NHL Booklet Final

Understanding
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
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2010 Lymphoma Research Foundation Information contained herein is the property of the Lymphoma Research Foundation (LRF). Any portion may be reprinted or reproduced provided that LRF is acknowleged to be the source.
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
ii Understanding Non-Hodgkin Lymphoma
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
Understanding Non-Hodgkin Lymphoma iii
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
Part 2: Treating Non-Hodgkin Lymphoma

Chapter 4 What You Should Know before Starting Treatment. . . . . . . . . . . . . . . . . . . . . . Communicating With Your Healthcare Team . . . . . . . . . . . . . . . . . . . . . . . . . . . . How to Be a Self-Advocate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Factors Affecting Treatment Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chapter 5 Types of Treatment for Non-Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . Watchful Waiting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conventional Chemotherapy Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radiation Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stem Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Novel Targeted Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New Versions of Established Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Interferon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Complementary and Alternative Remedies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug Costs: What to Do If Your Insurance Does Not Pay . . . . . . . . . . . . . . . . . . When to Consider a Clinical Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 30 32 33 37 37 38 44 46 50 56 57 58 60 60
iv Understanding Non-Hodgkin Lymphoma
Part 3: Treatment Side Effects

Chapter 6 Coping With Common Treatment Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . Side Effects Caused By: Chemotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rituximab and Other Biological Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . Bone Marrow or Stem Cell Transplantation. . . . . . . . . . . . . . . . . . . . . . . . . . Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Combating Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Difference Between Long-Term Effects and Late Effects . . . . . . . . . . . . . . Chapter 7 Sexuality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sexual Function During Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . When to Use Contraceptives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pregnancy and Breast-Feeding During Treatment . . . . . . . . . . . . . . . . . . . . . . . 61 61 69 70 70 71 71 71 73 75 75 75 76
Chapter 8 fertility Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 How to Protect Fertility in Men . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 How to Protect Fertility in Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Part 4: Children and Young Adults With Non-Hodgkin Lymphoma

Chapter 9 General Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Coping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Important Considerations for Childhood Lymphoma Survivors . . . . . . . . . . . . . Chapter 10 Special Concerns for Teenagers and Young Adults . . . . . . . . . . . . . . . . . . . . . . Specific Treatment Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Important Considerations for Long-Term Young Adult Survivors . . . . . . . . . . . Emotional and Practical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 80 80 81 81 81
83 83 84 84
Understanding Non-Hodgkin Lymphoma v
Part 5: Living With Non-Hodgkin Lymphoma

Chapter 11 Regaining Your Life During and After Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . Coping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Life After Remission. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Follow-Up Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 87 88 88
Chapter 12 Relapsed or Refractory NHL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Part 6: Clinical Trials

Chapter 13 Overview of Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 Basics of Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 Participating in a Clinical Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 Chapter 14 New Agents or Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Drugs Affecting Protein Disposal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Drugs Affecting How Cancer Cells Divide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 Teaching Cancer Cells How to Die . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 Agents Affecting Immunologic Targets. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Drugs Selectively Targeting Cancer Cell Gene Expression. . . . . . . . . . . . . . . . 105 Drugs Targeting Essential Lymphoma Biology . . . . . . . . . . . . . . . . . . . . . . . . . 107 New Derivatives of Old Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Glossary of Medical Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 About the Lymphoma Research foundation. . . . . . . . . . . . . . . . . . . . . . . . . . . 123 Resources for Patients, Survivors and Loved Ones. . . . . . . . . . . . . . . . . . . . . 123 Resources for Children and Young Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 How to Get Involved and Give back . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 Donate Now. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
vi Understanding Non-Hodgkin Lymphoma
Part
Part 1: Learning the basics
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.
Learning the Basics 1
Non-Hodgkin Lymphoma Overview

Lymphoma comprises about 67 subtypes of two related cancers that affect the lymphatic system, Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). There are six types of Hodgkin lymphoma and at least 61 types of non-Hodgkin lymphoma. Hodgkin lymphomas are somewhat different from non-Hodgkin lymphomas in the way they develop, spread and are treated. Lymphoma is the most common blood cancer and the third most common cancer among children. Lymphoma usually develops when a genetic error, or mutation, occurs within a lymphocyte, causing the abnormal cell to duplicate faster than a normal cell or live longer than a normal lymphocyte. Lymphocytes are small white blood cells that play a large role in the immune system, which defends the body against foreign invaders, such as bacteria or viruses. Like normal lymphocytes, cancerous lymphocytes can travel in the blood and grow in many parts of the body, including the lymph nodes, spleen, bone marrow, blood or other organs. As a result, while some NHLs are localized in one area of the body, most are present throughout the body by the time of diagnosis. Although the various types of NHL have some things in common, such as their lymphatic origin, they differ in their appearance under the microscope, their molecular features, their growth patterns, their impact on the body and how they are treated. Non-Hodgkin lymphoma is divided into two major groups: B-cell lymphomas and T-cell lymphomas. B-cell lymphomas develop from abnormal B-lymphocytes (B because B-lymphocytes come from the bone marrow) and account for 85 percent of all NHLs. T-cell lymphomas develop from abnormal T-lymphocytes (T because normally T-lymphocytes spend part of their lifespan in the thymus gland, a small organ in the chest) and account for the remaining 15 percent of NHLs. Non-Hodgkin lymphoma has grown from being a relatively uncommon disease to being the fifth most common cancer in the United States, nearly doubling in incidence since the early1970s, and increasing among women since 1991. According to the American Cancer Society, over 65,000 new cases of NHL are diagnosed annually.
2 Understanding Non-Hodgkin Lymphoma
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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.
The Lymphatic System

The lymphatic system is one of the most important parts of the immune system and protects the body from disease and infection. The lymphatic system is a circulatory system that is made up of a series of thin tubes called lymph vessels that branch out like blood vessels into all tissues of the body (see page 4). Lymph vessels carry lymph, a fluid that contains white blood cells called lymphocytes. Within this vast network of vessels are groups of small, bean-shaped organs called lymph nodes. Thousands of lymph nodes are found throughout the body, including the elbows, neck, armpits and groin. Lymph fluid flows through lymph nodes and specialized lymph tissues such as the spleen, tonsils, bone marrow and thymus gland. Lymph nodes filter lymph fluid, removing bacteria, viruses and other foreign substances from the body. If a large number of foreign substances are filtered through a node or series of nodes, swelling may occur and the nodes may become tender to the touch. Most swollen nodes are a reaction to infection and are not cancerous.
How Lymphocytes Work

Lymphocytes are a type of white blood cell that helps the body fight infections. They are made in the bone marrow, spleen and lymph nodes, and circulate in the blood and lymph vessels. Lymphocytes recognize
The immune system is the bodys defense against outside invaders.
ANATOMY Of THE IMMUNE SYSTEM
Tonsils and adenoids Lymph nodes
Thymus Lymph nodes
Lymph nodes (epitrochlear)
Spleen
Peyers patches Appendix
bone marrow
Lymph nodes Lymphatic vessels
IMMUNE SYSTEM INvADERS
Bacteria
Viruses
Parasites
Fungi
Pollution
Toxins
HOW CANCER fORMS INSIDE THE bODY
Abnormal Cells Evade the Immune System
Abnormal Cells Multiply (Cancer)
Tumors May form (Groups of Abnormal Cells)
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.
The Causes of Non-Hodgkin Lymphoma

Although the exact causes of non-Hodgkin lymphoma (NHL) remain unknown, some common factors appear to have an impact on risk. For example, NHL incidence increases with age. Approximately 70 percent of people diagnosed with NHL are 50 years old or more; they are more likely to be men than women; and they are more likely to be Caucasian than African-American. The disease is also more common among people with depressed immune systems and those exposed to environmental carcinogens, pesticides, herbicides, viruses and certain bacteria. Risk for developing lymphoma may be higher in individuals who: have a family history of NHL are affected with an autoimmune disease have received an organ transplant have been exposed to chemicals such as pesticides, fertilizers or organic solvents for a long period
1
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.
Where Non-Hodgkin Lymphoma Develops

Tumors may be present in a single lymph node or in several at once. Although some NHLs are localized in one area, most are found in multiple parts of the body by the time the diagnosis is confirmed. Some lymphomas can occur outside the lymphatic system and are identified by their tissue of origin, such as the mucosa (lining of organs) or skin.
Common Types of Non-Hodgkin Lymphoma

Classifying the type of NHL a patient has is determined through a tumor tissue biopsy. Since the two main types of lymphocytes are B-lymphocytes and T-lymphocytes, most lymphomas are designated as either B-cell or T-cell. Because there are so many types of NHL (at least 61), and new subtypes are continually being identified, classifying lymphoma is complicated and has evolved over the years. Most recently, the World Health Organization (WHO) adopted a lymphoma classification system that combines updated information on the appearance, growth pattern, immunologic and genetic features of the cells, as well as how the disease acts in the body. The WHO classification recognizes several new types of NHL and represents an advance in the ability to distinguish specific lymphomas. This new classification system has helped to facilitate cooperation and communication among doctors around the world. The WHO classification system is a modification of the Revised European American Lymphoma (REAL) classification, upon which it was based.
The Difference between Indolent and Aggressive Lymphomas

Because there are so many different forms of NHL, they are often grouped according to their clinical behavior and whether they are indolent (slowgrowing or low grade) or aggressive (intermediate or high grade). Indolent lymphomas are usually chronic but not curable. Aggressive lymphomas, while potentially life threatening, can often be cured. (See Grading and Staging Non-Hodgkin Lymphoma, on page 25.)
Types of Indolent Non-Hodgkin Lymphoma
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.
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

According to the American Cancer Society, approximately 15,000 new cases of CLL and 3,600 new cases of SLL are diagnosed annually. This form of cancer is usually diagnosed in older adults over the age of 50more than half of the people with CLL are over age 70. Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are considered B-cell malignancies and are essentially the same disease with slightly different manifestations. The same kind of cell,
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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.
Marginal Zone Lymphoma

Marginal zone B-cell lymphomas, a group of indolent lymphomas whose cells come from B-lymphocytes normally found in the marginal zone of the secondary lymphoid follicles in the spleen and lymph nodes, accounts for approximately seven percent of all NHLs. The median age for diagnosis of this type of lymphoma is 65. Marginal zone lymphomas encompass three basic types: (1) extranodal or mucosa-associated lymphoid tissue (MALT), occurring outside the lymph nodes, (2) nodal, occurring within the lymph nodes, and (3) splenic, occurring mostly in the spleen and blood. Skin-associated lymphoid-tissue-related B-cell lymphoma (SALT) is also considered a form of MALT lymphoma. Marginal zone and MALT lymphomas vary from other types of B-cell NHLs in a number of ways: their natural history is different many people who develop MALT lymphoma have a history of inflammation or autoimmune disorders
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).
Cutaneous T-Cell Lymphoma

