

### Understanding

### CLL/SLL

### Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

### A Guide for Patients, Survivors, and Loved Ones

October 2014

This guide is an educational resource compiled by the Lymphoma Research Foundation that provides general information on chronic lymphocytic leukemia and small lymphocytic lymphoma. Publication of this information is not intended to take the place of individualized medical care or the advice of a patient's doctor. Patients are strongly encouraged to talk to their doctors 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.

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This patient guide is supported through unrestricted educational grants from:

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©2014 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 acknowledged 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 input, and advice, which have truly enhanced this publication. The review committee 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 leukemia and 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.

## Review Committee

### Editorial Board Steering Committee

Editorial Chairman

**Morton Coleman, MD,** Weill Cornell Medical College/NewYork- Presbyterian Hospital

Senior Advisors

**Bruce D. Cheson, MD, FACP, FAAAS** , Georgetown University Hospital, Lombardi Comprehensive Cancer Center

**Thomas J. Kipps, MD, PhD,** UCSD Moores Cancer Center

**John P. Leonard, MD,** Weill Cornell Medical College/NewYork- Presbyterian Hospital

**Kanti R. Rai, MD, BS** , North Shore-LIJ Cancer Institute

Review Committee

**Jennifer R. Brown, MD, PhD** , Dana-Farber Cancer Institute

**John C. Byrd, MD** , The Ohio State University Comprehensive Cancer Center

**Asher Chanan-Khan, MD** , Mayo Clinic, Florida

**Nicholas Chiorazzi, MD** , The Feinstein Institute for Medical Research

**Carlo M. Croce, MD** , The Ohio State University Comprehensive Cancer Center

**Joanna L. Fawzy Morales, Esq**., Triage Cancer

**Alessandra Ferrajoli, MD** , The University of Texas MD Anderson Cancer Center

**David A. Frank, MD, PhD** , Dana-Farber Cancer Institute, Harvard Medical School

**Richard R. Furman, MD** , Weill Cornell Medical College/NewYork- Presbyterian Hospital

**Les Gallo-Silver, ACSW, LCSW-R** , LaGuardia Community College

**Meghan Gutierrez** , Lymphoma Research Foundation

**Neil E. Kay, MD** , Mayo Clinic, Rochester

**Nicole Lamanna, MD** , NewYork-Presbyterian Hospital/Columbia University Medical Center

**Susan O'Brien, MD** , The University of Texas MD Anderson Cancer Center

**William Plunkett, PhD** , The University of Texas MD Anderson Cancer Center

**David L. Porter, MD** , University of Pennsylvania Medical Center

**Tait D. Shanafelt, MD** , Mayo Clinic, Rochester

**Parameswaran Venugopal, MD** , Rush University Medical Center

**Anita E. Welborn, LMSW** , Lymphoma Research Foundation

**William G. Wierda, MD, PhD** , The University of Texas MD Anderson Cancer Center

# TABLE OF CONTENTS

List of Abbreviations
Introduction

Part 1 — Learning the Basics

Chapter 1: Understanding the Disease

Chapter 2: Seeking Medical Attention

Table 2.1. Symptoms of CLL/SLL
Chapter 3: Receiving a Diagnosis

Table 3.1. Flow Cytometry and Immunohistochemistry Tests

Table 3.2. The Three Main Types of Biopsies

Table 3.3. Types of Genetic Tests

Table 3.4. Chromosomal Changes and Genetic Mutations Most Commonly Found in CLL/SLL

Chapter 4: Work-up Before Treatment Can Begin

Table 4.1. Types of Imaging Tests

Table 4.2. Other Types of Biopsies

Table 4.3. The Rai Staging System for CLL

Table 4.4. The Binet Classification System for CLL

Part 2 — Treatment of CLL/SLL

Chapter 5: What to Know Before Starting Treatment

Table 5.1. Known Prognostic Factors for CLL/SLL

Table 5.2. The Eastern Cooperative Oncology Group PS Scale

Chapter 6: Treatments for CLL/SLL

Table 6.1. Common Drug Regimens for CLL/SLL

Table 6.2. Catheters Used to Administer Chemotherapy

Table 6.3. Terms Used to Describe the Outcomes of Treatment

Table 6.4. Forms of Complementary Therapy (Also Known as Integrative Medicine)

Part 3 — Living With the Side Effects of Treatment

Chapter 7: Common Treatment Side Effects

Table 7.1. The Four Main Conditions Caused by Decreased Blood Cell Production

Chapter 8: Managing Life During and After Treatment

Table 8.1. Coping Strategies

Part 4 — Clinical Trials and Advances in Treatment

Chapter 9: Overview of Clinical Trials

Table 9.1. The Four Main Types (or Phases) of Clinical Trials

Chapter 10: Advances in Treatment of Patients With CLL/SLL

About the Lymphoma Research Foundation

#

# LIST OF ABBREVIATIONS

ACA - Affordable Care Act

ANC - absolute neutrophil count

ASCO - American Society ofClinical Oncology

ASH - American Society of Hematology

BTK - Bruton's tyrosine kinase

CBC - complete blood count

CLL - chronic lymphocytic leukemia

CPR - cardiopulmonary resuscitation

CR - complete remission

CSF - cerebrospinal fluid

CT - computed tomography

DNA - deoxyribonucleic acid; genetic material

DNR - do not resuscitate

FDA - Food and Drug Administration

FISH - fluorescent in situ hybridization

FL - follicular lymphoma

FNA - fine needle aspirate

GVHD - graft-versus-host disease

HBV - hepatitis B virus

HL - Hodgkin lymphoma

_IGHV_ \- immunoglobulin heavy chain variable region

IHC - immunohistochemistry

IV - intravenous

LRF - Lymphoma Research Foundation

MALT - mucosa-associated lymphoid tissue

MR - minor response

MRI - Magnetic resonance imaging

MUGA - multi-gated acquisition scan

NCI - National Cancer Institute

NHL - non-Hodgkin lymphoma

NIH - National Institutes of Health

NK - natural killer cell

PCR - polymerase chain reaction

PET - positron emission tomography

PI3K - phosphoinositide 3-kinase

PICC - peripherally inserted central catheter

PML - progressive multifocal leukoencephalopathy

PR - partial remission

PS - performance status

SEER - Surveillance, Epidemiology, and End Results

SLL - small lymphocytic lymphoma

TLS - tumor lysis syndrome

# INTRODUCTION

The purpose of this booklet is to help patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), which are slow-progressing cancers, and their caregivers become active participants in their healthcare decisions. CLL and SLL are types of cancer that begin in white blood cells called lymphocytes. Chapters in this book address different issues faced by these patients, including what to expect during diagnosis, work-up, and treatment; how to cope with treatment side effects; and what questions to ask doctors. In addition to this booklet, information is available online at the Lymphoma Research Foundation's "Focus on Chronic Lymphocytic Leukemia" website (www.focusoncll.org/).

### _Part 1 - Learning the Basics_
### Chapter 1: Understanding the Disease

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are cancers that affect the same specialized white blood cells called lymphocytes. Lymphocytes work together with other cells in the immune system to defend the body against invasion by bacteria, viruses, parasites, and other foreign substances. Lymphocytes travel in the bloodstream and in another network of vessels called the lymphatic system. Lymphocytes are also found in specialized structures called lymph nodes. Lymph nodes are part of the lymphatic system and act like sentinels because they can detect viruses or bacterial infections.

Historically, when lymphoma cells were found in a patient's bone marrow and blood, their disease was called CLL; when lymphoma cells were found in the lymph nodes, the disease was called SLL. However, doctors later realized that CLL and SLL are really the same disease found in different locations in the body. Today, CLL and SLL are grouped together, acknowledging that the malignant lymphocytes found in the bone marrow, blood, and lymph nodes are considered the same disease.

This chapter explains these and other terms that will help you understand CLL and SLL and how they affect a person's health. A better understanding of the disease will help patients take a more active role in deciding the course of their treatment.

### What Is Cancer?

Cancer is a group of diseases that develop when abnormal cells gain the ability to divide uncontrollably and interfere with normal cell function.

The body is made up of many different types of specialized cells that are organized into tissues and organs to perform all the different tasks needed to stay healthy. To keep things running smoothly, the cells in the body grow, work, and divide in a very controlled fashion.

All of these cells also have a limited lifespan. Normally, a self-destruct mechanism is triggered when a cell becomes too old or when it stops working properly. However, sometimes damage to the genetic material (DNA) of a cell gives it the ability to override this self-destruct mechanism and allows the cells to continue to live and grow, making these abnormal cells "immortal" in many ways; this means that the cells that would normally be unable to divide and grow continue to grow indefinitely. Unless the body's immune system gets rid of them, these abnormal cells can cause cancer.

Most cancers are named after the organ or cell type of their origin. For example:A cancer that started in the pancreas is called pancreatic cancer.

  * A cancer that started in blood-forming cells in the bone marrow or cells in the blood is called _leukemia_.

  * A cancer that started in a lymph node or other lymphatic tissues in the body is called _lymphoma_. Lymphocytes work together with other cells in the immune system to defend the body against invasion by bacteria, viruses, parasites, and other foreign substances.

## What Are Red Blood Cells and White Blood Cells?

Red blood cells carry oxygen from the lungs to all the tissues in the body. Red blood cells also sweep up the carbon dioxide waste produced by cells and bring it to the lungs. In the lungs, the carbon dioxide is released into the air each time you breathe out (exhale).

White blood cells work as part of the immune system to help the body fight off infections. The main types of white blood cells are lymphocytes, granulocytes, and monocytes. There are also three types of granulocytes (neutrophils, basophils, and eosinophils) and three types of lymphocytes (B cells, T cells, and natural killer [NK] cells).

Because red and white blood cells have a limited lifespan, the body needs to constantly replenish its supply of these cells. Red blood cells live for about 120 days; most white blood cells have an even shorter life, ranging from a few hours to a few weeks.

Both red and white blood cells are made by blood stem cells, which are specialized cells found in the bone marrow (the spongy, fatty material inside large bones such as the pelvis, vertebrae, and ribs). Healthy bone marrow produces blood stem cells, which are immature (non- specialized) cells that can take on various roles. The blood stem cells in the bone marrow change and divide, becoming either a "myeloid" stem cell or a type of lymphoid-forming stem cell (see figure below).

Note: Details of the steps in the lineage diagram above, especially between stem cells and blast cells, are still under investigation. [Source: CLL PDQ NCI Patient version]

Stem cells become mature cells that travel in the blood, such as:

  * Red blood cells — These carry oxygen and other materials to tissues in the body. A low number of red blood cells causes _anemia_. A person with anemia may feel tired, weak, and short of breath.

  * Neutrophils, eosinophils, and basophils — Neutrophils are a type of white blood cell that helps fight off bacterial infections. A low number of neutrophils causes _neutropenia_. People with neutropenia are more likely to get infections than people with healthy numbers of neutrophils. Basophils are part of inflammatory reactions, like allergies. Eosinophils also help fight infections and are involved in allergic reactions.

  * Platelets — These are cell fragments that stop bleeding by causing blood clots to form. A low number of platelets is called _thrombocytopenia_. People with thrombocytopenia are more likely to bruise and bleed. They are also more likely to have severe and recurring nosebleeds and bleeding gums.

Once lymphoid stem cells detect pieces of foreign matter (antigens), they increase in size and become lymphoblasts. Lymphoblast cells specialize and divide. Types of lymphocytes include:

  * B lymphocytes (B cells)

  * T lymphocytes (T cells)

  * Natural killer (NK) cells

To learn more about these types of cells, see "What are Lymphocytes".

