other lymphomas Relapsed HL and B-cell NHL Follicular lymphoma Follicular and mantle cell lymphoma
Immunoconjugates
Other new versions of MAbs include various immonoconjugates that link an immunotoxin to the MAb scaffold in order to enhance the internalization and localization of the toxin conjugate. One example of this strategy that has proven very efficacious in anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL) is SGN-35. This molecule takes advantage of a MAb directed against the CD30 antigen on the surface of some cells, which is conjugated to a toxin called monomethyl auristatin E (MMAE). Monomethyl auristatin E (MMAE) is a highly potent chemical that cannot be given by itself, because of its toxicity. However, when it is conjugated to the CD30 MAb it is delivered precisely to the tumor cells without any unnecessary toxicity. This drug development platform represents a major advance in the treatment of challenging diseases such as ALCL and relapsed HL.
Agent
SGN-35
Comments
Anaplastic large cell lymphoma and Hodgkin lymphoma
Immunomodulatory Drugs
In addition to MAbs and immunoconjugates, there are a host of new immunomodulatory drugs modeled after thalidomide (Thalomid), including new agents such as lenalidomide (Revlimid) and pomalidomide (Actimid). These agents are known to activate the patients own immune system to mount an immune response against the cancer cells inside the patients body. While the exact mechanisms by which these drugs kill tumor cells are only now being slowly understood, it is clear that these drugs are having dramatic activity across many hematologic malignancies, including
102 Understanding Non-Hodgkin Lymphoma
myelodysplastic syndrome (MDS), multiple myeloma, T-cell lymphomas, follicular lymphoma and mantle cell lymphoma. The future development of these drugs is likely to be linked to their ability to treat small volumes of tumor, or minimal residual disease, in patients following primary therapy. Therefore, they are being studied as oral maintenance therapies in those lymphomas inclined to relapse following primary therapy.
Agent
Lenalidomide (Revlimid)
Comments
FDA approved in myeloma and disease of bone marrow failure; now being investigated in many forms of NHL FDA approved in myeloma; preceded approval of lenalidomide above Being investigated in solid tumors and blood disorders FDA approved in other types of cancer; under investigation in NHL Cutaneous T-cell lymphoma; AIDS-related lymphoma
Thalidomide (Thalomid)
Immunomodulatory
Pomalidomide (Actimid)
Immunomodulatory
Aldesleukin (Proleukin)
Immunomodulatory
Interleukin-12
Immunomodulatory
Agent
R788 (Fostamatinib disodium)
Comments
Several types of B-cell and T-cell NHL Relapsed B-cell NHL Relapsed B-cell NHL
PCYC-04753 PCI-32765
vaccines
Unlike monoclonal antibody therapy, which is a form of passive immunity, vaccines are considered a form of active immunity. In passive immunity, antibody generated outside the body in a special laboratory tags the lymphoma cells, which are then removed by the spleen. There is no memory of the exposure, and the effect is over once the antibody is cleared from the body. In active immunity, the vaccine is designed to stimulate the patients own immune system to recognize and respond only to those cells carrying the specific antigen, or tumor-specific idiotype, against which the vaccine was made. Vaccines are not yet available as standard treatments, but various vaccines are being evaluated in clinical trials. Lymphoma vaccines are designed to enhance the patients own immune defense system to fight his or her disease. These vaccines, often referred to as idiotype (e.g., patient specific) are custom-made, using a tumor sample from the patients lymph node. In order to create an individual vaccine, a patients lymphoma must be accessible for biopsy. It is not yet known how effective these vaccines will be, but the results from large randomized phase III trials are currently being evaluated. So far, two of these large clinical trials have failed to show sufficient benefit compared to standard treatment. The results of one other trial have produced positive results in selected patients.