Cutaneous lymphomas arise in the skin and account for approximately two percent to three percent of all NHL cases. Cutaneous lymphomas include both B-cell and T-cell lymphomas, though T-cells are more common. The age of presentation is, on average, between 50-60 years, though younger people are also diagnosed with cutaneous T-cell lymphoma (CTCL). The most common form of CTCL is mycosis fungoides, which is often indolent and appears as reddish skin patches, plaques or scales. An advanced, or variant, form of mycosis fungoides is called Szary syndrome, which is often characterized by redness and scaling of the skin, enlarged lymph nodes and malignant T-cells circulating in the blood. Depending on the symptoms or stage of disease, treatments are directed at the skin (e.g., ultraviolet light, topical steroids, topical chemotherapies, topical retinoids and electron beam radiation therapy) or the entire body (e.g., oral retinoids, photopheresis,
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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).
Types of Aggressive Non-Hodgkin b-cell Lymphoma
Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common form of NHL, accounting for up to one-third of newly diagnosed cases. Although most frequently seen in adultsthe median age at diagnosis is 57the disease may also be seen in young people. The disease is an aggressive, or fast-growing, lymphoma and can arise in the lymph nodes or outside of the lymphatic system. It may be localized or generalized (spread throughout the body). Despite being an aggressive lymphoma, DLBCL is potentially curable. The first sign of DLBCL is usually rapid swelling in the neck, armpit or groin caused by enlarged lymph nodes. Other symptoms include night sweats, chills, unexplained fevers and weight loss.
Mantle Cell Lymphoma

Mantle cell lymphoma is a B-cell lymphoma that affects approximately six percent of all NHL patients. Mantle cell lymphoma usually affects men over 50. Frequently, patients with mantle cell lymphoma have many lymph nodes, one or more organs and bone marrow involved. The gastrointestinal tract is a very common extra-nodal site of involvement. Mantle cell
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.
Burkitts Lymphoma, Burkitt-like Lymphoma (Small Non-Cleaved Cell Lymphoma)

Burkitts lymphoma is an aggressive B-cell form of NHL that occurs most often in children and young adults. There are three main types of Burkitts lymphoma: sporadic, endemic and immunodeficiency-related disease. While sporadic Burkitts lymphoma occurs throughout most of the world, endemic Burkitts lymphoma is found mostly in Africa and is often associated with the Epstein-Barr virus (EBV). Immunodeficiency-related Burkitts lymphoma is diagnosed most often in people infected with HIV/AIDS. The disease may affect the jaw, central nervous system, bone marrow, bowel, kidneys, ovaries or other organs. Burkitts lymphoma has a specific chromosomal abnormality called the t(8;14) translocation and behaves aggressively. Burkitts lymphoma is potentially curable.
Types of Aggressive Non-Hodgkin T-Cell Lymphoma
Peripheral T-Cell Lymphomas

Peripheral T-cell lymphomas refer to a large number of different T-cell lymphomas that together comprise between 10 percent and 15 percent of all cases of NHL and can occur anytime during adulthood. The term peripheral T-cell lymphoma is based on the fact that these tumors are composed of T-cells (not B-cells) and that the cells are mature. Most peripheral T-cell lymphomas are aggressive, with the exception of mycosis fungoides (see Cutaneous T-cell Lymphoma, on page 10). Some varieties of peripheral T-cell lymphoma are quite rare in the United States but can more commonly be found in Asia, notably Japan, where an infection with a virus called HTLV-1 is prevalent. Its presence makes it more likely for an individual to develop a specific type of peripheral T-cell lymphoma. It has also been found in individuals coming from Caribbean countries.
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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.
Blastic NK-Cell Lymphoma

Blastic NK-cell lymphoma is a very rare T-cell lymphoma, affecting only a few people (usually adults) each year. This lymphoma is very fast growing, is difficult to treat and can arise anywhere in the body. Since this disease is so rare, patients should consult with their medical team to find promising therapies or clinical trials.
Nasal T-Cell Lymphoma

Although this fast-growing lymphoma is very rare in the United States, it is relatively common in Asia and parts of Latin America, leading researchers to suspect that some ethnic groups may be more prone to this cancer, which affects both children and adults. This type of lymphoma is associated with the Epstein-Barr virus. As with other rare cancers, patients should consult with their medical team for treatment options and the availability of clinical trials.
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.
Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma (PCNSL) is a type of cancer that is limited to the brain or spinal cord but may also be found in tissues around the eye. An increasing occurrence of this disease has been seen in patients with AIDS and others whose immune system has been compromised. Median age of diagnosis for patients with PCNSL is 55 years for patients with a normal immune system and 31 years for AIDS patients. Although in the past the outlook for patients with this cancer has been poor, today the survival rate has greatly improved.
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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.)
Treatment-Related T-Cell Lymphomas

Treatment-related T-cell lymphomas sometimes appear after solid organ or bone marrow transplantation. The immune system suppression that is required for transplant patients can put them at risk for developing post-transplant lymphoproliferative disorders, certain unusual forms of peripheral T-cell lymphoma and other types of non-Hodgkin lymphoma. Treatment-related T-cell lymphomas may require therapy that differs from the standard treatments normally used to treat these conditions.
Enteropathy-Type T-Cell Lymphoma

Enteropathy-type T-cell lymphoma is an extremely rare subtype of T-cell lymphoma that appears in the intestines and is strongly associated with celiac disease. As with other rare cancers, patients should discuss treatment options with their medical team.
Hepatosplenic Gamma-Delta T-Cell Lymphoma

Hepatosplenic gamma-delta T-cell lymphoma is an extremely rare and aggressive disease that starts in the liver or spleen. This lymphoma may occur in young males with Crohns disease who are immunosuppressed. As with other rare cancers, patients should discuss treatment options with their medical team.
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.
Rare Immune System Cancers

Rare immune system cancers include a group of rare diseases that are neither B-cell nor T-cell lymphomas, but instead are cancerous forms of other types of white blood cells and include histiocytic and dendritic cell neoplasms. Patients diagnosed with these cancers should seek advice from their medical team about clinical trials that might be recruiting patients.
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.
Please refer to our website for additional and updated information.
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Chapter 2
Signs and Symptoms of Non-Hodgkin Lymphoma

A sign is something a provider detects on physical examination. A symptom is something a patient notices and states to their healthcare provider. Signs are actual findings found on evaluation by the healthcare provider. Symptoms are the patients reported physical experiences that may indicate the presence of disease. Some patients may not experience any symptoms and their lymphoma may be detected initially upon routine physical examination. Others may experience one or more of the following symptoms: chills, fever, sweating (most often at night), unexplained weight loss, headaches, lack of energy, itching, swollen lymph nodes or symptoms produced by enlarged lymph nodes, such as pain.
When to Seek Medical Attention

It is important that anyone who has persistent symptoms be seen by a doctor to make sure that lymphoma is not present. Serious illnesses are persistent. Seek medical attention if any of the above symptoms last longer than two weeks. Many of these symptoms can arise from different causes and need not be cancer.
What the Doctor Looks for

There is no one particular test that allows physicians to routinely screen for lymphoma. Anyone with symptoms suggesting NHL, should see their doctor who will take a medical history and perform a complete physical examination, checking for swollen lymph nodes under the chin, in the neck and tonsil area, above the shoulders, on the elbows, in the armpits and in the groin. The doctor may examine other parts of the body to see whether there is swelling or fluid in the chest or abdomen that could be caused by swollen lymph nodes. The abdomen will also be examined to
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.
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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.
Common Diagnostic Tests

Physicians may use some or all of the following tests as well as the patients medical history and the results of the physical examination to assess the best course of treatment or treatments that have the best chance of rendering either a remission or cure. COMMON TESTS USED TO EvALUATE NHL
Biopsy Blood tests Bone marrow examination Cerebrospinal fluid examination Imaging tests: X-ray CT (computerized tomography) scan MRI (magnetic resonance imaging) PET (positron emission tomography) scan Gallium (radioisotope) scan (rarely used any longer) Molecular diagnostic tests
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.
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.
Fine Needle Aspirate

An even more limited type of biopsy is called a fine needle aspirate (FNA), which is performed using a very small gauge needle. This technique yields mostly scattered cells, and intact lymph node architecture is not preserved. Such needle biopsies are more often used to confirm a relapse rather than an initial diagnosis because they often do not produce sufficient tissue to establish a precise diagnosis. After a tissue sample has been removed it is examined by a pathologist (a doctor who studies tissues and cells to identify diseases) who develops a report. To confirm a diagnosis, the oncologist uses this report along with the results of immunologic studies. If the pathologists interpretation of the biopsy is uncertain, the report should be reviewed by a hematopathologist, since a pathological diagnosis of lymphoma can sometimes be difficult to make.
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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.
bone Marrow Examination

Bone marrow is the spongy, soft material found inside our bones. Bone marrow contains immature cells called stem cells, which develop into three main types of cells found in the body: red blood cells that deliver oxygen to all parts of the body and take away the waste product carbon dioxide; white blood cells, primarily neutrophils and lymphocytes, which protect the body from infection; and platelets, which help blood clot. Non-Hodgkin lymphoma can spread to the bone marrow or start in the bone marrow. To determine whether lymphoma is present, doctors may examine part of the marrow by first numbing the area around the skin, tissue and surface of the bone with a local anesthetic and then inserting a thin needle usually into an area of the pelvic bone and extracting a small tissue sample. The procedure can be painful at the moment the marrow is withdrawn. Patients who are anxious about the test should talk with their doctor and nurse to see whether taking a calming medication before the procedure would be helpful.
Cerebrospinal fluid Examination

In a small number of patients, NHL can spread to the nervous system. When this happens, the fluid present around the spinal cord and the brain (cerebrospinal fluid) may be abnormal and contain cancer cells. To determine whether this has occurred, the physician may recommend a test called a spinal tap or a lumbar puncture, in which a thin needle is inserted into the lower back under local anesthetic. A small sample of fluid is then removed, and the cerebrospinal fluid is examined for chemical content and abnormal cells.
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.
CT (computerized axial tomography) Scan

A CT scan takes X-rays from different angles around the body. The pictures obtained are then combined using a computer to give a detailed image. People with NHL often have CT scans of the neck, chest, abdomen and pelvis. These tests are useful in determining how many lymph nodes are involved, how large they are and whether internal organs are affected by the disease.
MRI (magnetic resonance imaging)

An MRI is similar to a CT scan but uses magnets and radiofrequency waves instead of X-rays. An MRI can provide important information about tissues and organs, particularly the nervous system, that is not available from other imaging techniques. Because this testing technique works well to get clear images of the bones, brain and spinal cord, an MRI may be ordered when the physician wants to see whether the lymphoma has spread in these areas.
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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).
Molecular Diagnostic Tests

Over the past decade, scientists have gained a deeper understanding of how lymphoma works at the molecular level. This understanding has led to powerful new diagnostic tools and treatments. These tools include polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH), which can detect small amounts of genetic material, and a variety
QUESTIONS TO ASK YOUR DOCTOR bEfORE HAvING A PROCEDURE

Why is this procedure necessary? What will the procedure tell us about my condition? Can the same information be obtained in any other way? What is involved in doing this procedure? What are the possible risks, complications and side effects? How long will the procedure take? Will I feel pain? When will I know the results? When will we talk about the results? What will my out-of-pocket costs be? Should anyone else be present when I have the procedure? Will I need someone to take me home afterward?
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.
Grading Non-Hodgkin Lymphoma