## What Is the Lymphatic System?

As shown in the picture on the following page, the _lymphatic system_ is a circulatory system that is made up of a spidery network of thin tubes called lymph vessels. Similar to blood vessels, lymph vessels branch out into all tissues of the body. While people can clearly see blood vessels, especially at their wrists and on the top of their hands, lymph vessels are invisible to the naked eye.

Lymph vessels carry lymph, a type of liquid that contains lymphocytes to help fight infection. Within this huge network of vessels are groups of small, bean-shaped organs called lymph nodes, which are also commonly known as "glands." Thousands of lymph nodes are found at locations throughout the body, including the elbows, neck, underarms, and groin. Lymphocytes can mostly be found in lymph nodes, where they monitor the lymph for signs of infection in the body. The lymph nodes can change in size, becoming bigger or smaller depending on the number of lymphocytes inside them.

Lymph fluid flows through lymph nodes and specialized lymph tissues such as the spleen, tonsils, bone marrow, and thymus gland. Lymph nodes filter the lymph fluid, removing bacteria, viruses, and other foreign substances from the body. The liquid in lymph vessels usually gets dumped into a large blood vessel near the heart.

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.

##

## What Are Lymphocytes?

Lymphocytes are one type of white blood cell. There are three main types of lymphocytes:

  * B lymphocytes (B cells) — B cells make antibodies to fight infections.

  * T lymphocytes (T cells) — There are many types of T cells. Some help B cells make antibodies, some attack and kill infected cells, and others help control the way other parts of the immune system fight infections. They are called "T" cells because they may spend part of their lifespan in the thymus gland, a small organ in the chest.

  * NK cells — NK cells attack and kill cancer cells and virus-infected cells. They also make chemicals called cytokines that help the body get rid of viruses and tumor cells.

## How Does the Immune System Work?

The immune system is the body's defense against things that might harm it. As shown in the picture above, the immune system is made up of a network of cells, tissues, and organs that work together to detect and destroy invaders such as bacteria, viruses, and parasites that can make people sick.

The immune system provides two different types of immunity:

  * Innate immunity — This is provided by natural barriers in the body, chemicals in the blood, and specific types of cells that attack and kill foreign cells that invade the body. Examples of natural barriers include skin, mucous membranes (in the nose, mouth, eyelids, windpipe, lungs, stomach, intestine, and bladder), stomach acid, and the cough reflex. These barriers act like the walls of a castle to keep germs and other harmful things from entering the body. Inflammation (redness and swelling) is also a type of innate immunity.

  * Adaptive immunity — This is provided by the thymus gland, spleen, tonsils, bone marrow, circulatory system, and lymphatic system. These systems work together to make, store, and move specialized cells (such as T cells, B cells, and NK cells) and molecules (such as antibodies) that recognize specific parts (called antigens) of invading organisms, ridding the body of viruses, bacteria, or parasites that make these antigens. This is a tricky job because, in order for the immune system to destroy foreign invaders, it has to be able to recognize what things are part of the body ("self") and what things are not part of the body ("non-self"). Through a complicated process, the body's adaptive immune system "remembers" the identity of the invader, so that the next time the body is infected by the same virus, for example, the immune response will be even stronger. Vaccinations prevent disease by turning on the adaptive immune response before the body is exposed to the disease, ensuring it is prepared to recognize and fight the disease.

## What Is Lymphoma?

A _lymphoma_ is a type of cancer that affects lymphocytes. There are two major categories of lymphomas: non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Both of these major categories of lymphoma are further subdivided into several types, which are different in the way they develop and spread and how affected patients are treated.

## What Is Non-Hodgkin Lymphoma?

In the United States, NHL is the seventh most common type of cancer affecting adults. NHL does not refer to a single disease but to a large group of related cancers that occur in lymphocytes. The World Health Organization estimates that there are at least 60 types of NHL. While these various types share many common features, certain characteristics set them apart from each other, including:

  * How they look when examined under a microscope

  * Genetic and other molecular characteristics

  * How and where they grow in the body

  * How their growth and spread affect patients

  * How patients should be treated

NHL is divided into the following two major groups:

  * _T/NK-cell_ lymphomas — These develop from abnormal T lymphocytes or NK cells and account for about 15% of patients with an NHL diagnosis.

  * _B-cell_ lymphomas — These develop from abnormal B lymphocytes and account for about 85% of all patients diagnosed with NHL.

– CLL and SLL are in the family of B-cell lymphocyte malignancies. About 26% of patients with a B-cell lymphocyte malignancy have CLL or SLL.

Relative Frequencies of B-Cell Lymphomas

MALT, mucosa associated lymphoid tissue.

Percentages are based on the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data, 2002-2011.

In addition, NHL types are often grouped according to how quickly they grow:

  * _Indolent_ lymphomas (also called _low-grade_ lymphomas) usually grow slowly and tend to cause few symptoms. While indolent lymphomas are generally not curable, patients can live a long time with these types of lymphomas because they respond well to treatment and remain in remission for many years (even decades). Over time, some indolent lymphomas may develop into aggressive lymphomas. Despite being slow growing, many patients with indolent lymphoma have widespread disease at their diagnosis.

  * _Aggressive_ lymphomas (also called _intermediate-grade_ and high- _grade_ lymphomas) grow and spread more quickly than indolent lymphomas. Aggressive lymphomas, while potentially life threatening, can often be cured because many chemotherapy drugs can kill rapidly dividing tumor cells. Aggressive lymphomas tend to be more localized compared with indolent lymphomas.

_Pathologists_ (doctors who specialize in disease diagnosis) can distinguish among the many different types of NHL by examining biopsy tissue samples and blood and bone marrow samples under a microscope and by carrying out various laboratory tests. This information is critically important in deciding how to treat the patient.

## What Is CLL/SLL?

CLL and SLL are considered the same disease. The major difference between the two conditions is where the cancer predominantly occurs. In the 1990s, doctors believed that CLL and SLL were two different diseases, so patients were diagnosed with either CLL or SLL. However, doctors later realized that they are the same disease called different names depending on where the malignant lymphocytes are found in the body. If the malignant lymphocytes are found mainly in lymph nodes, the disease is called SLL, although some malignant ymphocytes may also be found in the blood and bone marrow. If the malignant lymphocytes are found mainly in the bloodstream and bone marrow, the disease is called CLL, even though the malignant lymphocytes can often be found in the lymph nodes and spleen as well. Over time, the diagnosis of a patient with relapsed CLL may change to an SLL diagnosis or vice versa for patients with relapsed SLL.

Since patients with CLL and SLL receive the same treatments, the rest of this booklet will use the term CLL/SLL, unless a distinction needs to be made between the two conditions.

CLL causes symptoms in four ways. The overgrowth of malignant lymphocytes takes up space in the blood, bone marrow, and other organs that is needed for normal cells to function. CLL/SLL also inhibits the normal function of the immune system, especially the production of antibodies, increasing a patient's risk of infection. Patients with CLL/SLL may also have increased autoimmunity, which occurs when a person's own immune cells attack their normal, healthy cells. Autoimmunity can lower a patient's red blood cell (anemia) or platelet (thrombocytopenia) levels. Finally, CLL/SLL also causes "B symptoms." These symptoms include fever and chills, night sweats, and weight loss, which are a result of increased chemical production by lymphocytes. Under normal circumstances, these chemicals are used for communication with other parts of the body. Because of the way CLL causes disease, doctors consider it to be a type of chronic disease, meaning that it develops and worsens over an extended period of time. This is different from acute disease, in which symptoms appear and change or worsen rapidly. Over time, CLL may occasionally progress to a more aggressive type of lymphoma (Richter syndrome).

According to the American Cancer Society, approximately 15,700 people in the United States are diagnosed with CLL/SLL each year. An average person has a one in 200 (0.5%) lifetime risk of developing CLL/SLL. This disease is rare in people younger than 40 years. The average age at diagnosis is 72 years.

## What Causes CLL/SLL?

The exact causes of CLL/SLL are not known. Like other types of indolent lymphoma, CLL/SLL develops over a long period of time after lymphocytes accumulate many genetic errors (called mutations and chromosomal abnormalities) that cause them to act abnormally. Some of these mutations make the abnormal lymphocytes reproduce faster and live longer than normal lymphocytes.

These abnormal cells accumulate in the lymph nodes, bone marrow, bloodstream, and other organs. The increasing numbers of cancerous lymphocytes in the blood and bone marrow crowd out healthy white blood cells, red blood cells, and platelets. Because of all these changes, patients with CLL/SLL are more likely to have infections, low levels of red blood cells in the blood, and bleed more easily.

Also, like their healthy siblings, cancerous lymphocytes can travel through the lymphatic system. This ability to move around lets the cancerous lymphocytes spread and grow in many parts of the body. This is why CLL/SLL and most other types of indolent NHL are already found throughout the body by the time a patient is diagnosed with the disease.

## Why Do People Develop CLL/SLL?

The reasons why people develop CLL/SLL are not understood. However, scientists have found that people with certain characteristics have a slightly higher risk of developing CLL/SLL compared with people who do not have these characteristics.

The characteristics that make a person possibly more susceptible to developing any type of disease are called _risk factors_.

Having one or more risk factors for CLL/SLL does not mean a person will develop the disease. In fact, most people with the known risk factors never develop CLL/SLL, and many people diagnosed with CLL/SLL do not have any of these risk factors. However, there does seem to be a connection between these risk factors and the development of CLL/SLL.

Known risk factors for CLL/SLL include:

  * Having a first-degree relative (parent, sibling, or child) with the disease doubles the risk.

  * Being exposed to Agent Orange (an herbicide used during the Vietnam war) and long-term exposure to some pesticides used in farming increases the risk.

  * Male gender — For unknown reasons, CLL/SLL is slightly more common in men than in women.

  * Ancestry — CLL/SLL is more common in North America and Europe and is rare in Asia.

Like other types of cancer, CLL/SLL cannot be caused by injury and cannot be caught from someone who has the disease.

## Why Is There no Single Cure for Cancer or a Vaccine Against it?

Cancer refers to a large group of very complicated diseases. A tricky aspect of cancer is that there are many different ways for a cell to become abnormal enough to cause cancer. Because of this, the path taken by a healthy liver cell to become a cancerous liver cell can be quite different from the path taken by a lymphocyte to become CLL/ SLL. This is why a treatment that works against one type of cancer may not necessarily work against another.

There is no single vaccine for cancer because vaccines work by taking advantage of the immune system's ability to recognize the difference between things that are normal parts of the body and those that are foreign organisms and substances. Cancer is caused by very complicated changes that occur in a person's own body that are unlike those made by attacking foreign organisms like viruses or bacteria. The immune system is not very good at recognizing cancer cells because they are not different enough from a person's healthy cells to trigger an alarm. Anticancer vaccines are very hard to make because cancer cells look almost the same as healthy cells. In addition, cancer cells can release substances that prevent the immune system from being able to attack the cancer.

There are also small, but important, differences in the cancer cells found in different patients diagnosed with the same type of cancer. Because of this, a treatment that may work very well in one patient may not have the same positive effect in another. These are some of the reasons why most cancers are much harder to treat or prevent than diseases like whooping cough (pertussis) or the measles, which are caused by infection from a single type of foreign organism.

### Chapter 2: Seeking Medical Attention

This chapter explains the signs and symptoms of CLL/SLL and discusses how a doctor determines whether or not a person has the disease.

A _sign_ is anything unusual that doctors or nurses notice when they examine their patients.