Agent
BiovaxID
Comments
Follicular lymphoma
is now under study in a large international phase II trial in patients with PTCL resistant to conventional chemotherapy. New orally available forms of belinostat are now in development and appear to be associated with a very favorable toxicity profile, ease of administration and promising activity in various subtypes of NHL. Another HDAC inhibitor being developed is panobinostat. Panobinostat, like vorinostat (Zolinza), is an orally available HDAC inhibitor that is chemically very similar to vorinostat (Zolinza). But unlike vorinostat (Zolinza), panobinostat has demonstrated marked activity in patients with Hodgkin lymphoma resistant to conventional chemotherapy. Panobinostat is now being studied across a variety of NHLs, including a FDA directed study for patients with relapsed or refractory Hodgkin lymphoma. This means, that should this trial demonstrate sufficient activity, it could become approved by the FDA for all patients with Hodgkin lymphoma. As this field continues to emerge, it is becoming increasingly more apparent that HDAC inhibitors will complement a whole host of other drugs, including proteasome inhibitors, Bcl-2 directed therapies, MAbs like rituximab (Rituxan) and other agents also known to affect gene expression, such as the hypomethylating agents. This latter class consists of two drugs now approved by the US FDA for the treatment of myelodysplastic syndrome: 5-azacytidine (Vidaza) and 5-aza-2-deoxycytidine. New evidence from a variety of different laboratories and clinical settings has begun to demonstrate that this two arm attack on gene transcription using both HDAC inhibitors and hypomethylating agents is a very promising strategy for the treatment of acute myeloid leukemia and possibly some forms of lymphoma. Future efforts will be directed toward understanding which genes are modulated following exposure to these drugs in an effort to identify certain biomarkers of response in specific patients with different types of lymphoma.
Agent
Panobinostat
Comments
Under investigation in relapsed HL, PTCL, other NHL PTCL, other NHL
Belinostat
HDAC-inhibitor
Another target that has emerged as essential and perhaps unique in the development of B-cell lymphoma is a protein known as protein kinase C-beta (PKC-beta). The identification that PKC-beta was an important target among patients with relatively poor prognosis diffuse large B-cell lymphoma (DLBCL) represented a unique opportunity to target this biology with drugs capable of inhibiting PKC-beta. One such drug that had been studied in rheumatologic disorders and inhibited PKC-beta was enzastaurin. To date, enzastaurin has been studied in a variety of phase I and phase II clinical trials in patients with DLBCL. While the drug appears to be modest in terms of its ability to shrink tumor, it has been found to produce very prolonged stabilization of disease in patients with otherwise very aggressive forms of lymphoma. Enzastaurin is now being studied in a large randomized controlled trial to determine whether administration of oral enzastaurin after primary chemotherapy for patients with poor risk DLBCL represents a maintenance type approach to enhance the survival of patients with otherwise aggressive forms of lymphoma.
Agent
Perifosine
Comments
Active in many blood cancers. New class of drugs with broad applicability NHL, under study in mantle cell lymphoma Approved for renal cell carcinoma. Being studied in many types of lymphoma, including mantle cell lymphoma Relapsed or refractory hematologic malignancies Under study in diffuse large-B cell lymphoma Relapsed aggressive lymphoma
RAD001 (Everolimus)
mTor inhibitor
Temsirolimus (Torisel)
mTor inhibitor
CAL-101
PI3K inhibitor
Enzastaurin HCl
PKC-b
Bevacizumab (Avastin)
VEGF
Other therapeutic strategies directed against both the tumor cell proper as well as the stromal microenvironment (i.e., the normal cellular milieu within which the tumor cell resides) include drugs capable of affecting angiogenesis (the growth of blood vessels that sustain growth of tumors). While drugs affecting angiogenesis have found an important niche in the
108 Understanding Non-Hodgkin Lymphoma
treatment of patients with solid tumor malignancies, like breast cancer, colon cancer and glioblastoma multiforme, the activity in patients with hematologic malignancies is less clear. Bevacizumab (Avastin) is a MAb that targets VEGF (vascular endothelial growth factor). VEGF and other angiogenic proteins are known to play an important role in stimulating lymphoma cells to divide by binding to proteins on their cell surface. They are also known to play an important role in regulating the stromal microenvironment of the lymph node in which the lymphoma cell resides. Precisely how drugs targeting VEGF work in hematologic malignancies remains uncertain. However, early data has suggested that while these drugs do not appear to exhibit marked activity in their ability to shrink tumor, they too, like enzastaurin, appear to be able to sustain protracted and prolonged durations of response compared to other conventional therapies. The role of these proteins and other angiogenesis inhibitors in lymphoma is still an area of active research.