Grading lymphoma tumors is important because it helps to define the usual growth pattern and aggressiveness of the lymphoma cells and helps the physician determine the kind of treatment to be prescribed. Lymphomas classified as low-grade, or indolent, tend to grow very slowly and may need treatment less urgently. Indolent lymphomas, although usually extremely responsive to therapy, are rarely cured with conventional therapy and are usually widespread at the time of diagnosis. Nevertheless, patients often live for a long time with a good quality of life. Some indolent lymphomas can transform over time into more aggressive types requiring more intensive treatment. Intermediate- and high-grade NHLs are often classified as aggressive because these tumors generally grow rapidly and may require treatment soon after diagnosis. Although people with more aggressive lymphomas often need more immediate intensive treatment, their cancers are potentially curable.
Staging Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma is divided into four stages, based on how far the disease has spread. Stages I and II are considered localized, while stages III and IV are considered advanced, widespread or disseminated. However, it is important to remember that being diagnosed with NHL at an advanced stage III or IV is common, andunlike a stage IV diagnosis in solid tumor cancers in which the primary cancer has spread to other sitesadvanced stages for NHL can be successfully treated and may still be cured. Staging the disease helps doctors to predict outcome or prognosis and determine treatment approaches.
The Meaning of the Letters A, b or E After the Stage

Each stage of NHL is further divided into A, B and E categories, depending on the symptoms patients have when they are diagnosed.
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.
Getting a Second Opinion

Before starting therapy, patients may want to consider getting a second opinion to confirm the diagnosis and treatment plan, particularly if some aspects of the NHL are complicated or uncertain. Some insurance programs require second opinions; others may cover it if a patient or physician requests it. Sometimes, second opinions are obtained at academic medical centers. The hematologists/oncologists specializing in lymphoma may provide a consultation and establish a collaborative relationship with a local oncologist for treatment and follow-up care. When seeking a second opinion, patients should remember that it is best to request a complete copy of all medical records and provide original X-rays, pathology materials, scans and reports that are requested by the consulting physician. It may be useful to keep a copy of the medical
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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.
Choosing an Oncologist and Treatment Center

Before agreeing to treatment by a physician or clinic, a patient should be certain that all of their medical and personal needs will be met. Take time to check: (1) the credentials of the physician, the other members of the medical team and the hospital or cancer center, (2) the portion of time the physician spends researching or treating NHL and (3) the patient resources within the cancer center. Patients should keep in mind that if in a managed care program, choices may be limited. However, if a patient is not entirely satisfied with their first consultation, they have the right to choose another healthcare team. Referrals may be obtained by speaking with other NHL patients or asking their primary physician. It is important that patients feel comfortable with their healthcare team and the quality of care they are receiving. QUESTIONS TO ASK WHEN CHOOSING A DOCTOR AND TREATMENT CENTER
before beginning treatment, ask these basic questions: How much experience does this doctor (treatment center) have in treating cancer in general, and lymphoma in particular? How many patients with lymphoma are being treated here now? Is the doctor board certified as an oncologist or hematologist? Has he or she passed qualifying examinations by the American Board of Internal Medicine that certify his or her competency in these specialties? Do the oncologists, hematologists or center participate in clinical trials? Does the clinic or center have state-of-the-art surgical facilities and diagnostic equipment? Is the doctor or clinic affiliated with any major medical center or medical school? What arrangements are made for medical coverage after hours and on weekends, in case of an emergency? Is my health insurance accepted at this center? Will the office file claims for reimbursement and process the paperwork? How may I learn more about my type of lymphoma?
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Part 2: Treating Non-Hodgkin Lymphoma
Chapter 4
What You Should Know before Starting Treatment

Getting a lymphoma diagnosis is frightening, and patients are naturally concerned about what their future may hold. Oftentimes, patients will ask their doctor about their outlook, or prognosis, the medical term used to describe how the disease will progress and the likelihood for recovery. To be an educated healthcare consumer, it is important to understand the nature of NHL and what to expect from treatments, including any possible effects on quality of life, such as lifestyle, emotions and financial issues. Prognosis is usually based on information gathered from hundreds or thousands of other patients who have had the same disease. This statistical information provides physicians with a general idea of what to expect when a patient is diagnosed with a specific type of NHL and also gives guidance on the kinds of treatments that have been most successful in treating that cancer. However, it is important to remember that no two patients are alike and that statistics from large groups of people do not
Treating Non-Hodgkin Lymphoma 29
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.
Communicating With Your Healthcare Team

People who are diagnosed with NHL are often anxious to learn all they can about their disease and treatment choices so they can play an active role in decisions about their care. For many people, getting an NHL diagnosis is shocking and it is normal to feel a lot of physical and emotional stress following diagnosis. Some people are uncertain about how to talk with physicians, and the combination of stress and uncertainty may make it difficult to know what to say or what questions to ask. Patients can ease their anxieties by establishing an open and honest dialogue with their physician and nurse regarding their diagnosis, and learning about what the prescribed treatment regimen is, how it works, what tests are involved and what side effects and complications may be associated with it. A good first step is to write down all of the questions that come to mind. Before meeting with a physician or nurse, whether for the first time or for follow-up visits, organize and write out all questions. Put the two or three most important questions at the top of the list, since time with physicians or nurses may be limited. But make sure that a member of the medical team reads all of the questions, because they may see some that are more important than the patient realizes. Also, it is helpful for patients to have a member of their family or a close friend accompany them to the physicians office or clinic to help ask questions and understand and remember answers. It can also be helpful to write down the answers to the questions. Some patients bring a recording device to record the answers. Patients should check with their physician before recording any conversations. Most oncology nurses are also very well informed about cancer treatments and are a good source of information on a wide range of topics. Oncology social workers are also available to assist with practical and emotional needs from the point of diagnosis onward.
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.
TIPS ON COMMUNICATING WITH YOUR DOCTOR

Keep a journal of your symptoms to help you remember the details you want to discuss with your doctor during your office visit and bring a list of your questions to your appointment. During your office visit, take notes or tape record your conversation to help you accurately review the information afterward. Bringing along a family member or friend for support and to take notes for you is also helpful. Do not be afraid to ask questions when you do not understand something. Doctors want to know when you are uncertain or confused and will try to explain information to you. Before leaving the doctors office, make sure you understand the next step in your care and ask if there is written information you can take home.
Writing an Advance Healthcare Directive and Appointing a Healthcare Proxy

Writing down wishes for critical medical care in an advance healthcare directive is a way that patients can inform their physician, family members and friends about their healthcare preferences and what special treatment they want or do not want at the end of life. Besides stating medical care instructions, the advance healthcare directive should also include the name of the patients healthcare proxy, or decision maker. This person should be someone the patient believes will carry out their wishes if they are unable to do so, including do not resuscitate (DNR) instructions. Before writing an advance healthcare directive, it is important that patients understand their rights and the laws regarding advance healthcare directives in their state. Consulting an attorney can provide the legal information, but patients do not have to use an attorney to write an advance directive. Some things a patient should consider when writing an advance healthcare directive include:
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.
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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.
factors Affecting Treatment Outcome

Before treatment, patients often wonder how they will respond to a specific regimen. This depends on the type of lymphoma as well as other factors, which may be remembered by the acronym APPLES.
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.
Levels of blood Proteins

Lactate dehydrogenase (LDH) and beta (2) microglobulin (B2M) are proteins found in the blood. Higher levels of LDH or B2M suggest that the lymphoma may be more aggressive. People who have normal levels of these proteins appear to have better outcomes than those with higher levels of these proteins.
Extranodal Disease (disease outside the lymph nodes)

Patients with NHL that has spread outside the lymph nodes to other areas, such as the bone marrow or nervous system, tend to have a lower cure rate compared with those whose disease has not spread.
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
Types of Treatment for Non-Hodgkin Lymphoma

Many effective treatment options exist for NHL patients. The type of treatment chosen depends on the type of lymphoma and its stage, as well as other prognostic factors. (See Factors Affecting Treatment Outcome on page 33.) This chapter includes a description of types of standard and approved therapies, including: (1) watchful waiting, (2) conventional chemotherapy approaches, (3) radiation therapy, (4) stem cell transplantation, (5) novel targeted agents, (6) newer versions of established agents and (7) interferon. For each section, a description of the mechanism of action will be presented, along with the therapies approved by the United States Food and Drug Administration (FDA) at the time of print. It is important to remember that new therapies may have been approved since this book went to print and that additional indications for the therapies discussed in this chapter may be granted as clinical trials reveal new uses. Refer to Chapter 14 for therapies under investigation. For the most up-to-date resources, visit lymphoma.org or fda.gov.
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.
Current Perspectives on Watchful Waiting

The standard of care for advanced-stage, asymptomatic follicular lymphoma is often the watch-and-wait approach. However, ongoing clinical studies are testing whether giving the monoclonal antibody rituximab (Rituxan)- either alone or in combination with chemotherapy- may prolong survival. This technique is sparking debate among physicians about whether to abandon the watchful waiting approach in some patients. However, watchful waiting is still appropriate for patients with a very low risk of disease progression based on prognostic data, and indicated after protracted courses of rituximab (Rituxan). As more drugs with high efficacy and very favorable toxicity profiles emerge, it is likely that these treatment opportunities will replace watchful waiting in selected patients.
Conventional Chemotherapy Approaches

Chemotherapy (chemo) is treatment with drugs (as opposed to radiation, for example).
Combining Chemotherapy Drugs

Chemotherapy for NHL often consists of giving several drugs together (combination chemotherapy) in a defined way (schedule), called a treatment regimen. Drug combinations are used because different medications damage or kill cancer cells in different ways making them more vulnerable to the treatment. Combining chemotherapy drugs together provides a more effective way to kill more tumor cells, because using the drugs together greatly augments the impact of each drug (called synergism). In addition, when some drugs are added together in lower doses it helps reduce the likelihood of side effects without reducing the overall amount of effective chemotherapy. For example, the combination of four drugs (cyclophosphamide, doxorubicin or hydroxydaunorubicin, vincristine and prednisone), referred to as CHOP chemotherapy, represents the standard therapy for diffuse large B-cell lymphoma (DLBCL). This combination uses drugs that are given in somewhat less toxic amounts while sustaining a full or augmented (synergistic) capacity to destroy NHL. Another reason for combination chemotherapy is to prevent the emergence of drug resistance.
Common Chemotherapy Drugs DNA-Altering Drugs

These drugs damage DNA, the building blocks of genes, to prevent cell growth. Chemical Name Brand or Other Name Examples of Use in Combination Chemotherapy
Bendamustine
Treanda
Bendamustine-Rituximab (Rituxan) (referred to as B-R)
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
Antitumor Antibiotics (Anthracyclines)

These drugs interact with DNA and decrease cell survival. They come from natural sources, such as plants or microorganisms. Chemical Name Brand or Other Name Examples of Use in Combination Chemotherapy
Bleomycin Doxorubicin
Blenoxane Adriamycin Doxil (pegylated form) Hydroxydaunorubicin Rubex
ABVD CHOP, ABVD, HyperCVAD, EPOCH
Synthetic Drugs That Act Like Doxorubicin (Anthracenediones)

Chemical Name Brand or Other Name Examples of Use in Combination Chemotherapy
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
Chlorodeoxyadenosine Cladribine Leustatin 2-CdA Cytarabine
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
GNP Single agent
Hormones
These drugs also affect cell growth.
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Brand or Other Name Diprolene Temovate Lidex Decadron Deltasone
Chemical Name Topical steroid creams
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.
Common Chemotherapy Regimens Used to Treat Non-Hodgkin Lymphoma