A _symptom_ is anything unusual in a normal body function, appearance, or sensation that a patient experiences. During a visit with a healthcare practitioner, patients should report all of their symptoms to their doctor or nurse. Symptoms may indicate the presence of CLL/SLL or another disease.

In patients who do not have any symptoms, doctors might discover CLL/SLL after blood tests given for another reason (such as during a routine physical examination) show blood cell count abnormalities that lead them to order more specialized tests.

## What Are the Signs and Symptoms of CLL/SLL?

Many patients with CLL/SLL do not have any obvious symptoms of the disease. Their doctors might detect the disease during routine blood tests and/or a physical examination. For others, the disease is detected when symptoms occur and the patient goes to the doctor because he or she is worried, uncomfortable, or does not feel well.

As shown in the table on the following page, CLL/SLL may cause different symptoms depending on the location of the tumor in the body. Keep in mind that, because these signs and symptoms are not specific to CLL/SLL or other types of non-Hodgkin lymphoma (NHL), they may be due to various other conditions.

Table 2.1. Symptoms of CLL/SLL

Having one or more of these symptoms does not mean that a person has CLL/SLL. Infections or other conditions (including other cancers) may also cause these symptoms.

When Should a Patient Seek Medical Attention?

Anyone who has an enlarged lymph node and/or _persistent symptoms_ should see a doctor to make sure that lymphoma or another serious condition is not present. A good rule of thumb is to seek medical attention if any of the symptoms listed above last longer than 2 weeks, or sooner if the symptoms are harsh enough to impact a person's daily life. Most patients with these symptoms do not have lymphoma, as diseases or conditions not related to lymphoma can also cause many of these symptoms.

What Does the Doctor Look for During the Visit?

There are no specific tests that doctors can use to routinely screen patients for CLL/SLL.

During the visit with the doctor, patients should describe all of their symptoms. The doctor will ask detailed questions about their medical history and perform a complete physical examination. During the physical examination, the doctor is likely to:

  * Measure blood pressure and pulse

  * Look for any physical signs of infection or any other cancers, especially on the skin

  * Check for swollen lymph nodes under the chin, in the neck and tonsil area, above the shoulders, on the elbows, in the underarms, and in the groin

  * Examine other parts of the body to see if there is swelling in the abdomen that may be caused by swollen lymph nodes

  * Examine the abdomen to see if the liver and/or spleen are enlarged

  * Listen to the heart and lungs

  * Ask about any pain the patient is experiencing

If the doctor suspects CLL/SLL after reviewing the symptoms reported and signs they have uncovered during the examination, they will order other tests that can confirm the diagnosis.

These tests should include a complete blood count (CBC) and may also include specific laboratory tests, chest X-rays, and other imaging tests. Biopsies from lymph nodes may be needed for patients with SLL. Doctors do not need a bone marrow test to make the CLL/SLL diagnosis, but they may find it useful during the course of treatment. These tests and procedures are discussed in more detail in Chapter 3.

### Chapter 3: Receiving a Diagnosis

Doctors need the results of various diagnostic tests to determine if a patient has CLL/SLL. This chapter explains the purpose of these tests and describes what to expect during and after these procedures.

How Is CLL/SLL Diagnosed?

Most cases of CLL/SLL are diagnosed on the basis of abnormal blood tests in people who do not have any clinical signs or symptoms of the disease. The doctor might suspect that a patient has CLL/SLL because of reported symptoms, results of the physical examination, and/or abnormal results from a blood test. The following tests are usually used to confirm the diagnosis:

  * CBC with differential

  * Hematopathology of blood smears and sometimes of a bone marrow biopsy

  * Immunophenotyping by flow cytometry of the B lymphocytes in the blood

  * Histopathology of lymph node biopsy (needed for SLL diagnosis, but not usually for CLL unless the flow cytometry does not provide enough information)

Patients diagnosed with a complicated disease like CLL/SLL will be asked to undergo a variety of procedures for the initial diagnosis and work-up before treatment begins, during the course of treatment, and during the follow-up period. Before patients agree to a procedure, they should make sure that they understand the reasons for the procedure and what will be involved.

Questions to Ask Before Having a Diagnostic Procedure

  * Why is this procedure necessary?

  * What will the procedure tell us about my condition?

  * Can the same information be obtained in another way?

  * What is involved in doing this procedure?

  * What are the possible risks, complications, and side effects?

  * Where will I have the procedure done?

  * Will I have to do anything to prepare for the procedure?

  * How long will the procedure take? Will I be awake? Will I feel pain?

  * How long will it take for me to recover from the procedure?

  * Should anyone else be present when I have the procedure?

  * Will I need someone to take me home afterward?

  * When will I know the results?

  * When will we discuss the results?

  * Will my insurance cover the procedure?

  * What will be my out-of-pocket costs?

To help determine the most effective treatment, the doctor might also order one or more additional genetic tests such as:

  * Fluorescent in situ hybridization (FISH) or cytogenetics to detect for changes in specific regions of the chromosomes

  * Molecular analysis to check on the mutation status of the immunoglobulin heavy chain variable region ( _IGHV_ ) gene

  * Flow cytometry or immunohistochemistry (IHC) to determine expression of specific proteins (such as CD38 and ZAP-70)

  * Sequencing of the _TP53_ gene to see if it contains mutations (changes)

What Is a Complete Blood Count With Differential?

For a CBC with differential, samples of blood are examined to find out the following:

  * The number of red blood cells

  * The amount of hemoglobin (the oxygen-carrying protein) in red blood cells

  * The number of total white blood cells and the different subtypes of white blood cells (neutrophils, lymphocytes, monocytes, eosinophils, and basophils)

  * The number of platelets

The results from the CBC with differential will help the doctor suspect a diagnosis of CLL/SLL. Most people with CLL/SLL have high levels of lymphocytes (a condition called lymphocytosis). Sometimes they have low levels of red blood cells (anemia) or low levels of platelets (thrombocytopenia).

The CBC with differential test is often repeated during the course of treatment to help find out how well the treatment is working against the cancer.

What Is Hematopathology?

Hematopathology is the study of blood, lymph node, and bone marrow samples to identify disease. These studies are interpreted by doctors who have been trained to recognize different cell types under the microscope. These specialists identify the cancer cells by looking at their shape and size and how they are grouped in samples from lymph nodes and bone marrow. These specialists include:

  * _Pathologist_ — A doctor specialized in the diagnosis of diseases by studying the cells from a patient's blood, body fluids, and tissue samples.

  * _Hematopathologist_ — A pathologist who has undergone additional training in the diagnosis of blood diseases by studying lymph nodes, blood, and bone marrow samples.

  * _Hematologist_ — A doctor specialized in the diagnosis and treatment of patients with blood cancers and other blood disorders.

What Is Immunophenotyping?

Immunophenotyping is a process used to distinguish between different types of cells (for example, between normal lymphocytes and lymphoma cells) by detecting specific molecules (cell "markers" or "antigens") found on the cell surface. These cell markers are detected using special antibodies made and chemically modified in the laboratory so that they will change color or emit light when they stick to their corresponding markers.

IMMUNOPHENOTYPING

Specific cell markers, called antigens, can be detected on the surface of lymphoma cells using antibodies.

Upon binding to specific antigens on the cell surface, the antibodies can be stained with chemicals so the markers appear as different colors and are studied under a microscope using immuno-histochemistry (IHC) analysis. Alternatively, a molecule can be attached to the antibody so that it can be made to emit light when it binds to the antibody, allowing the cells to be sorted and counted using a process called flow cytometry. Sometimes, both IHC and flow cytometry are necessary for accurate immunophenotyping.

## Table 3.1. Flow Cytometry and Immunohistochemistry Tests

What Is a Biopsy?

A _biopsy_ is a procedure in which a piece of tissue from an area of suspected disease is removed from the body and studied under a microscope. The information provided by this tissue sample is crucial to correctly diagnose the disease and decide on the best course of treatment.

The following are the three main types of biopsies used, when necessary, for the diagnosis of patients with CLL/SLL and other types of lymphoma:

Table 3.2. The Three Main Types of Biopsies

After a tissue sample has been removed, it is examined by a pathologist who develops a report. An oncologist/hematologist then uses this report, along with results of other diagnostic tests, to confirm a diagnosis. An _oncologist_ is a doctor specialized in treating patients with cancer ( _oncology_ is the scientific word for cancer). A _hematologist_ is specialized in treating patients with blood disorders.

If the pathologist's interpretation of the biopsy is uncertain, the report should be reviewed by a _hematopathologist_ (a specialist in the identification of blood diseases), because a pathologic diagnosis of lymphoma can sometimes be difficult to make.

What Is Cytogenetic Analysis?

Chromosomes are long strands of DNA, the genetic material of a cell. Healthy human cells have 23 pairs of chromosomes. Chromosomes are divided into two regions called "arms," which are called p (short arm) and q (long arm). Some lymphomas and other types of cancer have too few or too many chromosomes, or some have abnormal chromosome structures.

In cytogenetic analysis, chromosomes from cancer cells are examined under a microscope to check for changes in their number (too few or too many) or the presence of other abnormalities. It usually takes 2 to 3 weeks to get the results from cytogenetic testing because a sufficient number of cancer cells must be grown in the laboratory to get enough genetic material for the analysis.

The results of the cytogenetic analysis can help distinguish between CLL/SLL and other types of non-Hodgkin lymphoma (NHL).

  * One type of chromosomal abnormality found in CLL/SLL is called a _deletion_ —which happens when part of a chromosome is missing (see figure below). The most common deletions in CLL/SLL are seen in chromosomes 11, 13, and 17. Deletions in these chromosomes would be written as del(11q), del(13q), and del(17p) on a patient's chart. The cytogenetic analysis of the malignant lymphoma cells can also change over time. For example, some patients' malignant cells might develop 17p deletions over time. When no abnormalities are seen, the result is called "normal," but the cytogenetic test looks for very specific changes in only a few places on a few chromosomes. Other chromosomal abnormalities may be present but are not seen because they were not tested for.

  * Another type of chromosomal abnormality in CLL/SLL is _trisomy_ — which indicates the presence of an extra copy of a chromosome.

  * A third type of chromosomal abnormality that can be seen through a microscope is called a _translocation_ —which occurs when part of a chromosome breaks off from its normal location and becomes attached to another chromosome. This helps to differentiate CLL/ SLL (where this translocation is absent) from a type of NHL called mantle cell lymphoma that carries this translocation.

Finding out what chromosomal abnormalities and genetic changes are present in the CLL/SLL cells helps doctors determine the best course of treatment. The table on the following page shows the chromosomal changes and genetic mutations most commonly found in CLL/SLL as detected by FISH.

What Is the Purpose of Additional Genetic Tests?

Doctors may order additional genetic tests to confirm the results of cytogenetic tests or find out more detailed information about the types of damage to the genetic information of the lymphoma cells in the patient's body. The two main types of additional genetic tests used are shown in the table below.

Table 3.3. Types of Genetic Tests

Table 3.4. Chromosomal Changes and Genetic Mutations Most Commonly Found in CLL/SLL

Del means deletion of some of the genetic material. The numbers in parentheses (eg, 11q23) indicate the chromosome and the area on the chromosome where the deletion is located. FC/FCR, which stands for fludarabine plus cyclophosphamide with or without rituximab, is a type of chemotherapy.

Cautions About Interpreting Diagnostic Reports

  * Some tests can be reported as "normal" even though CLL/SLL may be present.

  * Some tests may be reported as "abnormal" even though CLL/SLL is not present.

  * Peripheral blood immunophenotyping and biopsy are definitive tests for CLL/SLL.