Comments
Under US FDA review for relapsed/refractory aggressive NHL Approved for brain cancer; being investigated in lymphomas of the central nervous system (CNS) Less cardiotoxic version of doxorubicin; active in NHL Many types of NHL and HL; related to doxorubicin
Temozolomide (Temodar)
Alkylating agent
Anthracycline
Anthracycline
lymphoma.org
Advanced disease: Disease that has spread to multiple locations. Aggressive lymphomas: Lymphomas that are fast growing and generally need to be treated immediately. Also called intermediate-grade or high-grade lymphomas. Allogeneic transplant: A procedure in which a patient receives bone marrow or stem cells donated by another person. Alopecia: Hair loss. Alopecia from chemotherapy is almost always
temporary; hair grows back when therapy is finished.
Anemia: A shortage of red blood cells, causing weakness and fatigue. Angiogenesis: The process of developing new blood vessels. Antiangiogenesis therapies: Drugs that prevent tumors from developing new blood vessels, thereby stopping or limiting tumor growth. Antibody: A substance made by B-lymphocytes that reacts with antigens
on toxins, bacteria and some cancer cells and either kills or marks them for removal.
Antiemetic: A drug that reduces or prevents nausea and vomiting. Antigen: Identifying proteins located on the surface of all cells. The
immune system uses antigens to determine whether cells are a necessary part of the body or need to be destroyed.
Autologous transplant: A type of bone marrow or stem cell transplantation in which a patient receives his or her own cells. Beta (2) microglobulin (B2M): A protein found in the blood. Higher
levels of B2M suggest that the lymphoma may be more aggressive.
111 Understanding Non-Hodgkin Lymphoma Understanding Non-Hodgkin Lymphoma 111 Glossary of Medical Terms
Bone marrow: Spongy material found inside the bones containing stem
cells that develop into three types of cells: red blood cells that deliver oxygen to the body and take away carbon dioxide; white blood cells that protect the body from infection; and platelets that help the blood to clot.
Bulky tumor: A large tumor, usually greater than five, seven or ten centimeters. Cancer: Abnormal cell growth that cannot be controlled by the bodys
natural defenses. Cancerous cells can grow and eventually form tumors.
Cerebrospinal fluid: Fluid that is present around the spine and brain. It may be examined to determine if NHL has spread to these parts of the body. Chemotherapy: Treatment with drugs to stop the growth of rapidly
dividing cancer cells, including lymphoma cells.
Chemotherapy regimen: Combinations of anticancer drugs given at a certain dose in a specific sequence according to a strict schedule. Clinical trial: A research study in which a new treatment is given to patients to
determine whether it is safe, more effective or less toxic than current therapies.
Combination Chemotherapy: Several drugs given together to increase response rate of certain tumors.
Complete remission (CR): Term used when all signs of the disease have
disappeared after treatment.
Cure: There are no signs or symptoms of lymphoma, and a significant period of time (usually defined by years) has passed during which there are no relapses. Decreased blood cell production: A decrease in the production of red
blood cells, white blood cells and platelets that may occur as a side effect of cancer or cancer therapies. Also called myelosuppression.
Diaphragm: The muscle below the lungs and heart that separates the abdomen from the chest. Disease progression: The term used if the disease worsens despite
treatment (also called treatment failure).
Dose intensity: A term used to describe giving the highest possible doses
of drugs over a specific period of time with acceptable side effects.
Durable remission: When a complete response lasts for years. Dysgeusia: When familiar foods taste differently. Echocardiogram: Use of ultrasound to examine the heart. It is ordered when potential cardiotoxic chemotherapy is used. Etiology: The study of the causes of a disease. Extranodal disease: NHL that has spread outside the lymphatic system. Fatigue: A decreased capacity for activity that is often accompanied by feelings of weariness, sleepiness or irritability.
UnderstandingGlossary of Medical Terms 113 Non-Hodgkin Lymphoma
Generalized disease: A cancer that has spread throughout the body. Genes: The basic building blocks of heredity that are present in all cells.
Genes are comprised of DNA and other materials.