(common brand names are in parenthesis) Note: Many of these regimens can also include the monoclonal antibody rituximab (Rituxan), which is often noted as an R.
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
How Chemotherapy Is Given

Depending on the regimen, chemotherapy may be administered in pill form, as an injection or as an intravenous drip. For patients receiving intravenous drugs (ones that are given through a vein) for multiple cycles, an intravenous catheter may be inserted to make it easier to give drugs. Catheters may be left in place temporarily or permanently. There are several types of catheters. One type, called a Hickman-Broviac catheter, consists of one to three tubes inserted through the chest wall into a vein. Six to twelve inches of tubing remain outside the skin. The main advantage of this type of catheter is that blood tests can be drawn and drugs given without having to pierce the skin. Disadvantages include: (1) the possibility of infection if the catheter is not cared for properly and (2) the tubes on the outside of the body make it more obvious that a catheter is in place. Patients who have this type of catheter will receive specific instructions from their healthcare team regarding proper care and cleaning. A second type of intravenous catheter, called an Infusa-Port or Portacath catheter, is placed under the skin and appears only as a bump on the chest. The advantage of this catheter is that it is easier for patient care because it only needs to be maintained by a nurse once a month (called
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.
The Importance of Maintaining Chemotherapy Dosing and Scheduling

Dose intensity is a term used to describe giving the highest possible doses of chemotherapy over a specific period of time, while maintaining an acceptable level of side effects. This approach has been shown to be very effective in curing some cancers, including some aggressive lymphomas. Studies have suggested that reducing the dose or delaying chemotherapy may decrease both the chance for a cure and long-term survival in some types of lymphomas. Patients should know that changing the regimen to reduce short-term side effects may actually be harmful in the long run. Some side effects may be unpleasant but tolerable. (See Coping With Common Treatment Side Effects on page 61.) Others may be serious but can often be anticipated and prevented. It is very important that chemotherapy schedules be maintained to the greatest extent possible.
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:
Electron beam (Eb) Radiation

Electron beam (EB) radiation is a form of external radiation therapy whereby a machine outside the body is used to send electrons, or negatively charged particles, directly to the area where the lymphoma is found and, potentially, to nearby lymph nodes.
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.)
Intensity-modulated Radiation Therapy (IMRT)

Intensity-modulated Radiation Therapy (IMRT) is a form of external radiation therapy whereby different doses of radiation are directed toward the cancer site using radiation beams of varying intensities.
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.
Total Skin Electron beam Radiation Therapy (TSEbT)

Total Skin Electron Beam Radiation Therapy (TSEBT) is often used for the treatment of cutaneous T-cell lymphoma (CTCL). TSEBT directs radiation to the entire surface of the body. However, the radiation only penetrates the outer layers of the skin, sparing deeper layers and other tissues from radiation exposure. For more information on this type of therapy and its use, visit the Cutaneous Lymphoma Foundations website at clfoundation.org.
Photopheresis or Extracorporeal Photochemotherapy

When using photopheresis, a fraction of a patients blood is removed and treated with an agent that makes lymphocytes more susceptible to cell death when exposed to ultraviolet A light. The blood is then exposed to ultraviolet A light and re-infused back into the patient. This form of therapy has been approved by the US Food and Drug Administration for the treatment of cutaneous T-cell lymphoma. It may also be effective in the treatment of graft versus host disease (GVHD), a common complication following allogeneic stem cell transplantation. For more information on this type of therapy and its use, visit the Cutaneous Lymphoma Foundations website at clfoundation.org.
Stem Cell Transplantation

Bone marrow transplants are now called stem cell transplants because they use three types of blood-forming stem cells: Bone marrow Peripheral (circulating) blood (also called peripheral blood stem cells or PBSC) Cells collected from an umbilical cord after a baby is born
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.
Reduced-intensity Transplants (Mini-Allogeneic Transplants)

Reduced-intensity transplants (also called non-myeloablative or minitransplants) use less-intense conditioning to prepare patients for allogeneic transplantation. These transplants use just enough chemotherapy and/or radiation to allow the patients body to accept the new cells. This approach takes advantage of the graft-versus-disease effect, in which the transplanted cells (the graft) recognize the cancerous cells in the patients body as foreign and destroy them. Patients receiving reducedintensity transplants may avoid some of the side effects seen with higher-dose chemotherapy.
How Transplants Are Done

Transplants are performed in four steps: Step 1: Collecting stem cells Stem cells are collected (harvested) in one of three ways: Bone Marrow - To harvest bone marrow, physicians use a hollow needle inserted into the hip bone. This is done in an operating room and the donor receives general or local anesthesia. Once the marrow is harvested, it is either quickly transported to the waiting patient (in an allogeneic transplant) or frozen until needed for an autologous transplant.
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.
Novel Targeted Agents

Monoclonal Antibodies
Plasma cells, the most mature B-cells in the body, are white blood cells that specialize in making antibodies. Each plasma cell is responsible for one antibody, otherwise known as a monoclonal antibody (MAb). Each MAb acts specifically against a particular antigen, which is like a beacon that attracts antibodies and immune cells. Scientists can now produce large amounts of antibodies that can be directed to a specific antigen on the cells surface. A MAb is similar to a guided missile that homes in on a target (an antigen) on the lymphoma cell and destroys the cell. A number of strategies involving the use of MAbs to treat cancer are being studied, including (a) MAbs that react with specific types of cancer cells, thereby enhancing a patients immune response to the cancer; (b) MAbs that are combined with other anticancer toxins or radioisotopes, allowing the delivery of radiation therapy, toxins or radiation directly to the tumor and bypassing toxicity to most normal cells; and (c) MAbs that are used to help purge and destroy cancer cells before a patients stem cells are reinfused in autologous bone marrow transplantation.
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.
Denileukin Diftitox (Ontak)

Denileukin Diftitox (Ontak) is a targeted therapy referred to as a fusion toxin. This molecule combines the interleukin-2 receptor with a diphtheria toxin. When this drug targets and binds to the interleukin-2 receptor on the surface of a cell, it releases the toxin. This toxin then interrupts protein synthesis within the cell and leads to cell death. Dinileukin diftitox (Ontak) is approved by the FDA for the treatment of cutaneous lymphomas and is currently under investigation in other forms of NHL, including CLL.
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.
Histon Deacetylase Inhibitors (HDAC)

Histone deacetylase inhibitors, referred to as HDAC inhibitors, are a new kind of drug that interferes with a process within cells known as acetylation and deacetylation. These reactions (acetylation and deacetylation) are known to influence the activation or inactivation of many genes inside tumor cells. Some of these genes, as well as proteins affected by acetylation and deacetylation, can influence the growth and survival of lymphoma and other cancer cells. Some HDAC inhibitors have been found to affect genes and proteins involved in the cell cycle arrest and cell death of lymphoma cells. Targeting these pathways in the treatment of cancer is an important new strategy. Although the understanding of how these drugs work in specific cancers cells is still early, learning how to best modulate those genes and proteins involved in the development of cancer is a focus of current research and many new treatment approaches.
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.
Newer versions of Established Agents

Scientists continuously examine new uses for established agents and also explore how to create newer versions of existing therapies to make them more effective and less toxic. The two drugs below represent therapies recently approved in the United States.
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 and Alternative Remedies

The concept of holistic medicine to treat the mind, body and spirit became popular in the 1970s and is commonly known today as complementary and alternative medicine, but the terms have distinctly different meanings. Alternative therapy refers to unproven or disproven treatments that are used instead of standard or proven therapy. Currently, there are no viable alternative therapies to conventional cancer care, and NHL patients should never use alternative remedies in lieu of standard care. Complementary therapy may be considered in addition to standard medicine to help improve a patients quality of life and to relieve the effects of chemotherapy, radiation and surgery.
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.
How Integrative Medicine Helps

AcupunctureSome studies show that acupuncture may relieve pain, nausea, fatigue, hot flushes and neuropathy (numbness and tingling in the feet and hands) associated with chemotherapy and may help decrease mild depression. Using ultra-thin needles applied to specific points on the body, acupuncture is safe and painless. Needles used should be disposed of and only used once. Mind/Body techniquesMeditation, guided imagery and self-hypnosis are all methods used to manage stress. Yoga and Tai chi minimize stress and improve balance and flexibility. Touch therapiesMassage, reflexology (foot massage) and Reiki involve applying therapeutic pressure to the body to restore a sense of harmony, relaxation and well-being. Studies suggest that massage may lessen pain. NutritionFor patients undergoing treatment, it is recommended that they eat a healthy, well-balanced diet that contains five to seven servings of fruits and vegetables a day, fish or poultry and whole grains. Adding nutritional supplements to the diet may also be beneficial.
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.
QUESTIONS TO ASK YOUR DOCTOR

Am I a candidate for integrative medicine? What types of integrative medicine would be most beneficial for me? How much physical activity should I have each day? What food and drinks should I avoid?
Drug Costs: What to Do if Your Insurance Does Not Pay

Many cancer patients today face the problem of how to pay for soaring healthcare costs. Cancer organizations like the Lymphoma Research Foundation (lymphoma.org) and CancerCare (cancercare.org) offer limited financial assistance to patients who qualify. Most pharmaceutical companies have patient assistance programs in place that provide drugs for free to qualifying patients. If you are in need of financial assistance, talk with your doctor about available options and how to enroll in an appropriate program. Before undergoing a medical procedure, check with your insurance carrier to ensure that it is covered. If there is a dispute about coverage or if coverage is denied, ask your insurance carrier about its appeals process. If you are unsuccessful, contact your states department of insurance to file an appeal.
When to Consider a Clinical Trial

Contrary to what many cancer patients may believe, participating in a clinical trial is not an indication that they have run out of standard treatment options, that it is their last chance for survival or that they are guinea pigs. The purpose of a clinical trial is to safely monitor the effects of a new drug on patients over time and to identify more effective therapies for specific diseases. In fact, development of new therapies is solely dependent on the clinical trial process. Participation in a clinical trial is especially crucial for lymphoma patients, because NHL comprises a group of rare diseases, and it is often difficult to find enough patients to enroll in the studies. If you are interested in participating in a clinical study, ask your doctor if there is an appropriate trial for you and what the potential risks and benefits may be. (See Chapter 13.)
Part 3: Treatment Side Effects
Chapter 6
Coping With Common Treatment Side Effects

Non-Hodgkin lymphoma patients may experience a range of side effects, also called toxicity, from the cancer treatment they receive. The various treatments, including chemotherapy, radiation, steroids and surgery, cause different side effects. Fortunately, there are many effective ways to make them more tolerable. Patients should ask their healthcare team about possible treatment side effects and inform the physician if they experience any. In many cases, side effects can be lessened with medications or lifestyle changes.
Side Effects Caused by Chemotherapy

Chemotherapy is generally most effective at killing cells that are dividing rapidly, such as cancer cells. However, chemotherapy drugs are not selective. Therefore, they can also affect normal healthy cells, especially cells that are fast-growing, such as hair cells and those in the mouth, the
Treatment Side Effects 61
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
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.
Decreased blood Cell Production