  * Other conditions can mimic CLL/SLL.

  * The interpretation of tests, such as imaging studies or scans, can be lengthy and difficult in some situations.

  * Follow-up tests are often needed to determine the significance of previous results; additional biopsies may be needed to clarify the results.

  * Some patients like to review their written reports; when doing so, it is important for the patient to carefully review the findings with their doctor.

### Chapter 4: Work-up Before Treatment Can Begin

After the initial diagnosis of CLL/SLL, the doctor may order other tests such as blood tests, genetic tests, imaging studies, heart function tests, a bone marrow biopsy, and, less frequently, additional biopsies. This process is often called the "work-up" or "staging studies." Some of these work-up studies are needed to see if and how much the disease has spread to other parts of the body. Doctors will use these test results to determine the state of advancement, or _stage_ , of a patient's disease. Other tests will check how the disease has affected a patient's overall health and major organ functions.

Together, all of these tests will provide the information needed to help patients and their doctors decide on the best course of treatment. This chapter will help you understand how CLL/SLL is staged, the reason for these tests, how these tests work, and what to expect.

What Tests Are Used in the Work-up for CLL/SLL?

Most patients with CLL/SLL will undergo the following work-up tests before starting treatment, and many of these tests will be repeated during the course of treatment:

  * Physical examination with special attention to the size of the lymph nodes, liver, and spleen

  * A determination of general health status (also called performance status) to see how well a patient feels and how well they can carry out their normal daily activities (such as getting washed and dressed, going to work, and doing chores)

  * Presence or absence of fever, night sweats, and weight loss (these are also called "B symptoms")

  * Complete blood count with differential and platelets

  * Comprehensive metabolic panel

  * Testing for signs of infection with hepatitis viruses

Other tests that might be useful for some patients include:

  * Quantitative immunoglobulins

  * Reticulocyte count, haptoglobin, and direct Coombs' test

  * Neck, chest, abdominal, and pelvic computed tomography (CT) scans

  * Blood tests for beta-2 microglobulin, serum lactate dehydrogenase (which is found in high levels in the blood of many patients with fast- growing tumors), and uric acid

  * Bone marrow biopsy and/or aspirate

  * Positron emission tomography (PET), which is not usually used for CLL/SLL but may be needed if the doctor suspects that the CLL/SLL might be changing into a fast-growing type of diffuse large B-cell lymphoma (this change is called Richter's transformation)

What Is a Comprehensive Metabolic Panel?

A comprehensive metabolic panel measures the amount of different chemicals in the blood that will show if the CLL/SLL is affecting any of the main bodily organs. The comprehensive metabolic panel usually includes 14 specific tests that measure liver and kidney function, electrolyte balance, acid/base balance, and the levels of blood sugar and different blood proteins. Calcium, magnesium, potassium, and sodium are some of the electrolytes found in the body; abnormal levels of electrolytes can make a patient sick.

The results from these tests will help patients and their doctors decide between different types of treatments. Many of these blood tests will be repeated during the course of treatment to check if and how the treatment and the cancer are affecting body functions.

Levels of immunoglobulin, a blood protein, may also be evaluated to make sure that there are enough antibodies to fight infections. People with CLL/SLL often have low levels of immunoglobulin. High levels of another blood protein, beta-2 microglobulin, can indicate a more advanced stage of CLL/SLL.

What Types of Imaging Tests May Be Used?

A doctor will most likely order imaging tests to help find areas of the body where there may be cancer, to learn how far the cancer has spread, and to check how well the treatment is working later on. Most of these tests are painless and require no anesthetic. Several types of the following imaging procedures may be needed to thoroughly evaluate the extent of disease.

Table 4.1. Types of Imaging Tests

Why Might Another Type of Biopsy Be Needed?

Once the diagnosis is made, the doctor may order other types of biopsies for additional pathology studies and other tests to see if and how the disease has spread to other parts of the body. These additional tests are not usually necessary for patients with CLL/SLL.

Table 4.2. Other Types of Biopsies

How Is CLL Staged?

Staging is used to describe how widely the cancer has spread in patients with CLL and other types of cancer. Because of how blood and bone marrow are involved in CLL, these staging systems are different from those used for other types of NHL, including SLL (see next section). There is no single standardized staging system for CLL. Patients with CLL are staged using either the Rai staging system or the Binet classification system. Doctors in the United States tend to use the Rai system, while the Binet system is more popular in Europe.

The following table shows the Rai staging system.

Table 4.3. The Rai Staging System for CLL

The table below shows the Binet classification system.

Table 4.4. The Binet Classification System for CLL

How Is SLL Staged?

To stage SLL, doctors use the Ann Arbor staging system developed for other types of NHL. Although the older system is still in use, a modification of the Ann Arbor staging system, the Lugano Classification, was proposed in 2014, which is shown in the following figure. There are two main classifications (limited and advanced disease) and four stages of lymphoma designated by the Roman numerals I through IV. Stages I and II are considered limited disease, although Stage II can be considered advanced in some cases. Stages III and IV are considered advanced disease.

Stage II disease that is also _bulky_ , which means that the patient has a tumor greater than 6 to 10 centimeters (2-4 inches) wide, can sometimes be considered advanced disease.

The newer staging system is similar to the previous Ann Arbor system, except that the "A" and "B" designations are no longer used.

Doctors use the stage of disease, risk group, test results, and/or prognostic information to help decide the best time to begin treatment and what drugs are likely to be the most effective for each patient.

Patients with SLL, whose disease is mostly found in the lymph nodes, often develop disease that is reclassified as CLL; in other words, more malignant lymphocytes eventually appear in the bone marrow.

### _Part 2 - Treatment of CLL/SLL_
### Chapter 5: What to Know Before Starting Treatment

Receiving a cancer diagnosis can be an overwhelming experience. It is perfectly normal to be shocked by the diagnosis, anxious about the future, and confused about the medical information and decisions that need to be made. This chapter will help patients and caregivers prepare for the start of treatment by explaining the next steps and providing tips for talking with a patient's doctor about any questions or concerns.

First Steps to Take After Receiving a Diagnosis

  * Take care of yourself (eat, sleep, rest, and exercise).

  * Seek the support of family, friends, and others who you trust and rely on.

  * Learn about the disease and treatment options.

  * Find medical care that meets your needs.

  * Find emotional and social support.

  * Understand the cost of care, what your insurance will cover, and what financial assistance programs may be available to you.

  * Maintain a copy of your medical records (paperwork, test results, your own notes).

Who Will Plan and Carry Out the Treatment?

Treatment is usually overseen by a medical oncologist or hematologist who specializes in the treatment of patients with lymphoma. Depending on the patient's healthcare needs, the doctor may sometimes work with a radiation oncologist.

The healthcare team may also include other healthcare professionals such as an oncology nurse, nurse practitioner, physician assistant, social worker, and registered dietitian. The healthcare team will work together and consult with the patient to plan, carry out, and monitor the treatment and plan the patient's cancer care.

What Is a Prognosis?

_Prognosis_ is the medical term doctors use for predicting how the disease will progress and the likelihood for recovery, which is often one of the first things that patients ask their doctor. A prognosis is usually based on information gathered from hundreds or thousands of other patients who have had the same disease. This statistical information provides doctors with a general idea of what to expect when a patient is diagnosed with CLL/SLL, and it also gives guidance on the kinds of treatments that have been most successful in treating this disease.

While doctors and scientists have learned a lot about CLL/SLL, it is not always possible to predict which specific treatments are most likely to work in an individual patient.

**Keep in mind that no two patients are alike and that statistics from large groups of people cannot accurately predict what will happen to a specific patient.** The doctor most familiar with the patient's situation is in the best position to help interpret these statistics and understand if and how they may apply to a patient's particular situation.

What Are Prognostic Factors?

The characteristics that help predict a person's prognosis are called _prognostic factors_. _Favorable prognostic factors_ tend to be associated with a better outcome, while _adverse prognostic factors_ tend to be associated with a worse outcome.

Table 5.1. Known Prognostic Factors for CLL/SLL

Keep in mind that prognostic factors are generated by studying the outcomes of large groups of patients. **No two patients are alike. It is impossible to accurately predict what will happen to a specific patient. A patient should talk with their doctor to understand if and how prognostic factors might apply to their situation.**

What Is Performance Status?

_Performance status (PS)_ is a numerical way to describe a patient's general health, presence or absence of chronic health problems, and ability to carry out normal daily activities (such as getting washed and dressed, going to work, and doing chores). As shown below in the table depicting the Eastern Cooperative Oncology Group PS scale, PS is graded on a 0 to 4 scale, with the lower numbers indicating a better PS. Doctors do not generally use PS values unless the patient is part of a clinical study. Many clinical studies of new drugs restrict participation to the more physically fit patients (those with lower PS grades).

Table 5.2. The Eastern Cooperative Oncology Group PS Scale

How to Decide What Is the Best Treatment

Many patients with CLL/SLL do not need to be treated when they are first diagnosed. If the patient's doctor decides it is time to begin treatment, there are many effective treatment options for patients with CLL/SLL. To identify which treatments may work best, doctors consider the following factors:

  * The stage and risk category (see "How is CLL Staged?")

  * Prognostic factors (see "Table 5.1")

  * Symptoms

  * Overall health and age

  * A patient's preferences

  * Whether the treatment is the first the patient has received or if the disease has returned after prior therapy

A doctor will discuss the risks, benefits, and side effects associated with the different treatment choices applicable to the patient's particular situation. Patients and caregivers should share questions and concerns with the doctor so that together they can decide which option is best. The following questions can be used to guide the conversation and help make an informed decision.

Questions to Ask Before Treatment Begins

  * What is my exact diagnosis? May I have a copy of the report from the pathologist?

  * What is the stage of my disease? What is my risk category?

  * What are my prognostic factors?

  * What are my treatment choices? Which do you recommend for me? Why?

  * Are clinical trials available that are studying new treatments? Would a clinical trial be appropriate for me?

  * Do I need more than one type of treatment?

  * What is the goal of treatment?

  * What are the expected benefits of each type of treatment? How will we know if the treatment is working? What tests will I need to have to see if it is working? How often will I need to get tested?

  * What are the risks and possible side effects of each treatment? Can these side effects be prevented or controlled?

  * What should I do to take care of myself during treatment?

  * Are there any late or long-term side effects that I should be aware of? Will treatment impact my ability to have children?

  * How long will the treatment last?

  * What are the chances that the treatment will be successful?

  * How will the treatment affect my normal activities (for example, work, school, childcare, driving, sexual activity, exercise)?

  * Will I be able to work during treatment?

  * How often will I need a checkup?

  * How much will the treatment cost? Will my insurance cover it?

When to Get a Second Opinion

Before starting any type of treatment, a patient may consider getting a second opinion—especially if some characteristics of the diagnosis are complicated or uncertain. The purpose of the second opinion is not to question the doctor's expertise, but to make sure that the suggested treatment plan is reasonable and optimal for the patient's particular case.

Most doctors will be supportive and helpful if you tell them that you would like to get a second opinion. Ask the doctor if it would be okay to briefly delay the start of treatment to provide the time needed to get a second opinion. Keep in mind that some insurance programs require second opinions; others may provide coverage for the cost of a second opinion if a patient or doctor requests it.

Getting a Second Opinion

  * Some hematologists/oncologists/lymphoma specialists associated with medical schools or cancer centers may provide a consultation and be willing to work together with a local oncologist to provide treatment and follow-up care.

  * As part of the second opinion, another pathologist must review the tissue and blood samples to confirm the diagnosis. Try to find a pathologist with a lot of experience diagnosing patients with lymphoma.