Grade: A method of classifying a tumor on the basis of how aggressively it is growing. Graft versus host disease (GVHD): Occurs when a donors bone marrow (graft) recognizes the recipient of the marrow (the host) as foreign. In response, the immune cells in the donor marrow attack the foreign cells in the host. Harvesting: A procedure in which stem cells are obtained from the blood
or bone marrow for use in repopulating the bodys cells after high-dose chemotherapy.
Idiotype: A unique fingerprint portion of an antibody present on the surface of B-cells. Idiotype vaccine: A lymphoma vaccine that is custom-made to attack
an individual patients lymphoma and contains idiotype (unique) tumor material and an immune stimulant.
Immune system: One of the bodys defense mechanisms. All lymphomas are diseases of the immune system. Immunological tests: Blood tests that detect the presence of diagnostic proteins or antigens on a tumor. Immunotherapy: See biologic therapy. Improvement: This term is used if a tumor shrinks following therapy
but is still more than one-half of its original size.
Indolent lymphoma: Lymphoma that is slow growing and has few symptoms. Also called low-grade lymphoma. Lactate dehydrogenase (LDH): An enzyme found in the blood. Higher
levels of LDH suggest that the lymphoma may be more aggressive.
Leukemia: Disease generally characterized by the overproduction of abnormal or immature white blood cells that circulate or are present in the blood. Leukopenia: A shortage of white blood cells, resulting in the inability to fight infecting organisms such as bacteria, fungi and viruses. Localized disease: A cancer that is only present in a limited part of the body, for example, the neck or armpits.
115 Understanding Non-Hodgkins Lymphoma UnderstandingGlossary of Medical Terms 115 Non-Hodgkin Lymphoma
Local therapy: A therapy that only affects a small area. Low-grade lymphoma: Lymphoma that grows slowly and has few symptoms. Also called indolent lymphoma. Lymph: The watery fluid in the lymph system that contains white blood cells (lymphocytes). Lymph nodes: Small bean-shaped glands located in the small vessels of the lymphatic system. There are thousands of lymph nodes located throughout the body, with clusters of them in the neck, under the arms, the chest, abdomen and groin. Lymph nodes filter lymph fluid, trapping and destroying potentially harmful bacteria and viruses. Lymphatic system: The channels, tissues and organs that store and carry lymphocytes that fight infection and other diseases. Lymphocyte: A type of white blood cell. Lymphocytes, carried along
by the lymph fluid, are part of the immune system and fight infection.
Malignant: Cancerousa malignant tumor is a cancerous tumor. Medical oncologist: A physician who specializes in the use of chemotherapy, hormone therapy and many other types of biologic therapies to treat cancer.
Myelosuppresion: A reduction in the bone marrows ability to make red blood cells, white blood cells and platelets. Neutropenia: An abnormally low level of neutrophils (the white blood
cells responsible for fighting bacterial infections).
Neutrophils: The primary type of white blood cells found in the blood that fight bacteria, etc. Non-bulky tumor: A small tumor, usually less than five centimeters (approximately two inches) Non-Hodgkin lymphoma (NHL): A group of several closely related cancers that arise from the lymphatic system. Although the different types of NHL have some things in common, they differ in what the cancer cell looks like under a microscope, how the cells grow and how the tumor affects the body. Oncologist: A physician who specializes in treating cancer. Some
specialize in chemotherapy (medical oncologists), radiotherapy (radiation oncologists) or surgery (surgical oncologists).
Palliation: Treatment that is given to remove or relieve symptoms. Para-aortic: The area close to the aorta. The aorta is the largest vessel in
the body and rises from the heart.
Partial remission (PR): The term used when a cancer has shrunk in size
by at least half but has not totally disappeared. The cancer can still be detected, and other treatments may be recommended.
Primary therapy: The first therapy given after a diagnosis of cancer. Prognosis: The likely outcome of a disease, including the chance
of recovery.
Radiation field: The part of the body that receives radiation therapy. Radiation oncologist: A physician who specializes in treating cancer
with radiation.
Radiation therapy: The use of radiation beams (X-rays) to treat a cancer. High doses of high-energy radiation beams carefully focused on a tumor will kill cancer cells. Radiation therapy (with or without chemotherapy) is used to treat certain lymphomas. Radioimmunotherapy: A therapy that is prepared by attaching a radioactive isotope to a monoclonal antibody. Radionuclide tests: Tests that use radioactive substances to help evaluate
the function of tissues.