Red blood cells, white blood cells and platelets are constantly being produced in the bone marrow. Both chemotherapy and chemoimmunotherapy treatment may temporarily interfere with the ability of the bone marrow to produce adequate numbers of blood cells. When this occurs, it is called myelosuppression. Anemia is the term used when myelosuppression causes a reduction in the number of red blood cells. Anemia can cause people to feel very tired and have shortness of breath. Mild or moderate anemia is common with many chemotherapy regimens, and treatment for the anemia may be necessary. Neutropenia is the term used when myelosuppression causes a decrease in neutrophilsthe primary type of white blood cells found in the blood. Because neutrophils play a very important role in fighting infection, a low count may cause patients to develop serious or even life-threatening infections that require hospitalization or antibiotic therapy. Also, if the absolute neutrophil count (ANC) is too low, the chemotherapy dosage may need to be reduced or treatment delayed rather than risk infection. Infection is often accompanied by fever. Other symptoms of infection may include chills and night sweats. To prevent and control neutropenia, physicians will check patients white blood cell and neutrophil counts before and during each chemotherapy
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.
TIPS fOR DETECTING INfECTION DUE TO LOW bLOOD CELL PRODUCTION

Fever (greater than 100.5F) Sore Throat Rash Diarrhea Redness, swelling or pain around a wound Cough
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
TIPS fOR COPING WITH fATIGUE

Keep a diary to help you keep track of when you have the most energy and which activities make you feel fatigued or give you energy. This can help you plan your activities for the times when you have the most energy. Ask for help. This may be difficult for many people. Accept help if someone offers to assist you or if you need something you do not have the energy to do for yourself. Many family members or friends are happy to give assistance. Exercise if your doctor says it is okay to do so, but do not overdo it. Simple stretching, range-of-motion exercises or a short walk may give you more energy and not decrease the energy you have. Begin slowly and build up to the level that is right for you. Your doctor, nurse or physical therapist can help you create a personal exercise plan. Rest and sleep during therapy are very important, but try not to rest more than necessary because it may decrease your energy level. Many patients find that taking an afternoon nap leaves them feeling less fatigued for the rest of the day, but others find that napping causes less restful nighttime sleep. If you are having trouble sleeping, talk to your healthcare team to determine the reason and what you can do about it.
TIPS fOR CARING fOR HAIR LOSS

These steps can help alleviate chemotherapy-induced hair loss: Pat your hair dry rather than rubbing it with a towel after shampooing. Use a soft-bristle brush and a wide-tooth comb when fixing your hair. Avoid curlers and hair dryers. Avoid coloring your hair or using chemicals on it. Some patients use a wig, scarf, turban or soft cotton hat or head wrap. Some health insurance companies cover the cost of wigs with a prescription from your doctor. Check your policy to see if you are covered. Use a hat or scarf to protect your scalp when out in the sun.
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
TIPS fOR PREvENTING OR CARING fOR MOUTH SORES

Keep your mouth clean. Use a soft-bristle toothbrush, nonabrasive toothpaste and lip moisturizer. Avoid mouthwashes that contain alcohol. Your physician or nurse may recommend a swish-and-swallow mouth rinse. Avoid citrus fruits and juices. Avoid spicy foods. Eat soft foods while you are taking chemotherapy to avoid bruising the membranes in your mouth. Avoid flossing your teeth if your blood counts are low.
TIPS fOR CONTROLLING OR MINIMIzING NAUSEA AND vOMITING

Consume a liquid diet before chemotherapy such as broth, consomm or water. Avoid milk. Avoid foods that are too hot or too cold and too sweet or too spicy. Eat smaller and more frequent meals rather than a few large meals each day. Avoid strong or offensive odors. Get plenty of fresh air. Take prescribed antiemetics before chemotherapy to prevent nausea. If vomiting occurs, be careful to avoid dehydration (loss of body fluids).
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.)
Other Possible Side Effects

Some of the other possible side effects of chemotherapy include cough, a decrease in lung function, skin rashes and general weakness. Some drugs may also cause damage to the nervous system called peripheral neuropathy. Nerve damage can cause side effects such as constipation or a tingling sensation in the fingers and toes. Patients should immediately report any painful local rash (which sometimes may be accompanied by blisters) to their physician. Other possible side effects include a sore throat and a loss of balance or coordination. Although many of these effects are temporary, some may last for an extended period.
Side Effects Caused by Radiation

In NHL, radiation therapy (or radiotherapy) is sometimes used to shrink an enlarged spleen or swollen lymph nodes, eliminating symptoms stemming from those growths. Radiation therapy uses an invisible radioactive ray or beam of high-energy particles aimed at specific sites to kill cancer cells. While radiotherapy is painless, there are side effects associated with the treatment. The consequences of radiation therapy depend on the treatment dose, the part of the body being treated (usually side effects occur only in the specific area of the body being radiated) and the age of the patient, among other factors. Some common side effects caused by radiation therapy in NHL patients include: Fatigue Nausea Skin reactions Long-term and late effects Radiation may also cause a drop in the number of white blood cells, which help protect the body against infection. Therefore, white blood cells will be monitored during treatment.
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.
Side Effects Caused by Steroids

Steroid drugs, such as cortisone, dexamethasone and prednisone, may cause a variety of side effects, including insomnia (the inability to fall asleep), increased appetite, mood or personality changes, high blood pressure and weight gain. Prednisone may also trigger diabetes in patients prone to that disease or make the diabetes worse in patients who already have the disease. High-doses of steroids may also cause osteoporosis in at-risk patients. Patients are advised to alert family and friends that personality changes may occur. Patients should avoid making hasty decisions. If personality changes occur, the physician should be informed the dose may need to be reduced.
Side Effects Caused by Rituximab and Other biological Therapies

Although side effects caused by biological therapies vary according to the specific type of treatment, they usually occur during treatment administration and may include flu-like symptoms such as chills, fever, muscle aches, weakness, loss of appetite, nausea, vomiting and diarrhea. Rituximab (Rituxan) reduces immunoglobulin levels, particularly when given as maintenance. As a result, some patients may experience an increase in infection, particularly sinusitis and upper respiratory infections, which may prove more difficult to treat and sometimes require gammaglobulin.
Side Effects Caused by bone Marrow or Stem Cell Transplantation

Patients receiving high doses of chemotherapy and radiation before undergoing a stem cell transplant may be at increased risk for developing infection, bleeding and other side effects. In addition, patients receiving stem cells from a donor are at risk of developing graft versus host disease (GVHD), a condition where the donated marrow attacks the patients tissues. Graft versus host disease can occur at any time after the transplant. Drugs may be given to reduce the risk of developing GVHD or to treat the problem once it develops.
Side Effects Caused by Surgery

Although surgery is used primarily to make a diagnosis, there are instances when surgery is used to treat NHL. Side effects caused by surgery depend on several factors, such as the location of the tumor, the type of operation and the patients general health. Pain is a common side effect after surgery but is easily controlled with medication. It is also common to feel tired or weak following surgery. How long it takes to recover from surgery varies from patient to patient.
Combating Side Effects

Pain Management
Pain may result from treatment. For example, pegfilgrastim (Neulasta), given to stimulate white blood cells, may cause bone pain. Pain may also occur as a result of procedures or tests (such as bone marrow biopsy). Pain may be acute (comes on quickly) or chronic (lasts over a long period of time). Living with pain can have a negative effect on overall quality of life. However, many medical advances have been made in the treatment of pain, including an improved understanding of how medication works to relieve it. Many healthcare teams now include pain specialists. Several techniques, such as relaxation, guided imagery and biofeedback, may also relieve pain. Keeping a journal of when pain occurs, what it feels like
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.
The Difference between Long-Term Effects And Late Effects

Long-term effects are defined as toxicities that happen during cancer treatment and continue for months or several years, such as fatigue, menopausal symptoms and cardiovascular problems. Late effects are side effects of cancer treatment that become apparent only after treatment has ended and may arise many months, years or even decades after treatment is completed, such as infertility, osteoporosis and secondary cancers, such as lung cancer. In general, chemotherapy tends to cause more long-term side effects than late effects in NHL survivors, and radiation usually causes more late effects. There is evidence, however, that the combination of doxorubicin (Adriamycin) and radiation, especially when the radiation is directed to the chest area, may result in late effects to the heart, causing a decrease in cardiac function and accelerated atherosclerosis in which plaque builds up on the inside of the arteries. (See Cardiotoxicity, page 62).
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.
When to Use Contraceptives

Lymphoma is not a contagious disease, and it cannot be caused by or transferred through sexual intercourse. However, because small quantities of chemotherapy may be found in semen or vaginal fluid of people undergoing treatment, using condoms is recommended during sexual intercourse. It is especially important for men to use condoms and women to use birth control if they are getting chemotherapy and should be mandatory when taking immunomodulatory drugs, such as thalidomide
QUESTIONS TO ASK YOUR DOCTOR AbOUT SExUAL fUNCTION

How will my treatment affect my sexuality? Will sexual function be restored after my treatment is completed? How long will it take for sexual function to be restored? Are there successful treatments for my sexual dysfunction? What can I do to restore sexual desire and function?
(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.
Pregnancy and breast-feeding During Treatment

Women who are undergoing diagnostic procedures or receiving treatments for lymphoma should inform their doctor if there is any possibility that they may be pregnant. Lymphoma diagnosed during pregnancy is problematic, but treatment can often be prescribed that is less likely to harm the fetus. In some types of lymphoma, particularly slow-growing ones, such as follicular lymphoma, it may be possible to wait to treat the disease until the baby is born. Breast-feeding is generally not recommended when a woman is undergoing chemotherapy for lymphoma because of the possibility that the drugs are passed to the child through the mothers milk. Women of childbearing age should discuss these issues and all possible options with their doctor.
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.
How to Protect fertility in Men

Infertility occurs in men when the testes stop producing normal sperm cells. Preserving fertility in men is much easier and more effective than preserving fertility in women. It involves collecting semen and then freezing and storing it in a process known as sperm banking. The sperm can later be thawed and used for intrauterine insemination or in vitro fertilization. For men with low sperm counts, a procedure called testicular sperm extraction (TESE) can be performed in which testicular tissue is removed and the tissue and/or the sperm extracted can then be frozen and stored for later use. Some men who lose fertility immediately following treatment may regain fertility in the future, although the chance of recovering fertility depends on several factors such as age (younger people are more likely to get their fertility back than older people), the amount and duration of radiation to pelvic areas and types of chemotherapy treatments.
How to Protect fertility in Women

Cancer treatment may cause women to enter early menopause or may result in damage that does not allow for a successful pregnancy. Although preserving fertility in women is more difficult than in men, there are several options available to women. The most widely available and successful way of preserving fertility before cancer treatment is by removing eggs, fertilizing them in vitro with the sperm of a spouse or donor and then freezing and storing the embryos for future use (embryo banking). Eggs may also be stored unfertilized (egg banking), although that process is more difficult. Banking and using unfertilized eggs is more difficult, but it is a technique that has been recently developed. Both of these techniques require several weeks of treatment to complete, therefore, they may not be advisable for women needing immediate treatment of their lymphoma. Another fertility preservation method under investigation is ovarian tissue cryopreservation (OTC). Giving injections of the drug leuprolid (Lupron) to halt production of hormonal function before chemotherapy begins may limit ovarian exposure to the treatment, thereby protecting the quality of the eggs, although the drugs use is highly controversial. Before treatment begins, all women of childbearing age should talk to their doctor and a fertility preservation expert about the options available to them. The following websites are good resources for finding the latest information on fertility preservation techniques: Fertile Hope (Fertilehope.org); Institute for Fertility Preservation (Fertilitypreservation.org); and Myoncofertility.org.
4 Part 4: Children and Young Adults With Non-Hodgkin Lymphoma
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)
Important Considerations for Childhood Lymphoma Survivors