  * To get a second opinion, you will have to provide the consulting doctor a complete copy of all medical records, original X-rays, pathology materials, scans, and reports. When you set up the appointment, ask their office for a list of all the materials they will need. It may be useful to keep your own copy of all these records in case you have questions or concerns later on.

To identify lymphoma specialists to contact for a second opinion:

  * Ask your current doctors, family members, other patients, friends, and coworkers.

  * Contact the patient referral service at your local hospital and at the nearest hospital associated with a medical school; many hospitals have online directories that can be searched to find a specialist in your area.

  * Visit the American Society of Clinical Oncology (ASCO) website at www.cancer.net to search their oncologist database.

  * Visit the American Society of Hematology (ASH) website at www.hematology.org/patients to search for hematologists with an interest in lymphoma.

  * Visit the National Cancer Institute (NCI) at www.cancer.gov/ researchandfunding/extramural/cancercenters/find-a-cancer-center to identify the nearest NCI-designated cancer center, and call (800-4-CANCER or 800-422-6237) or visit their website to find out about their lymphoma specialists.

  * Visit the American Board of Medical Specialists (ABMS) at www.ABMS.org and click on "Is Your Doctor Certified?" to find out if doctors are board certified in a particular speciality.

  * Visit the Lymphoma Research Foundation (LRF) website at www.lymphoma.org or contact LRF directly by phone (800-500-9976) or email (LRF@lymphoma.org).

How to Find an Oncologist and Treatment Center

Patients' primary care doctor will probably make a referral to a specialist—likely a medical oncologist, hematologist, or hematologic oncologist. Oncologists are physicians who specialize in diagnosing and treating patients with cancer. Hematologists are physicians who specialize in diagnosing and treating patients with disorders of the blood and lymphatic system.

Before agreeing to treatment by a specific doctor and treatment center, make sure that they will be able to meet all of the patient's medical and personal needs. Patients and caregivers should feel comfortable with the healthcare team and the quality of care they provide.

Here are some questions to ask when selecting a medical team:

  * What are the credentials of the doctor, the other members of the medical team, and the hospital or cancer center?

  * Is the doctor board certified as a medical oncologist or hematologist? Has he or she passed qualifying examinations by the American Board of Internal Medicine to certify competency in these specialties?

  * How much experience do the doctor and treatment center have in treating patients with non-Hodgkin lymphoma (NHL), and CLL/SLL in particular?

  * How many patients with this disease are being treated here now?

  * Does the doctor and/or center participate in clinical trials?

  * Is the doctor a member of the American Society of Clinical Oncology (ASCO) and/or the American Society of Hematology (ASH)?

  * Does the clinic or center have modern 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 assistance after hours and on weekends, in case of an emergency?

  * Is my health insurance accepted at this center? Will the treatment center file claims for reimbursement and process the paperwork?

  * What kind of patient resources does the clinic or cancer center have for patients with CLL/SLL?

  * If I see other specialists (cardiologist, endocrinologist, etc), will you coordinate my cancer care with my other doctors?

Patients enrolled in a managed care program may have limited choices. However, patients have the right to choose another healthcare team if they are not entirely satisfied with their first consultation visit. They should talk with other patients and caregivers about their experiences and ask them if they would recommend their doctor and healthcare team. Also, patients and caregivers who are not satisfied should share their concerns with their primary doctor and ask for a referral to a different doctor.

How to Communicate With the Healthcare Team

Patients and caregivers can ease some of their anxieties by establishing open, honest communication with their healthcare team regarding their diagnosis. Open communication with the healthcare team can help patients and caregivers better learn 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 questions that come to mind. Before meeting with a doctor or nurse, for the first time or for follow-up visits, consider organizing questions to bring to the visit. The two or three most important questions should be put at the top of the list, since time with doctors or nurses may be limited. However, make sure that a member of the medical team reads all of the questions, because they may see some that are more important than you realize.

Patients should consider having a family member or close friend accompany them to the doctor's office or clinic to help ask questions and understand and remember answers. A companion could also help by taking notes during the visit. Some patients bring a recording device to record the answers. It is recommended to ask the doctor or nurse for permission 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 time diagnosis is received and onward.

Although family members are often very concerned about their loved one and want information concerning his or her care, confidentiality rules prohibit doctors from giving out information to anyone without the patient's expressed permission. For efficiency, designate one family member as the family contact. The patient must remember to specifically tell the doctor the identity of the primary family contact.

Communicating With Your Doctors

At home

  * Keep a journal of your symptoms to help you remember the details you want to discuss with your doctor during your next office visit.

  * Ask your doctor or nurse which symptoms need to be communicated immediately to them and which can wait for your next visit.

  * Make a list of questions that you want to ask your doctor. However, if the questions are urgent, do not wait for the next visit; call the doctor's office to discuss your concerns.

At your next doctor's visit

  * Bring your symptom journal and list of questions, and discuss them with your doctor or nurse.

  * Ask a family member or friend to come with you to provide emotional support and take notes.

  * Do not be afraid to ask questions if you do not understand something. Your doctor will want to know if you are uncertain or confused and will be happy to explain things to you.

  * Clarify who you should contact for specific questions or for weekend support, and find out how you can reach them.

  * Ask if members of your healthcare team communicate by email.

  * Before leaving the doctor's office, make sure that you understand the next steps in your care.

  * Ask for written information that you can take home to help you.

  * Download the free _Focus on Lymphoma_ mobile app from the Lymphoma Research Foundation to help you plan appointments, keep track of medications and blood work, and document treatment side effects (available at: www.lymphoma.org/mobileapp).

What Is the Purpose of an Advance Healthcare Directive and Appointing a Healthcare Proxy?

Having an Advance Healthcare Directive (a _living will_ ) and appointing a healthcare proxy is something that all adults should consider doing regardless of their healthcare status. This is something for everybody to think about, not just people with cancer, because accidents and other unforeseen circumstances can happen anytime.

Writing down wishes for critical medical care in an Advance Healthcare Directive is a way to formally tell the doctor, family members, and friends about healthcare preferences and what special treatments someone does or does not want if they become critically ill or injured and are unable to make and communicate their decisions.

Besides stating medical care instructions, people may also consider naming a healthcare proxy, or decision maker, in an Advance Healthcare Directive. This should be someone who will carry out their wishes, including any do-not-resuscitate (DNR) instructions. It is best to have both an Advance Healthcare Directive and a healthcare proxy.

Before writing an Advance Healthcare Directive, it is important to understand patients' rights and the laws regarding Advance Healthcare Directives in each state. Consulting an attorney can provide the legal information, but an attorney is not required to write an advance directive. An Advance Healthcare Directive may include:

  * Specific instructions on medical care, including the type of special treatment that is or is not desired, such as cardiopulmonary resuscitation (CPR), artificial respiration, drugs to make the heart function, kidney dialysis, artificial feeding, and certain surgical procedures

  * A choice of a healthcare proxy

For more information about Advance Healthcare Directive laws for your state, please visit the "Planning Ahead" section of the National Hospice and Palliative Care Organization website at www.caringinfo.org.

How to Be a Self-Advocate

Being a self-advocate and an active participant in healthcare decisions can be a positive experience and may help restore a sense of control that may have been lost following the diagnosis. Patients and caregivers should remember that they are partners in their treatment plan. Many patients feel better when they actively participate in their own care.

The first steps in participating in treatment are to ask questions, learn about options, and work closely with the doctor. It is important to be comfortable with the doctors and the approach that they take. If patients or caregivers are not comfortable, they should openly discuss their concerns. Confidence in the medical team often leads to confidence in treatment. If there is a feeling that the team is not a good match, ask for a referral.

Questions will likely vary depending on the purpose of the meeting with the doctor (such as the initial visit to discuss the diagnosis or a routine visit to monitor a remission). Ask for the timing of office visits, treatments, and tests. The doctor can help explain what the tests will look for and define the possible responses and 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 situation and who may have had similar concerns can be a source of great comfort. If the patient or caregiver is interested in talking to and learning from people who have had similar experiences, ask the oncologist, hematologist, oncology nurse, or the oncology social worker about any support groups in the area.

Before agreeing to any tests, check with the healthcare team to determine which costs are covered by insurance and which are not. Do not be afraid to talk to the healthcare team about non-medical issues, such as transportation, finances, insurance, working through treatment or taking time off, and childcare.

Self-Advocacy

  * Do not be afraid to ask your doctor or nurses questions about your care.

  * Learn more about CLL/SLL by asking your doctor for information and visiting reliable websites, such as the Lymphoma Research Foundation at www.lymphoma.org.

  * Take advantage of counseling, support groups, nutritional counseling, fitness classes, expressive arts, and other services offered at your doctor's office, cancer center, or hospital.

  * Consider joining the Lymphoma Support Network, a nationwide buddy program that matches patients and caregivers with people who have had similar experiences. For information about the program, call (800) 500-9976 or email support@lymphoma.org.

### Chapter 6: Treatments for CLL/SLL

In this chapter, you will learn about the most common therapies that are currently used in the treatment of patients with CLL/SLL. Keep in mind that new therapies may have been approved by the US Food and Drug Administration (FDA) since this book went to print. Read Chapter 10 to learn more about new agents under investigation.

What Types of Treatments Are Used in Patients With CLL/SLL?

There are five general types of treatments for patients with CLL/SLL:

  * Watchful waiting (no treatment given) in which the patient is closely monitored to see if/when treatment should be started

  * Drug therapy, which includes one or more of the following types of drugs:

    * Chemotherapy, which affects general cell growth and division

    * Monoclonal antibodies, which can specifically attack lymphoma cells

  * Targeted or biologic therapies, which affect special characteristics of tumor cells

  * Stem cell transplantation

  * Radiation therapy, which uses high-energy radiation to kill lymphoma cells

  * Surgery to remove the spleen (splenectomy)

These types of therapy are described in detail throughout this chapter.

What Is Watchful Waiting?

About one-third of patients with CLL/SLL never need treatment for their disease. With the _watchful waiting_ approach, patients do not receive any anti-lymphoma treatments, but their health and disease are monitored through regular checkup visits and follow-up evaluation procedures, such as laboratory and imaging tests. These patients continue to remain untreated as long as they do not have any symptoms and there is no evidence that the lymphoma is growing or spreading.

Doctors recommend watchful waiting for selected patients with indolent (slow-growing) stage 0 CLL/SLL and some patients who have no symptoms with stage I or II CLL/SLL. This approach may be started after the initial diagnosis or after initial treatment. Active treatment is started if the patient begins to develop lymphoma-related symptoms or if there are signs that the disease is progressing.

Watchful waiting is not a treatment option for patients with advanced CLL/SLL. Usually, treatment for these patients should start as soon as possible after diagnosis.

Questions to Ask Before Starting Watchful Waiting

  * What happens if I choose watchful waiting and then change my mind?

  * Will the disease be harder to treat later?

  * How often will I have checkups?

  * Between checkups, what symptoms and other problems should I report?

What Is Chemotherapy?

Chemotherapy drugs work against general characteristics of cancer cells such as their tendency to grow and multiply very quickly. Depending on the drug, patients may have to swallow a pill or receive a liquid infused directly into a vein ( _intravenous infusion_ or _IV_ ).

During chemotherapy, patients receive the drug(s) at certain intervals, such as once every 4 weeks, followed by a rest period. This regular treatment schedule is called a _cycle_. The length of the rest period and the number of cycles vary depending on the patient's disease and the types of drugs used.