Refractory disease: A cancer that is resistant to treatment. Regimen: A specific combination of drugs (chemotherapy), their doses
and their schedules of administration. A regimen may also include radiotherapy.
Risk factors: Factors that may increase the chance that a person will
develop NHL. It is important to note that most people with risk factors never develop lymphoma, and many who are diagnosed have no identifiable risk factors.
Spleen: An organ on the left side of the upper abdomen, near the stomach.
A key component of the lymphatic system, the spleen produces and stores lymphocytes and releases them when required as part of the bodys response to infections and other stimuli. The spleen may store blood and remove old blood cells from circulation.
Stable disease: The disease does not get better or worse following therapy. Stage: The extent of cancer in the body, including whether the disease has
spread from the original site to other body parts.
Standard therapy: The most widely used primary therapy. Synergism: The term used when two or more drugs given together provide
a better anti-cancer effect than expected from the additive effects from the medications alone.
X-ray: Radiation that is used in low doses to provide images of the inside
of the body and in high doses to treat cancer.
lymphoma.org
Lymphoma Newsline
Lymphoma-related news can be distributed to you directly through this free electronic news services. Sign-up is required by clicking on the register icon on LRFs homepage at lymphoma.org.
Multi-Media Programs
Because LRF understands that lymphoma information continually changes throughout the year, the on-going production of webcasts, podcasts and teleconferences enable you to access the latest information on specific topics anywhere, anytime.
Webcasts
Webcast programs offer you the opportunity to navigate through a synchronized audio and slide presentation.
Podcasts
Podcast (MP3) programs are presented in audio format only and can be downloaded to your portable MP3 player.
Teleconferences
Teleconferences are hour-long interactive telephone programs that provide an opportunity to learn more about lymphoma, treatments and promising research from leading lymphoma experts. These are conducted live and the archived version is available after the program.
Publications
booklets
In addition to this publication, LRF also produces Understanding Hodgkin Lymphoma: A Guide for Patients, Survivors and Loved Ones and Understanding Chronic Lymphocytic Leukemia (CLL): A Guide for Patients, Survivors and Loved Ones.
fact Sheets
Fact sheets are available to provide you with the latest disease- and treatment-specific information and are available in either hard copy or in PDF on LRFs website. New topics are added on a regular basis, so be sure to check to see if the topic you are looking for is available.
Newsletters
To keep you abreast of LRF research and news in the wider lymphoma community, you can sign-up to receive any of LRFs regular newsletters either electronically or via mail. Any of LRFs publications may be ordered by visiting lymphoma.org. Individual and bulk copies are available free of charge.
Planet Cancer
Planet Cancer (a program of the Lance Armstrong Foundation) is a peer support community for Young Adults going through the tremendously isolating experience of cancer between the ages of 18 and 40. On Planet Cancer, young adult patients and survivors connect 24 hours a day, 7 days a week through a dynamic and irreverent social networking website and face-to-face retreats. Planet Cancer also provides advocacy programs to build awareness about the unique medical and psychosocial needs of this often-overlooked age group. Visit planetcancer.org to access these services. Ulman Cancer fund for Young Adults This organization focuses on how cancer affects young adults and offers scholarships, community grants, advocacy services and a guidebook; ulmanfund.org.
HOW TO GET INvOLvED AND GIvE bACK Take Action to Make a Difference
The LRF Advocacy Program is a network of people and programs dedicated to increasing awareness and support for the lymphoma community. The Advocacy Program focuses on taking action on laws, policies and positions that affect every lymphoma patient and survivor. By contacting elected officials via phone calls, email and letters in support of these priorities, local advocates help LRF to make lymphoma a national health priority. To become involved, visit lymphoma.org/advocacy.
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Donate Now
The Lymphoma Research Foundation (LRF) is a nonprofit health organization with 501(c)(3) status. If you would like to support LRF, your generous gift will help us move closer to finding a cure, while helping those affected by the disease.
Three easy ways to give: Website: lymphoma.org/donatenow Call: (800) 235-6848 Mail: Cut out this form and mail it to Lymphoma Research Foundation, 115 Broadway, 13th Floor, New York, New York 10006 or Fax: (212) 349-2886
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