Childhood lymphoma survivors may be at risk for developing late effects from their NHL treatment. For example, some treatments have been linked to cardiotoxicity, secondary cancers and infertility later in life. Therefore, it is important to review the potential long-term health implications of all treatments being considered with the physician prior to their administration. It is also important for childhood lymphoma survivors to adhere to an appropriate follow-up care plan so that any late effects resulting from their previous NHL treatment can be diagnosed and treated as early as possible.
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
Special Concerns for Teenagers And Young Adults 4

Individuals diagnosed with NHL as teenagers or young adults may have unique needs, as compared to younger or older individuals. Awareness is growing and a new movement in cancer care has begun. In 2006, the National Cancer Institute and the Lance Armstrong Foundation convened a group of experts and published Closing the Gap: Research and Care Imperatives for Adolescents and Young Adults with Cancer: Report of the Adolescent and Young Adult Oncology Progress Review Group which defined adolescents and young adults (AYAs), those diagnosed between the ages of 15-39, as an orphaned group in cancer care and outlined research and practice areas of need. While an individuals risk of developing lymphoma increases with age, the disease affects people of all ages, including teenagers and young adults. Lymphomas are among the top five most common cancers diagnosed among those 15-39.
Specific Treatment Considerations

Because AYAs span a large age range, treatment options do not fit neatly into the two medical categories within oncology, pediatric or adult, which have different treatment protocols and approaches to care. Therefore, patients diagnosed in their late teens and early twenties may be treated by either pediatric or adult oncologists. The treatment options for young adults diagnosed with lymphoma may vary based on whether they are treated with adult (see Chapters 5 and 14) or pediatric (see Chapter 9) protocols or standards of care. Treatment options include chemotherapy, radiation, transplantation, immunologic agents and novel therapeutic agents. Recent research also suggests the need to more fully understand how common treatment regimens work or do not work in AYA patients. Dosing, in particular, may be unique for this population. Adolescents and young adults may be able to tolerate different dosing regimens better than
,,,
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.
Important Considerations for Long-Term Young Adult Lymphoma Survivors

People in their twenties and thirties often change jobs and geographic locations frequently, take more risks and are the highest uninsured age range. All of these factors combined may make follow-up care logistically challenging. However, follow-up care is critical to detecting and treating long-term and late effects of NHL treatment. Follow-up care plans may vary based on the type of treatment used, other existing health conditions and age, among other factors. Most often, young adults will be encouraged to live a balanced, healthy lifestyle (e.g., not smoking, eating a balanced diet and exercising regularly), visit a general practitioner (and an OB-GYN for women) and receive regular follow-up care. Patients should ask their doctor what early health screenings they should have, such as mammograms, colorectal screenings, prostate exams and thyroid, cardiac and bone density tests, and when to schedule them. Some of these tests may be suggested at an earlier age for cancer survivors than the general population. Survivorship recommendations may vary for those diagnosed under or over the age of 18. People diagnosed with lymphoma at any age should speak with their physician about how specific follow-up guidelines translate into plans for their individual care. It is ideal to begin this dialogue as primary (first) therapy is being completed.
Emotional and Practical Considerations

Intimate relationships, careers and finding ones place in the world are just beginning to evolve for people in their twenties and thirties. Therefore, a lymphoma diagnosis during this stage of life may be very different emotionally than at other points in life. Newly diagnosed young adults may wish to consider joining on-line communities to meet other young adults with lymphoma. Planet Cancer, a program of the Livestrong Foundation) offers a peer community specifically for young adults. The Ulman Fund for Young Adults with Cancer (ulmanfund.org) also provides
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.
TIPS fOR HEALTHY LIvING

Do not smoke or use any form of smokeless tobacco. Eat a balanced diet that includes five or more servings of fruit and vegetables each day, protein (poultry, fish and eggs) and whole grains. Maintain a regular exercise program that includes at least 30 minutes of some form of aerobic exercise (walking, bicycling or swimming) several days a week. Check with your doctor about a specific exercise plan for you.
lymphoma.org
Part 5: Living With Non-Hodgkin Lymphoma
Chapter 11
Regaining Your Life During And After Cancer

Coping with NHL varies among individuals. Some common coping strategies are highlighted below.
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.
Coping with Physical Changes

Hair loss, weight loss/gain and changes in physical appearance may occur as a result of treatment. To cope with these changes, patients should speak with their healthcare team, get ideas from other NHL survivors and use techniques most comfortable to them.
Maintaining a Healthy Lifestyle

Eating a healthy diet, engaging in regular physical exercise and getting sufficient rest can help combat the stress and fatigue of NHL and its treatment. (See Combating Side Effects, on page 71.)
Life After Remission

Although finishing NHL treatment can be significant, it is normal to experience ongoing feelings of anxiety and worry about a relapse. Adjusting to the new normal routines of life during and after cancer may take a few weeks or months to complete. Developing a wellness plan with guidance from the healthcare team may lead to a better sense of overall well-being. Some changes to consider making: Quit smoking Reduce alcohol consumption Exercise (walking, biking, swimming) Eat a healthy diet
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
Relapsed or Refractory NHL

A relapse (sometimes called a recurrence) is when an individuals disease returns after treatment. An individuals disease is considered refractory when it does not respond to treatment. Numerous treatment options exist for patients with relapsed or refractory NHL, which are often referred to as secondary therapies. Chemotherapy regimens used for relapsed or refractory lymphoma are usually different from the initial therapy (see chart included in this chapter). Rituximab (Rituxan) may be used in combination with many of these chemotherapy regimens. Radioimmunotherapy agents ibritumomab tiuxetan (Zevalin) and tositumomab (Bexxar) are also used in the relapsed setting. Many centers will consider using autologous or allogeneic transplantation for patients with relapsed or refractory NHL. Sequential transplantations are possible if the disease continues to return or does not fully respond. Exactly what type of treatment is optimal for individual patients with relapsed or refractory NHL depends on several factors, including type of lymphoma, age, extent of disease, overall health and previous therapies received. It is important to remember that while relapses may occur for patients with either indolent or aggressive NHLs, the specific treatment options may vary. Patients who do not go into complete remission following treatment or who do not respond to treatment should not lose hope. Complete remission may be achieved following a diagnosis of relapsed or refractory disease. Many of the novel therapeutic agents that have been approved by the FDA (e.g., bortezomib, pralatrexate) and those being investigated in clinical trials focus specifically on those who have relapsed or refractory disease. It is important to remember that patients may seek second opinions at any point from diagnosis onward and often chose to do so if their disease relapses or is considered refractory.
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.
Chemotherapy Regimens Used for Relapsed Non-Hodgkin Lymphoma

(common brand names are in parenthesis) Note: Many of these regimens can also include the monoclonal antibody rituximab (Rituxan), which would be noted by the letter R.
Regimen Abbreviation DHAP
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)
Part 6: Clinical Trials
Chapter 13
Overview of Clinical Trials

A clinical trial is a research study designed to answer basic questions about a new treatment or a new way of using an old treatment. There are hundreds of NHL clinical trials now underway in hospitals, cancer centers and physicians offices around the country. The government, pharmaceutical and biotechnology companies, universities and physician groups often sponsor clinical trials. The Food and Drug Administration (FDA) and the institutional review board of participating hospitals or institutions must approve each phase in a clinical trial.
basics of Clinical Trials

Clinical trials are performed to study new drugs and treatment strategies. Clinical trial investigations may study the following: novel drug A new indication (use) for a drug already approved by the FDA as A a treatment for a different disease ompare a new treatment with a standard treatment to determine C which one is more effective or has fewer side effects
Clinical Trials 93
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
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.
Use of a Placebo in Phase III Trials

A placebo, or sugar pill, is an inactive ingredient that is used is some types of clinical trials to ensure that the test results are unbiased. It is important to note that clinical trial participants will never receive a placebo in phase III trials if standard therapy exists. Patients would only potentially receive a placebo if there were no standard therapies to test against. Placebo-controlled trials are never done in a manner to deny patients an effective therapy.
Participating in a Clinical Trial

Clinical trials should not be considered a last resort by patients. Non-Hodgkin lymphoma patients can often benefit from participation in clinical trials both in the frontline treatment setting and in the relapsed treatment setting. Clinical trials offer patients therapies that are not otherwise available to all patients and are monitored very closely.
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.
The Cost of being in a Clinical Trial

Clinical trials are very expensive undertakings for the study sponsor. Patient costs vary depending on the study, who is sponsoring the trial, what portion of the trial-related expenses the sponsor will cover and the patients health insurance coverage. Some health insurance and managed healthcare providers will pay for the basic medical procedures associated with the trial, such as lab tests, scans and hospitalization when required,
Clinical Trials 95
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
New Agents or Applications

Many drugs are approved by the United States Food and Drug Administration (FDA) for very specific and often restricted indications. This chapter will focus exclusively on those drugs that are not currently FDA approved for lymphoma and may represent major advances in our efforts to cure or manage cancer better. Therefore, patients may find that these drugs are only available in clinical trial. This chapter will forego detailed discussions about presently approved agents in lymphoma and efforts to expand their indications in specific subtypes of the disease. Refer to Chapter 5 for more detailed description of already approved agents in lymphoma. It is critical to remember that todays science is moving very fast. Therefore, the charts in this chapter may not be entirely comprehensive or accurate depending on when this information is being read. Please check with the Lymphoma Research Foundation or your physician for additional information and recent updates.
Drugs Affecting Protein Disposal

In an effort to improve on the therapeutic efficacy of bortezomib (Velcade), scientists have focused on trying to develop new proteasome inhibitors with similar biochemical properties. Bortezomib (Velcade), while very active in patients with multiple myeloma and mantle cell lymphoma, is also associated with a sometimes significant neurotoxicity that may leave patients with numbness in their fingers and toes. Also, bortezomib (Velcade) is thought to be a reversible proteasome inhibitor. The reversibility of the drug effect implies a need to repeatedly administer the drug to obtain optimal inhibition of the proteasome. New versions of proteasome inhibitors have focused on trying to accomplish the following: (1) to develop proteasome inhibitors with markedly less neurotoxicity; (2) develop potentially irreversible inhibitors of the proteasome that require less frequent dosing of the drug; (3) to develop proteasome inhibitors with very selective abilities to inhibit the complex proteasome; and (4) to develop orally available proteasome inhibitors.
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)
Predominant Mechanism of Action

Proteasome inhibitor
Comments
Similar to bortezomib; known to be an irreversible proteasome inhibitor; no neurotoxicity Relapsed or refractory lymphoma NHL and HL; orally available
NPI-0052
MLN-9708
Drugs Affecting How Cancer Cells Divide

The intrinsic features of every cancer cell revolve around the ability of the tumor cell to divide when it should not, and their ability to resist cell death when it should die. One very exciting area of new drug discovery and development is focused on targeting those proteins directly involved in stimulating cancer cells to grow. The intrinsic control of any cancer cells growth, just as in a car, involves an accelerator and brake system. Clearly, two strategies to intervene would involve turning off the accelerator and turning on the brakes in cell division. An exciting number of new drugs have emerged which appear to selectively turn off the accelerator in tumor cells and to selectively turn on the brakes. One class of drugs with this property
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