Most patients with CLL/SLL are treated with combination chemotherapy, meaning two or more drugs, instead of a single drug. These chemotherapy drugs are given in a specific order (or _schedule_ ) during certain days of each treatment cycle—this is called a _treatment regimen_. The reason to combine drugs is to increase how effectively they damage or kill cancer cells.

Oncology nurses are usually responsible for administering the chemotherapy prescribed by the doctor. Most patients receive their chemotherapy in an outpatient clinic, hospital outpatient department, or doctor's office, but sometimes patients have to stay in the hospital for their treatment.

Common Drug Regimens for CLL/SLL

Many of these regimens combine chemotherapy drugs with monoclonal antibodies such as rituximab (Rituxan; which is abbreviated by the letter "R"), ofatumumab, or obinutuzumab.

This list is subject to change as new approvals are made by the FDA.

Table 6.1. Common Drug Regimens for CLL/SLL

How Is Drug Therapy Given?

Depending on the regimen, patients will be given chemotherapy in pill form, as an injection, or as an IV drip through a vein. To make it easier to give and receive multiple cycles of chemotherapy by IV, the doctor may insert an IV catheter that will stay in place for a few weeks or for the duration of the chemotherapy treatment. There are several types of catheters, which are described in the following table. Patients and caregivers should discuss with their doctor which catheter, if any, would be best for their particular situation.

Table 6.2. Catheters Used to Administer Chemotherapy

Why Is it Important to Adhere to the Drug Treatment Schedule?

Patients should adhere to their chemotherapy treatment schedule because a full course of chemotherapy given on time works best in the treatment of their disease. In clinical studies, doctors have found that reducing the dose or delaying chemotherapy may decrease the chance of a cure and long-term survival for patients with certain types of lymphomas. 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. Other side effects may be serious, but they can often be anticipated and prevented. It is very important that chemotherapy schedules be maintained to the greatest extent possible.

What Are Monoclonal Antibodies?

As part of our immune system, specialized white blood cells (plasma cells) make proteins called antibodies. Antibodies help fight infection by recognizing and sticking to anything that the body considers "foreign." Each antibody our body makes is naturally designed to recognize one specific type of molecule.

_Monoclonal antibodies_ are molecules engineered in the laboratory that are designed to recognize and stick to a specific part of a particular molecule (called an _antigen_ ) on, for example, the surface of cancer cells. When a monoclonal antibody attaches itself to a cancer cell, it can stop or slow down its growth or it can make it easier for the immune system to recognize and kill it.

The monoclonal antibodies obinutuzumab (Gazyva), ofatumumab (Arzerra), and rituximab (Rituxan) are being used to treat patients with CLL/SLL. Obinutuzumab, ofatumumab, and rituximab recognize different parts of CD20, a molecule found on the surface of almost all B cells, as antigens. CD20 is also found on the surface of malignant lymphocytes in CLL/SLL.

Once injected in the patient, the monoclonal antibodies travel through the blood and stick to the cells that have the antigen they recognize. Most of these will be CLL/SLL cells. Once they stick, the antibodies trigger an alarm that draws cells from the immune system to help destroy and kill the tumor cells.

Monoclonal antibody therapies are given to patients as IV infusions during visits at the doctor's office or clinic. To prevent serious allergic reactions, patients are given oral antihistamines, acetaminophen (Tylenol), and sometimes steroids before the antibody infusion. All patients should be tested for active hepatitis. To avoid life-threatening infections, patients being treated with monoclonal antibodies should not be vaccinated with live attenuated virus vaccines, such as those for shingles (herpes zoster), yellow fever, and the Sabin vaccine for polio. Read the following sections for additional information about each of these monoclonal antibodies.

Obinutuzumab

In 2013, obinutuzumab was approved by the FDA for the treatment of patients with previously untreated CLL/SLL when given together with the oral chemotherapy drug chlorambucil.

Obinutuzumab treatment is given as an IV infusion. Patients usually receive two doses during the first week followed by one dose a week for 2 weeks (this is the first cycle of therapy), then once every 28 days for five more cycles.

The most common side effects caused by obinutuzumab include infusion reactions, low white blood cell count (neutropenia), low platelet count (thrombocytopenia), low red blood cell count (anemia), fever, cough, and muscle and joint pain. Serious side effects include severe allergic reactions (usually to the first infusion), and rarely reactivation of hepatitis B virus (HBV) that can lead to liver failure. Another rare but serious side effect of obinutuzumab is _tumor lysis syndrome_ (TLS; see _tumor lysis syndrome_ ).

Ofatumumab

In 2009, ofatumumab was approved by the FDA for the treatment of patients with CLL/SLL that has not responded to previous therapy with the chemotherapy drug fludarabine and the monoclonal antibody alemtuzumab. Ofatumumab is sometimes used as monotherapy (alone, not in combination with other drugs) for patients with relapsed or refractory CLL/SLL. In 2014, ofatumumab was approved for the treatment of newly diagnosed patients with CLL/SLL in combination with chlorambucil for whom fludarabine-based therapy is not considered appropriate.

When given as a monotherapy, ofatumumab is administered as an IV infusion once a week for 8 weeks and then once every 4 weeks for four more doses. When given in combination with chlorambucil, it is administered on the first and eighth day of treatment during the first cycle, then on the first day of each 28-day cycle.

The most common side effects caused by ofatumumab include low white blood cell count (neutropenia), low platelet count (thrombocytopenia), low red blood cell count (anemia), pneumonia, fever, cough, diarrhea, fatigue, difficulty breathing, rash, nausea, bronchitis, and infections. Rare but serious side effects include severe allergic reactions (usually to the first infusion), reactivation of HBV that can lead to liver failure, and the potentially deadly brain disorder progressive multifocal leukoencephalopathy (PML). Another rare but serious side effect of ofatumumab is TLS (see "Infections").

Rituximab

In 1997, rituximab became the first monoclonal antibody approved by the FDA for the treatment of patients with cancer—specifically for patients with relapsed or refractory low-grade or follicular B-cell non-Hodgkin lymphoma (NHL). As of 2014, rituximab is approved by the FDA for the treatment of patients with the following:

  * NHL

  * CLL/SLL

  * Other indications include treatment for rheumatoid arthritis, Wegener granulomatosis, and microscopic polyangiitis

Rituximab is used in various combinations with chemotherapy drugs or other monoclonal antibodies (see Table 6.1.). Rituximab treatment is given as an IV infusion usually once every 28 days, but the schedule varies depending on the type of combination regimen used. Rituximab is usually given during the first day of each chemotherapy cycle.

The most common side effects caused by rituximab include infusion reactions, fever, low number of lymphocytes (lymphopenia), low number of white blood cells (neutropenia), chills, infection, and feeling weak (asthenia).

Rarer, more serious side effects (some of which have caused death) include severe allergic reactions (usually during the first infusion), severe skin and mouth reactions (painful sores, ulcers, blisters on skin, lips, or mouth, peeling skin, rash, and pustules), reactivation of HBV, PML, bowel stoppage and bowel injuries, and TLS.

Rituximab treatment can make a person more susceptible to infection during and for up to 6 months after treatment. Because of this, rituximab is not recommended for use in patients with severe, active infections.

What Are Targeted Therapies?

A better understanding of the biology and genetics of CLL/SLL is helping researchers identify specific molecules in lymphoma cells that may be good targets for new drugs. Most of these recently discovered molecules help control the growth and survival of lymphoma cells.

The drugs that target these molecules are broadly called _targeted_ or _biologic therapies_. These drugs may kill the lymphoma cells or slow down or stop their growth. Targeted therapies attack cancer cells in a more specific way than chemotherapy drugs. As of the publication of this booklet, the drugs ibrutinib and idelalisib are the only targeted therapies approved by the FDA for the treatment of patients with CLL/ SLL. Additional information about ibrutinib and idelalisib, which are both "oral oncolytics" (meaning taken orally), is provided below. For more information on oral agents, refer to the Lymphoma Research Foundation's fact sheet _Oral Agents in Lymphoma_ , which is available at www.lymphoma.org.

Ibrutinib

Ibrutinib (Imbruvica) inhibits a type of molecule called a tyrosine kinase. Tyrosine kinases are specialized proteins found near the surface of cells. The main job of tyrosine kinases is to send signals from the cell surface to the cell's control center (its nucleus). These signals help both healthy and cancer cells grow and survive. Cancer cells are more dependent on this signaling system because they grow much faster than healthy cells. Ibrutinib blocks (inhibits) the signals from Bruton's tyrosine kinase (BTK), a tyrosine kinase that is especially important for B cells. By inhibiting the signal from BTK, ibrutinib helps stop or slow down the growth of CLL/SLL cells.

Ibrutinib comes in capsules that must be swallowed whole with a large glass of water at about the same time once a day, every day. Patients should not open, break, or chew the capsules. During the course of treatment with ibrutinib, patients should not eat or drink grapefruit products or Seville oranges as these products may interact with ibrutinib.

Early in 2014, ibrutinib was approved by the FDA to be used as monotherapy for the treatment of patients with previously treated CLL/ SLL or CLL/SLL with a 17p deletion, and patients with previously treated mantle cell lymphoma, a rare type of NHL. These approvals were based on results from clinical studies that showed improved anticancer responses with this drug.

Some of the most common side effects caused by ibrutinib are diarrhea, upper respiratory tract infections, fatigue, muscle and bone pain, and swelling of hands, feet, ankles, and lower legs (see Chapter 7).

Idelalisib

Idelalisib (Zydelig) is a type of small molecule that blocks (inhibits) the signals from phosphoinositide 3-kinase (PI3Κ)-delta. The main job of PI3Κ-delta is to transmit signals that help B cells grow, move, divide, and survive. By inhibiting the signal from PI3Κ-delta, idelalisib helps stop or slow down the growth of CLL/SLL cells. Idelalisib has also been shown to kill CLL/SLL cells in laboratory studies.

Idelalisib comes in tablets that must be swallowed whole, twice a day, and they can be taken with or without food. Patients should not open, break, or chew the tablets. If a dose is missed by less than 6 hours, the missed dose should be taken right away and the next one should be taken at the usual time. If a dose is missed by more than 6 hours, the patient should wait and take the next dose at the usual time.

In July 2014, idelalisib was approved by the FDA to be used in combination with rituximab for the treatment of patients whose CLL has returned (relapsed) and to be used as monotherapy for the treatment of patients with SLL or relapsed follicular B-cell NHL (FL) who have relapsed after at least two prior therapies. The approval for CLL was based on results from a clinical study that showed improved survival and anticancer response when idelalisib was given together with rituximab compared with rituximab alone. The approvals for SLL and FL were based on results from clinical studies that showed improved anticancer responses with this drug.

Some of the most common side effects caused by idelalisib are diarrhea, fever, fatigue, nausea, cough, pneumonia, abdominal pain, chills, and rash (see idelalisib).

What Is Radiation Therapy?

_Radiation therapy_ (also called _radiotherapy_ ) uses high-energy X-rays or other types of radiation to kill cancer cells and shrink tumors. The term is used to describe _external beam radiotherapy_ , in which radiation is delivered using an external radiation beam.

A radiation oncologist will be in charge of the radiation therapy. The area of the body selected to receive the radiation therapy is called the _radiation field_. Doctors usually limit the radiation field to affected lymph nodes, the areas immediately surrounding lymph nodes, or other non-lymph node areas where the lymphoma started. Doctors will decide on the type and size of the radiation field depending on the type of tumor and the extent of disease.