CDK Inhibitor
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
Forodesine hydrochloride (BCX-1777) Ixabepilone
Cutaneous T-cell lymphoma
Approved in breast cancer; under investigation in NHL Aggressive NHL
Liposomal vincristine (Marquibo) SB-921
Tubulin polymerization
Kinesin spindle protein inhibitor
HL
Teaching Cancer Cells How to Die

Perhaps one of the most exciting new areas in cancer drug discovery over the last decade has revolved around the discovery and development of new small molecules which appear to teach cancer cells how to die. As noted above, one intrinsic feature of every tumor cell is its ability to divide when it should not and to resist dying when it should die. This cell death thermostat is established by the expression of a variety of proteins in the cell known as pro- and anti-apoptotic modulators. Pro-apoptotic proteins
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)

Bcl-2 only
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, Bcl-XL, Bcl-W
Obatoclax mesylate (GX15-070)
Bcl-2
YM-155 AMG-655
Survin inhibitor TRAIL
Agents Affecting Immunologic Targets

Monoclonal Antibodies
Because lymphomas are derived from cells known to play a critical role in the immune system, scientists and physicians have been trying to find ways to manipulate the immune system in order to treat various lymphomas. The success of rituximab (Rituxan) represents one significant breakthrough that has established proof of principle. Targeting proteins expressed solely on the surface of B-cells with a monoclonal antibody (MAb) can lead to significant improvements in long-term survival of patients with B-cell malignancies. Given the success of rituximab (Rituxan) and other MAbs in lymphoma, there is now a significant national and international effort to identify new engineered MAbs with unique properties to broaden their activity and improve their efficacy across these different diseases. Examples of new MAbs include lumiliximab, GA101, veltuzumab and others listed in the table below, some of which are designed to target unique antigens other than CD20 on the surface of B-cell malignancies.
Agent
GA-101 Ocrelizumab AME-133v Veltuzumab Epratuzumab (LymphoCide) Inotuzumab ozogamicin (CMC544) SAR3419 Lumiliximab Alemtuzumab (Campath)

CD20 CD20 CD20 CD20 CD22 NHL NHL NHL NHL NHL
Comments
CD22 CD19 CD23 CD52
NHL Relapsed B-cell NHL CLL FDA indication in B-cell CLL Relapsed HL NHL, including CLL continued
XmAb2513 SGN-40 (Dacetuzumab)
CD30 CD40
Clinical Trials 101
Agent
TRU-016 HCD122 Galiximab Anti-CTLA-4

CD37 CD40 CD80 CD152
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

CD30
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
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)

Immunomodulatory
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
Therapies Interfering with the b-Cell Receptor

Finally, another drug class that has recently emerged with significant promise includes those therapies directed toward interfering with the B-cell receptor. The B-cell receptor plays an important role on B-cells by regulating the growth and proliferation. The B-cell receptor mediates B-cell interactions with other proteins or cells in the body, which can cause lymphoma cells to divide and grow continuously. New drugs designed to interfere with the B-cell receptor, including Syk inhibitors, have shown promising activity in patients with very heavily pretreated B-cell malignancies. BTK inhibitors are drugs that interfere with signaling molecules within the B-cell referred to as Brutons tyrosine kinase (BTK). Inhibiting the production of BTK may also stop the overproduction of malignant B-cells. Continued research into the understanding of the underlying biology of B- and T-cell lymphomas will lead to the identification of new disease-specific targets that will eventually contribute to the development of new drugs targeting this biology in a very selective way.
Clinical Trials 103
Agent
R788 (Fostamatinib disodium)

Syk inhibitor
Comments
Several types of B-cell and T-cell NHL Relapsed B-cell NHL Relapsed B-cell NHL
PCYC-04753 PCI-32765
BTK inhibitor BTK inhibitor
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

Idiotype
Comments
Follicular lymphoma
Drugs Selectively Targeting Cancer Cell Gene Expression

One of the more exciting areas of drug development over the last decade has emerged from our understanding of how tumor cells turn on and turn off specific genes that contribute to their ability to proliferate (multiply) and resist cell death. This process is governed by a balance of expression of two sets of enzymes known as HATs (histone acetyltransferases) and HDACs (histone deacetylases). The acetylation of specific proteins in DNA can open DNA and turn on a number of different genes involved in growth and survival. The removal of those acetyl groups from the proteins of the DNA leads to silencing of those genes. The recent discovery that certain drugs could inhibit the deacetylation process, specifically the HDACs, allows the DNA to be maintained in an open and transcriptionally active state. By using small molecules, physicians and scientists are now able to potentially turn on a host of genes within the tumor cell, which may help reverse the malignant process. The first of this class of drugs that has been approved for the treatment of cancer was vorinostat (Zolinza) for cutaneous T-cell lymphoma (CTCL). For reasons that are not entirely clear, this class of drugs seems to have activity across all different types of T-cell lymphomas and appears to complement the activity of many conventional and other investigational drugs now being studied for the treatment of cancer. Following the approval of vorinostat (Zolinza) for the treatment of CTCL, another HDAC inhibitor, known as romidepsin (Istodax) was recently approved in November 2009 for CTCL. Romidepsin (Istodax) is an intravenously administered HDAC inhibitor that appears to be associated with a very good overall response rate and durable remissions in patients with CTCL resistant to vorinostat (Zolinza) and other conventional drugs used for this disease. In addition to these drugs, and with our ever-growing knowledge around this biology, there are now a number of new HDAC inhibitors that have exhibited very promising activity in a variety of different forms of lymphoma. One of those drugs, known as belinostat, is administered as an intravenous preparation and has been shown to have significant activity in patients with peripheral T-cell lymphoma (PTCL). Belinostat
Clinical Trials 105
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

HDAC-inhibitor
Comments
Under investigation in relapsed HL, PTCL, other NHL PTCL, other NHL
Belinostat
HDAC-inhibitor
Drugs Targeting Essential Lymphoma biology

One of the major challenges in cancer research over the last several decades has been trying to understand the specific biologic differences between normal B- and T-lymphocytes and malignant B- and T-cell lymphomas. Intensive investigation into these biological differences has begun to reveal a number of unique targets that appear to be overrepresented in malignant B- and T-cell lymphomas, compared to their normal, benign (non-cancerous) B- and T-cell lymphocyte counterparts. For example, it has been recently discovered that an important pathway controlling the translation of genetic information from DNA to protein, the PI3Kinase- AKT-mTor pathway is markedly overexpressed in a whole variety of different lymphoproliferative malignancies. Over the last decade, a number of new drugs have been developed which specifically target this pathway including mTor inhibitors such as rapamycin, temsirolimus (Torisel) and everolimus, which seem to inhibit an important protein in this pathway known as the mammalian target of rapamycin. Inhibition of this protein effects genes involved in the development of lymphoma, including but not limited to cyclin-D1, Bcl-2 and NFkB, all of which play an important role in stimulating the growth and inhibiting the death of malignant cells. Other drugs that appear to target this pathway selectively include those drugs targeting PI3 kinase (PI3K) directly, such as CAL101, which appears to have very promising activity in patients with mantle cell lymphoma in very early clinical trials. Other drugs targeting this pathway include agents capable of inhibiting the AKT pathway (e.g., perifosine), which also has effects on tumor cells similar to that seen with the mTor inhibitors. The recent elucidation of this important pathway on which many B- and T-cell lymphomas have been found to be addicted, represents a unique opportunity to target the biology of the lymphomas. Future studies of these agents will be directed toward the combined inhibition of the pathway and the merits of combining these drugs with conventional drugs known to be effective in treating lymphomas.
Clinical Trials 107
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

AKT inhibitor
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
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.
New Derivatives of Old Drugs

While there are some examples where scientists are trying to improve existing drugs, the bulk of the effort has been focused on the discovery of new agents that selectively target the unique biology of the lymphoma. Other examples of new versions of older drugs are provided in the following table.
Agent
Pixantrone

Anthracycline-like
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
Liposomal doxorubicin (Doxil)
Anthracycline
Epirubicin hydrochloride (Epirubicin)
Anthracycline
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GLOSSARY Of MEDICAL TERMS

Absolute neutrophil count (ANC): A measurement of the number
of mature neutrophils (a type of white blood cell) that are available for fighting infection. A low ANC increases the risk for infection.
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.
Apheresis: The part of the stem cell transplantation procedure in which

stem cells are removed from the blood.
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
Biologic therapy: Treatment that uses or stimulates the immune system

or other body systems to fight infection and disease.
Biopsy: Removal of a small piece of tissue for evaluation under

a microscope.
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.
Catheter (intravenous access): A device that is temporarily or permanently

put into a vein that makes it easier to give medications.
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 cycle: Term used to describe the process in which

chemotherapy is given, followed by a period of rest in which the body is allowed to recover.
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.
112 Understanding Non-Hodgkin Lymphoma Understanding Non-Hodgkin Lymphoma
Glossary of Medical Terms 112
Complete remission (CR): Term used when all signs of the disease have
disappeared after treatment.
CT or CAT (computerized axial tomography) scan: This imaging test

provides a series of detailed pictures of inside the body using an X-ray machine linked to a computer.
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).
DNA: Abbreviation for deoxyribonucleic acid, an essential component

of genes.
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
Gallium (radioisotope) scan: When injected into the body, radioactive

gallium is a chemical that collects in some tumors. The body is then scanned to see whether the gallium has collected in a tumor.
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.
Gene therapy: Therapy approaches that alter the genetic structure of

tumor cells, making them more susceptible to either the immune system or chemotherapy drugs.
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.
Hematologist: A physician who specializes in treating diseases of the

blood and blood-forming tissues.
Histology: The study of tissue characteristics that may lead to identifying

a specific type of tumor.
Hodgkin lymphoma: One of the two major types of lymphoma that

begin in the lymph nodes and tissues of the lymphatic system. All other lymphomas are classified as non-Hodgkin lymphomas. Hodgkin lymphoma has a characteristic cell, the Reed-Sternberg cell, seen by the pathologist under the microscope when looking at the tissue from the biopsy.
Hypogeusia: When the flavors of foods are not as strong as normal.

114 Understanding Non-Hodgkin Lymphoma Understanding Non-Hodgkin Lymphoma Glossary of Medical Terms 114
Hypothyroidism: A condition in which there is lower than normal

production of thyroid hormone. Low thyroid levels can lead to a variety of effects, including mild weight gain, dry skin, fatigue and sleepiness.
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.
Laparoscopy: Passing a tube through the abdominal wall to obtain a

small sample of tissue for examination under the microscope.
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.
Lymphoma: A malignant disease that begins in the lymph nodes,

organs and tissues of the lymphatic system (immune system). Hodgkin lymphoma is one type of lymphoma; the other major type is called non-Hodgkin lymphoma. There are approximately 61 types of nonHodgkin lymphoma.
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.
Memory cells: Memory cells are types of B-lymphocytes and

T-lymphocytes. After a foreign invader or unwanted cell has been destroyed, surviving B- and T-lymphocytes develop into specialized memory cells that remain on watch and can provide protection if the invader is encountered in the future.
116 Understanding Non-Hodgkin Lymphoma Understanding Non-Hodgkin Lymphoma
Understanding Non-Hodgkin Lymphoma 116 Glossary of Medical Terms 116
Metastasize: To spread to other organs of the body. Cancer may spread

from its primary site to other sites or organs.
Monoclonal antibodies: Biologic therapies that act specifically against

a particular antigen. Scientists can produce large amounts of antibody that can be directed to a single target (or antigen) on the cells surface. Monoclonal antibodies have been developed to help combat specific cancers, including some forms of non-Hodgkin lymphoma.
MRI (magnetic resonance imaging): MRI uses magnets and radio

frequency waves to produce images of inside the body. MRIs can provide information about tissues and organs that is not available from other imaging techniques.
Mucositis: Inflammation of the lining of tissues and organs. In the mouth,

it is characterized by sores or inflammation.
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).
117 Understanding Non-Hodgkin Lymphoma Non-Hodgkins Lymphoma
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.
Pathologist: A physician who specializes in studying disease through

microscopic evaluation of body tissues and organs. Any tissue suspected of being cancerous must first be examined by a pathologist to confirm the diagnosis.
PCR (Polymerase chain reaction): A molecular test that can identify

small amounts of genetic material. This test is done if looking for minimal residual disease.
Performance status: A term used to describe a persons ability to follow a

typical lifestyle.
Peripheral neuropathy: Damage to the nerves. This condition can

be caused by some drugs and is usually characterized by tingling and weakness or numbness in the extremities.
PET (positron emission tomography) scan: A type of test that may

be used instead of gallium scans to identify areas in the body that are affected by non-Hodgkin lymphoma. This test evaluates metabolic activity in different parts of the body using a radioisotope.
Plasma cell: A mature B-cell that makes antibodiesthese antibodies

help the body destroy or remove toxins, bacteria and some cancer cells.
Primary therapy: The first therapy given after a diagnosis of cancer. Prognosis: The likely outcome of a disease, including the chance
of recovery.
Pulmonary function test: A procedure for determining the capacity

of the lungs to exchange oxygen and carbon dioxide efficiently.
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.
Relapse: The return of cancer after treatment. Lymphoma may recur

in the area where it first started, or it may occur in another place.
Remission: The absence of disease. A patient is considered in remission

when the lymphoma has been treated and tumors have diminished by at least 50 percent (partial) or have totally disappeared (complete). Remission does not necessarily mean cure. Patients with intermediate or aggressive lymphomas must achieve a complete remission and maintain it for a period of time, usually five or more years, before there is consideration of cure. Patients with low-grade tumors are usually not considered cured because the disease can reappear even with a long remission of many years. Patients may have a complete or partial remission.
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.
Salvage therapy: Therapy that is given if the primary therapy is not

successful or if the disease disappears and then comes back.
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.
Systemic symptoms: Symptoms that affect the entire body. Examples of

these include fever, night sweats and weight loss.
Thrombocytopenia: A shortage of platelets in the blood, which reduces

the ability of the blood to clot.
Thymus gland: A gland located behind the sternum (breastbone)

that enhances the reproduction and development of lymphocytes. T-lymphocytes are processed in the thymus.
Toxicities: The unwanted side effects of cancer therapies, such as a

decrease in blood cells, nausea and vomiting, and hair loss.
Tumor: An abnormal mass or swelling of tissue. Tumors may occur

anywhere in the body. A tumor may be benign (non-cancerous) or malignant (cancerous).
Vaccine: A substance or group of substances meant to cause the immune

system to respond. A vaccine can help the body recognize and destroy cancer cells. Lymphoma vaccines often combine cancer antigens with a substance to stimulate the patients own natural defenses to fight the disease. These vaccines in lymphoma are custom-made for each patient, using a sample of tumor obtained from the patients lymph nodes.
VEGF (Vascular Endothelial Growth Factor): One of a number of

substances that stimulate angiogenesis, blood vessel formationa process necessary for tumor growth.
Watchful waiting: An approach in which no immediate medical, surgical

or radiation therapy is given. Patients are followed closely to make sure the cancer does not progress. Watchful waiting is an appropriate option for some patients with indolent (slow-growing) non-Hodgkin lymphoma.
Xerostomia: A temporary reduction in the production of saliva or

dry mouth.
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.
Glossary of Medical Terms 121
lymphoma.org
About The Lymphoma Research foundation

The Lymphoma Research Foundation (LRF) is the nations largest lymphomafocused nonprofit health organization devoted exclusively to funding lymphoma research and providing patients and healthcare professionals with the most current information on the disease. The Foundations mission is to eradicate lymphoma and serve those touched by this disease. The Lymphoma Research Foundation was formed in 2001 with the merger of the Cure For Lymphoma Foundation (CFL) and the Lymphoma Research Foundation of America (LRFA). Both organizations were founded by lymphoma advocates who wanted to turn a life-altering diagnosis into a positive experience for others with the disease. Ellen Glesby Cohen founded LRFA in Los Angeles in 1991. Until her death in 2000, Ellen was a tireless champion for patients and their families who created new education and support programs and served as a staunch advocate for improved government legislation. Jerry and Barbara Freundlich founded CFL in 1994 in New York City. Jerry is a long-term survivor of non-Hodgkin lymphoma.
Resources for Patients, Survivors and Loved Ones

Receiving a diagnosis of lymphoma can be challenging. Whether you or someone you love is newly diagnosed or a long-term survivor, understanding the latest medical information and accessing appropriate support services may help. LRF offers a wide array of programs and support services to assist you from the point of diagnosis through long-term survivorship.
Patient Services and Support

Lymphoma Helpline and Clinical Trials Information Service
Through this phone and e-mail service, trained staff members are available to answer your questions and provide individual support to you and your loved ones. Services are available in any language.
The Lymphoma Research Foundation 123
Lymphoma Support Network (LSN)

This national one-to-one peer support program matches lymphoma patients or caregivers with volunteers who have had similar lymphomarelated experiences.
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.
In-Person Patient Education Programs

North American Educational forum on Lymphoma
This two-day forum is held annually and provides critical information about making the best decisions on treatment options, patient support issues and the latest in lymphoma research.
Lymphoma Workshop: Understanding Lymphoma basics & Current Treatment Options

These regional, full-day educational programs provide the latest information about lymphoma, current treatment options and patient support issues.
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.
Resources for Children and Young Adults

Lymphoma in Your Teens, 20s and 30s
LRF offers a wide array of webcasts and podcasts for individuals affected by lymphoma in their teens, 20s and 30s, including topics specifically designed to help friends and family. Visit lymphoma.org/youngadults to access these programs. Lance Armstrong foundations LIvESTRONG Young Adult Alliance The LIVESTRONG Young Adult Alliance is a coalition of organizations with the goal to improve the survival rates and quality of life for young adults with cancer between the ages of 15 and 40. By visiting livestrong.org/ yaa you can access the websites of all member organizations that specifically provide services for young adults with cancer.
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 Access Programs and Services

Many of the aforementioned programs are available on LRFs website at lymphoma.org. For additional information about these resources, call (800) 500-9976; e-mail us at helpline@lymphoma.org. If you would like to order additional copies of Understanding NonHodgkin Lymphoma: A Guide for Patients, Survivors and Loved Ones, please call (800) 500-9976 or go to lymphoma.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.
Start or Join a Local Chapter

LRF meets the needs of the lymphoma community through our nationwide chapter network. Chapter volunteers work tirelessly to educate people about lymphoma, conduct outreach, raise funds for research and participate in public policy and advocacy initiatives. To learn more about a chapter in your area or how to start one, please visit lymphoma.org/chapters or call (800) 235-6848.
Raise funds and Awareness

Raise funds and awareness by participating in a variety of events being held across the country such as Lymphomathon walks, bike rides, golf tournaments, galas, lunches, young professional social events and much more. Visit lymphoma.org/events for more information.
Join Team LRf

Team LRF is a program through which people across the country raise much-needed funds and awareness for lymphoma research through sporting events such as marathons, half marathons, triathlons, hiking adventures, bowling tournaments, soccer matches, bike rides, lacrosse tournaments, paddling events, dance-a-thons, spin-a-thons, yoga-a-thons and much more. Join Team LRF in an existing LRF-partnered event in your area, or join Team LRF Teammates Across the Country if you wish to raise funds by starting your own event or by participating in an event in which LRF does not have official charity entries. Visit lymphoma.org/ teamlrf for more information.
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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
FAX
Amount of donation $ Make checks payable to the Lymphoma Research Foundation.

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Understanding Non-Hodgkin Lymphoma 131
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Understanding

Abbott Oncology Lilly Oncology

ii Understanding Non-Hodgkin Lymphoma

Understanding Non-Hodgkin Lymphoma iii

Part 2: Treating Non-Hodgkin Lymphoma

iv Understanding Non-Hodgkin Lymphoma

Part 3: Treatment Side Effects

Part 4: Children and Young Adults With Non-Hodgkin Lymphoma

Understanding Non-Hodgkin Lymphoma v

Part 5: Living With Non-Hodgkin Lymphoma

Chapter 12 Relapsed or Refractory NHL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

Part 6: Clinical Trials

vi Understanding Non-Hodgkin Lymphoma

Part 1: Learning the basics

Learning the Basics 1

Non-Hodgkin Lymphoma Overview

The Lymphatic System

How Lymphocytes Work

The immune system is the bodys defense against outside invaders.

ANATOMY Of THE IMMUNE SYSTEM

Tonsils and adenoids Lymph nodes

Thymus Lymph nodes

Lymph nodes (epitrochlear)

Peyers patches Appendix

Lymph nodes Lymphatic vessels

4 Understanding Non-Hodgkin Lymphoma

IMMUNE SYSTEM INvADERS

HOW CANCER fORMS INSIDE THE bODY

Abnormal Cells Evade the Immune System

Abnormal Cells Multiply (Cancer)

Tumors May form (Groups of Abnormal Cells)

Learning the Basics 5

The Causes of Non-Hodgkin Lymphoma

Where Non-Hodgkin Lymphoma Develops

Common Types of Non-Hodgkin Lymphoma

Learning the Basics 7

The Difference between Indolent and Aggressive Lymphomas

Types of Indolent Non-Hodgkin Lymphoma

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

8 Understanding Non-Hodgkin Lymphoma

Marginal Zone Lymphoma

Cutaneous T-Cell Lymphoma

10 Understanding Non-Hodgkin Lymphoma

Types of Aggressive Non-Hodgkin b-cell Lymphoma

Diffuse Large B-Cell Lymphoma

Mantle Cell Lymphoma

Learning the Basics 11

Burkitts Lymphoma, Burkitt-like Lymphoma (Small Non-Cleaved Cell Lymphoma)

Types of Aggressive Non-Hodgkin T-Cell Lymphoma

Peripheral T-Cell Lymphomas

12 Understanding Non-Hodgkin Lymphoma

Learning the Basics 13

Blastic NK-Cell Lymphoma

Nasal T-Cell Lymphoma

Primary Central Nervous System Lymphoma

14 Understanding Non-Hodgkin Lymphoma

Treatment-Related T-Cell Lymphomas

Enteropathy-Type T-Cell Lymphoma

Hepatosplenic Gamma-Delta T-Cell Lymphoma

Learning the Basics 15

Rare Immune System Cancers

Please refer to our website for additional and updated information.