To prepare for radiation therapy, the healthcare team will precisely mark the patient's body with tiny ink dots (called _tattoos_ ) to make sure that only the targeted areas receive radiation. During the day of treatment, they will use lead shields to protect a patient's normal tissues around the radiation field. They use plastic forms, pillows, and rolled blankets to make the patient comfortable and keep him or her in the proper position. Patients need to lie still on a table beneath a large machine that delivers the radiation painlessly. 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 1 to 6 weeks. During and after the radiation treatment, patients will have to carefully protect the radiation site from the sun.

Radiation therapy is only used to treat patients with CLL/SLL under certain circumstances.

What Is a Splenectomy?

A _splenectomy_ is the surgical removal of the spleen, a small organ found inside the rib cage, near the far upper-left side of the stomach. The spleen filters the blood to recycle old and abnormal red blood cells. It also stores platelets and white blood cells until they are needed. While the spleen works as part of the lymphatic system to fight off infections, it is possible to lead a normal life without it.

The spleen becomes enlarged in some patients with CLL/SLL and causes discomfort or pressure. A splenectomy is an option if radiation therapy and/or chemotherapy do not provide enough relief. Removing the spleen might also improve low blood counts. People without a spleen have an increased risk of developing serious bacterial infections and should promptly call their healthcare team at the first symptoms of infection. These symptoms might include pain, swelling, fever, and/or redness. To reduce the risk of infection, doctors may recommend that patients who have had a splenectomy receive vaccines, particularly to help prevent pneumonia. They may also advise patients to promptly take antibiotics when they develop a fever.

What Is Stem Cell Transplantation?

There are different types of stem cell transplantation, depending on who donates the stem cells. In an _autologous stem cell transplant_ , the patient is his or her own donor. Autologous stem cell transplantation is not used in patients with CLL/SLL because their stem cells are often contaminated with the disease. Therefore, this type of stem cell transplantation is not discussed in this booklet.

In an _allogeneic stem cell transplant_ , the donor is another person who is genetically similar to the patient; this is typically a brother or sister, but the donor can also be an unrelated person. Allogeneic stem cell transplantation may be an option for some relatively physically fit patients with advanced or refractory CLL/SLL who have a suitable donor.

Patients undergoing a standard stem cell transplant receive high doses of chemotherapy, often in combination with radiation therapy, that destroy their bone marrow cells. This method is used in an attempt to eliminate all of the cancer cells. Because high-dose therapy and allogeneic stem cell transplantation place great strain on a patient's body, they are not options for everyone. In deciding if transplantation is a good option, doctors will consider the patient's health status, age, medical history, cancer stage, prognostic factors, and responses to previous therapy.

ALLOGENEIC STEM CELL TRANSPLANTATION

Stem cell transplant using stem cells from a donor who is genetically similar to the patient.

Reduced-intensity transplantation (also called non-myeloablative or mini-allogeneic stem cell transplantation) uses lower doses of chemotherapy and/or radiation prior to allogeneic transplantation. This approach takes advantage of the graft-versus-host disease (GVHD) effect, in which the transplanted cells (the "graft") recognize the cancerous cells in the patient's body as foreign and destroy them. Patients receiving reduced-intensity transplants may avoid some of the side effects seen with higher-dose chemotherapy.

Questions to Ask Before Deciding to Undergo Allogeneic Stem Cell Transplantation

  * Why do you think this is a good idea?

  * What are the risks associated with this procedure?

  * Why do you recommend this particular type of transplantation?

  * How will I find a donor?

  * How long will I need to be in the hospital?

  * Will my insurance cover this procedure?

  * What type of special care will I receive?

  * How sick will this treatment make me?

  * What will you do to lessen the side effects?

  * How will we know if the treatment is working?

  * How and for how long will the treatment affect my normal activities (for example, work, school, childcare, driving, sexual activity, exercise)?

  * What is my chance of making a full recovery?

For more information on transplantation, please visit the National Marrow Donor Program's website at www.bethematch.org.

What Terms Do Doctors Use to Describe the Outcome of Treatment?

Table 6.3. Terms Used to Describe the Outcomes of Treatment

What Is Relapsed or Refractory CLL/SLL?

_Relapsed CLL/SLL_ means that the disease has returned after responding to treatment—this is sometimes also called a _recurrence_. _Refractory CLL/SLL_ means that the patient's disease does not respond to a specific treatment or that the response to the treatment does not last very long. There are many treatment options for patients with relapsed or refractory CLL/SLL. Exactly what type of treatment is optimal for individual patients with relapsed or refractory CLL/SLL depends on factors such as age, extent and location of disease, overall health, type of previous therapies received, and length of response to previous therapies.

Some centers will consider using allogeneic stem cell transplantation for some patients with relapsed or refractory CLL/SLL, depending on a patient's age, overall health, and other characteristics.

Patients who do not go into CR following treatment or who do not respond to treatment should not lose hope. Lasting responses to therapy may be achieved after a diagnosis of relapsed or refractory disease. Many patients seek second opinions at any point from diagnosis onward and often choose to do so if their disease relapses or is considered refractory. Clinical trials are a good option for patients at all stages of disease.

Many of the novel therapeutic agents most recently approved by the FDA and those being investigated in clinical trials are used specifically for patients with relapsed or refractory disease. Lymphoma research continually evolves as doctors and scientists discover new therapies and more effective ways of giving existing treatments. Chapter 10 describes some of the options currently under investigation.

When Should a Clinical Trial Be Considered?

Clinical trials are appropriate for patients at all stages of disease (see "Overview of Clinical Trials"). The purpose of a clinical trial is to safely monitor the effects of a drug on patients over time and to identify more effective therapies for specific diseases. By participating in a clinical trial, patients may or may not get access to the newest therapies but will, at a minimum, receive quality care and the standard treatment in a very carefully controlled and supportive environment.

Participation in a clinical trial is especially important for patients with CLL/SLL because it is not a common disease, which makes it very hard to find enough patients to enroll in studies. If patients are interested in participating in a clinical study, they should ask their doctor if there is an appropriate trial for them and what the potential risks and benefits may be. For more information about clinical trials, please refer to the Lymphoma Research Foundation's Clinical Trial Information Service available at www.lymphoma.org/clinicaltrials _for patients.

What Are Transformations of CLL/SLL?

Transformations, very serious and rare complications of CLL/SLL, occur when the disease undergoes additional changes to become more aggressive (faster-growing) forms of NHL, such as:

  * Richter syndrome — A diffuse large cell lymphoma; this is the most common CLL/SLL transformation and is seen in about 5% of patients with CLL/SLL

  * Prolymphocytic leukemia

  * Other rarer transformations could occur such as Hodgkin lymphoma, acute lymphocytic leukemia, and acute myeloid leukemia

Patients with these CLL/SLL transformations are treated in the same way as patients with these types of cancers. However, their prognosis tends to be worse. The change to a more aggressive disease will also determine the patient's treatment goals and therapies.

What Are Alternative and Complementary Remedies?

Alternative therapy refers to treatments that are used instead of standard therapy recognized as effective by the medical profession.

Currently, there are no proven alternative therapies to conventional cancer care for patients with CLL/SLL and other types of NHL. Patients should not use alternative remedies to replace the standard care suggested by their doctors.

Complementary therapy is used in addition to standard medicine to help improve a patient's quality of life and to relieve the effects of drug therapy, radiation, and surgery. Patients and caregivers should talk to their doctor and healthcare team before starting any form of complementary therapy because some of these practices can make their cancer treatment less effective.

Table 6.4. Forms of Complementary Therapy (Also Known as Integrative Medicine)

Drug Costs: What to Do if Insurance Will Not Pay

Many patients today face the problem of how to pay for rising healthcare costs. Cancer organizations such as the Lymphoma Research Foundation (www.lymphoma.org) offer limited financial assistance to patients who qualify. Most pharmaceutical companies have patient assistance programs in place that help provide drugs to qualifying patients.

Patients in need of financial assistance should talk with their doctor and social worker about available options and how to enroll in an appropriate program. Before undergoing a medical procedure, check with the insurance carrier to ensure that it is covered. If there is a dispute about coverage or if coverage is denied, ask the insurance carrier about their appeals process. If a claim is repeatedly denied, the patient should contact their state's insurance agency.

### _Part 3 - Living With the Side Effects of Treatment_
### Chapter 7: Common Treatment Side Effects

Patients with CLL/SLL may experience various side effects or toxicities caused by their cancer treatment. All treatments, including chemotherapy and biologic or targeted therapies, can cause side effects. Fortunately, medications and lifestyle changes can effectively prevent or lessen the severities of most side effects. Ask the healthcare team about possible treatment side effects and how to prevent and manage them, and tell the doctor or nurse about any side effects the patient experiences. This chapter explains the causes of these side effects, the types of side effects caused by different treatments, and steps to take to minimize these side effects.

Why Does Chemotherapy Cause Side Effects or Toxicities?

Chemotherapy drugs cause side effects because of the non-specific way these drugs attack cancer cells. Most chemotherapy drugs are designed to kill cells that divide rapidly like cancer cells (meaning that they are multiplying quickly). Most normal cells in the body do not divide as quickly as cancer cells. However, healthy cells in hair roots and cells in the mouth, gastrointestinal tract, and bone marrow do divide rapidly and can be damaged or killed by chemotherapy. Some chemotherapy drugs can also damage cells in the heart or other organs and tissues.

The type and severity of side effects caused by chemotherapy vary widely depending on the types of drugs that are given and an individual patient's response. The same drug may cause no side effects in one patient, while in others it may cause anything from very mild to very serious side effects.

What Is the Difference Between Long-Term Effects and Late Effects?

_Long-term effects_ are toxicities that occur during cancer treatment and continue for months or several years. Fatigue, menopausal symptoms, and cardiovascular problems are examples of long-term effects.

_Late effects_ of treatment become apparent after treatment has ended and may arise many months, years, or even decades after treatment is completed. Infertility, osteoporosis, and secondary cancers (such as melanoma) are examples of late effects. Compared to people without the disease, people with CLL/SLL have a higher risk of developing secondary cancers such as skin cancers (melanoma and non- melanoma), leukemia, lung cancer, lymphoma, and breast cancer.

What Side Effects Are Caused by Chemotherapy?

Side effects vary depending on the type of chemotherapy; additionally, these adverse effects can be caused by things other than chemotherapy.

Some of the most common side effects caused by chemotherapy used to treat patients with CLL/SLL include:

  * Changes in taste

  * Decreased blood cell production leading to anemia, or an increased risk of infection or bleeding

  * Increased chance of infections

  * Fatigue

  * Hair loss

  * Loss of appetite

  * Mouth sores

  * Nausea and vomiting

  * Diarrhea

  * Problems with sexual function

  * Cognitive problems (trouble concentrating, impaired memory)

  * Peripheral neuropathy (tingling or numbness in the hands and feet)

Changes in Taste

Some patients will experience a change in the way foods or beverages taste. Familiar foods may taste differently ( _dysgeusia_ ), or the flavors of foods may not be as strong (hypogeusia). Some patients may also feel that foods have a metallic taste. These side effects are temporary and usually disappear after the end of chemotherapy.

Decreased Blood Cell Production

The bone marrow constantly produces red blood cells, white blood cells, and platelets. Patients with CLL may have decreased blood cell production due to their disease. However, some types of chemotherapy and immunotherapy also temporarily interfere with the ability of the bone marrow to produce enough of one or more of these different types of blood cells. This is called _myelosuppression_.

To prevent and control myelosuppression, samples of a patient's blood are tested for complete blood count, which measures the number of white blood cells, red blood cells, and platelets, and the differential, which measures the numbers of the different types of white blood cells. These tests are usually done before and sometimes during each chemotherapy cycle.

Table 7.1. The Four Main Conditions Caused by Decreased Blood Cell Production

Infections

Some kinds of treatments can lower a patient's ability to fight infections. Patients are sometimes at increased risk for viral infections, particularly shingles (herpes zoster), and sometimes the doctor will prescribe medication to prevent a shingles outbreak during therapy.

Many of these side effects are temporary, but some could last for an extended period.

If a patient has a fever of 100.5°F or greater, they should call their doctor or go to the emergency room. The patient should ask their doctor what to do if they have a sore throat, rash, diarrhea, cough, or redness, swelling, or pain around a wound. The doctor should be contacted if the patient experiences any painful local rash with or without blisters.

To reduce the risk of infections, patients may be prescribed antibiotic medications to prevent them from getting infections. Other ways to reduce the risk of infections are included below.

Reducing Your Risk of Serious Infection During Chemotherapy

  * Check with your doctor to make sure your vaccinations are up to date prior to beginning treatment.

  * Wash your hands diligently and regularly.

  * Avoid crowds.

  * Cook all food; avoid raw foods that may carry germs as your body is more sensitive to them.

  * Avoid fresh flowers and gardening.

  * Avoid swimming.

  * Do not sleep with pets.

Fatigue

Fatigue is a common side effect of many types of therapy. Fatigue should decrease after patients complete their lymphoma treatment, but it could take weeks or months until they return to their normal energy levels.

Coping With Fatigue

  * Keep a diary to help you keep track of when you have the most energy and which activities make you feel tired or give you energy. Use this information to plan your activities for the times when you have the most energy.

  * Ask for help.

  * Exercise if your doctor says it is okay to do so, but do not overdo it. Try simple stretching and range-of-motion exercises or a short walk; these activities may energize you without tiring you out.Start slowly and build up to the level that is right for you. Ask your doctor, nurse, or physical therapist to help you create a personalized exercise plan.

  * Rest and sleep during therapy are very important, but do not rest more than you need because it may decrease your energy levels. An afternoon nap helps many patients feel less tired for the rest of the day. Other patients cannot sleep at night if they nap during the day. If you have trouble sleeping, talk to your healthcare team to find out why and what you can do about it.

  * Be patient. These symptoms usually improve once treatment is completed.

Hair Loss

Certain chemotherapy drugs can cause thinning or loss of hair ( _alopecia_ ) anywhere in the body including the scalp, eyebrows, eyelashes, arms, legs, and pelvis. The amount of hair loss may vary.

If hair loss occurs, it often starts 2 or 3 weeks after the first chemotherapy treatment. Remember that hair loss caused by chemotherapy is usually temporary. Hair will probably grow back after the end of chemotherapy treatments. When the hair first grows back, it may have a slightly different texture or color than it had before treatment. Over time, the texture and color usually return to normal.

Managing Chemotherapy-Induced Hair Loss

  * After washing your hair, pat it dry instead of rubbing it with a towel.

  * Brush your hair with a soft-bristle brush or a wide-tooth comb.

  * Do not use curlers or hair dryers.

  * Do not color or perm your hair, or treat it with other chemicals.

  * Many patients choose to use a wig, scarf, turban, soft cotton hat, or head wrap. Some health insurance companies cover the cost of wigs if you have a doctor's prescription. Check your policy to see if it covers this cost.

  * Use a hat or scarf to protect your scalp when you are out in the sun and to help you keep warm when you are indoors.

Mouth Sores

Some chemotherapy drugs can cause a patient's mouth to become red, sore, or irritated—this is called _mucositis_. Some patients undergoing chemotherapy become more susceptible to viral or fungal infections of the mouth and throat.

The doctor should be informed if the patient develops a sore throat. The doctor will examine the patient's throat and may take a swab to send to the laboratory to check for infection. Several medications are available to treat different types of infections. To help decrease chances of infection, patients should have a complete dental checkup and cleaning before starting chemotherapy.

Preventing and Caring for Mouth Sores

  * Clean your mouth and teeth. Use a soft-bristle toothbrush, nonabrasive toothpaste, and lip moisturizer.

  * Do not use mouthwashes that contain alcohol. Your doctor or nurse may recommend mouth rinse.

  * Do not eat citrus fruits (such as oranges, grapefruit, lemons, or clementines) or drink citrus juices.

  * Do not eat spicy foods **.**

  * Eat soft foods while you are receiving chemotherapy to avoid bruising your gums or other soft tissues in your mouth.

  * Do not floss your teeth if your blood counts are low.

Nausea or Vomiting

Some chemotherapy drugs can cause nausea or vomiting, usually on the day chemotherapy is administered but sometimes 1 or 2 days later. The doctor may prescribe a drug that prevents vomiting (antiemetic) before chemotherapy. Examples of antiemetics include: aprepitant (Emend), ondansetron (Zofran), granisetron (Kytril), metoclopramide (Reglan), prochlorperazine (Compazine), dolasetron (Anzemet), and a variety of corticosteroids, such as prednisone (Deltasone) or dexamethasone (Decadron). In most cases, these antiemetics are able to partially or completely prevent nausea and vomiting.

Controlling or Minimizing Nausea and Vomiting

  * Before chemotherapy, drink a liquid diet such as broth, consommé, or water. Do not drink milk or have a meal whose main ingredients are dairy products.

  * Do not eat foods that are too hot or too cold, greasy or fatty, or sweet or spicy.

  * Eat smaller and more frequent meals instead of fewer large meals each day.

  * Avoid strong or offensive smells. Get plenty of fresh air.

  * Take prescribed antiemetics before chemotherapy to prevent nausea.

  * If you vomit, make sure to avoid becoming dehydrated.

  * Finding the best approach is often a process of trial and error. Try different approaches to determine what works best for you.

Diarrhea

Some types of therapy may cause diarrhea. While most patients do not experience severe diarrhea, the most important thing to remember is to avoid dehydration, which is a loss of body fluids. The doctor should be contacted if the patient has bloody diarrhea or fever with diarrhea.

Avoiding Dehydration From Diarrhea or Vomiting

  * Drink plenty of liquids (8 glasses a day) such as water or electrolyte replacement drinks like Gatorade and Powerade. Sometimes it helps to drink small amounts very frequently rather than too much at once. Soup, especially broth, is a rich source of nutrients.

  * Look for the following signs of dehydration: dry mouth or skin, decreased urine, or feeling dizzy or lightheaded when you stand up.

  * Do not drink or eat milk products because they can worsen diarrhea.

  * Do not eat high-fiber and other hard-to-digest foods because they can worsen diarrhea.

  * Eat plenty of bananas and other high-potassium food (check with your doctor or dietitian to make sure that these foods will not interfere with your chemotherapy or other medications that you are taking).

  * Take the medicines that your doctor recommends to control diarrhea or vomiting (call your doctor if symptoms persist).

Problems With Sexual Function

Psychological factors, such as fear about illness, altered body image due to hair loss and depression, and the physical side effects of treatment can cause a drop in sex drive ( _libido_ ). Usually, a normal libido returns after treatment is finished. Patients should not be embarrassed to talk with their doctor about any problems or concerns they have about changes in their libido or sexual function. The doctor might order tests to track hormone levels, recommend seeing a specialist, or prescribe medications to restore erectile function in men or hormone therapy to alleviate vaginal dryness and other menopausal symptoms in women.

Sterility

Since chemotherapy may damage sperm and egg cells, it can sometimes cause temporary or permanent sterility in both men and women. The potential for developing sterility depends on the treatment type and specific dose, the number of therapies given, and the patient's age at the time of treatment. Options to preserve fertility include possible protection of the ovaries or cryopreservation of sperm cells and egg cells, or in vitro-fertilized embryos. Speak with the doctor about fertility preservation before beginning chemotherapy. For more information and resources about sterility, visit the Lymphoma Research Foundation's web page on Fertility available at www.lymphoma.org/fertility.

Patients receiving chemotherapy should always use birth control since these drugs may harm the fetus or cause birth defects.

Cognitive Problems

Chemotherapy can result in mild cognitive impairment such as trouble concentrating, impaired memory, or issues with motor control. While such symptoms can be stressful, they typically disappear over time.

Peripheral Neuropathy

Some chemotherapy drugs may damage the nervous system by affecting signaling between the central nervous system (the brain and spinal cord) and the rest of the body through all the nerves that make up the peripheral _nervous system_. This damage causes _peripheral neuropathy_ symptoms such as numbness, a tingling or prickling sensation in the fingers and toes, sensitivity to touch, and muscle weakness.

Cardiotoxicity

Cardiotoxicity refers to damage to cells in the heart or heart muscle. Long-term use of certain chemotherapy drugs can cause heart damage in some patients. Doxorubicin is an example of a drug that is possibly cardiotoxic.

In general, patients with CLL/SLL are rarely treated with potentially cardiotoxic chemotherapy and receive these drugs at dose levels and numbers of cycles such that cardiac toxicity is usually not a problem.

Careful monitoring by the healthcare team can reduce the chances of developing cardiotoxicity. Before deciding to treat patients with a cardiotoxic drug, most doctors will prescribe either an echocardiogram or a multi-gated acquisition (MUGA) scan to measure their cardiac function. This will ensure that patients are prescribed a safe chemotherapy dose given their current heart function and that they are monitored more intensively if needed.

Other Possible Side Effects

Chemotherapy can also cause other side effects such as cough, skin rashes, general weakness, sore throat, and loss of balance or coordination.

What Side Effects Are Caused by Radiation Therapy?

Radiation therapy itself is painless, but it can cause short-term and long-term side effects. The side effects caused by radiation therapy vary depending on the type of radiation, the radiation dose used, and the part of the body treated. Side effects are usually worse when radiation therapy and chemotherapy are given at the same time, which is not normally done for patients with CLL/SLL. Side effects from radiation include dry mouth, fatigue (tiredness), loss of appetite and taste, nausea, and skin reactions.

What Side Effects Are Caused by Steroids?

Dexamethasone, prednisone, and other steroid drugs can cause side effects such as _insomnia_ (the inability to fall asleep), increased appetite, mood or personality changes, anxiety, high blood pressure, fluid retention, and weight gain.

Prednisone can also trigger diabetes in patients prone to that disease or worsen diabetes in patients who already have the disease. High doses of steroids can also cause osteoporosis in at-risk patients. Patients should alert family and friends that personality changes may occur during their treatment. Patients should avoid making hasty decisions. If personality changes do occur, the doctor should be informed, as the dose may need to be reduced.

What Side Effects Are Caused by Monoclonal Antibody Therapies?

The monoclonal antibodies used to treat patients with CLL/SLL cause similar side effects, such as low blood cell counts and infusion reactions, which are usually mild but could become life threatening. Other rare, but potentially very serious, side effects include infections and tumor lysis syndrome (TLS). These side effects are explained in the following sections.

Infusion Reactions

When they occur, infusion reactions typically occur during or within 24 hours after the infusion and are most likely to happen after the first infusion. Symptoms of infusion reactions include dizziness, fainting, headache, feeling warm or flushed, fever or chills, hives, itching, shortness of breath, changes in heart rate and blood pressure, pain in the back or abdomen, and swelling of the face, tongue, or throat.

To prevent infusion reactions, patients are given antihistamines and acetaminophen, and sometimes corticosteroids, before the antibody infusion. Nurses closely monitor patients during the infusions. Patients should report any new symptom that they experience during or after an infusion as soon as it occurs.

Infections

Reactivation of hepatitis B virus (HBV) infection is a rare but very serious side effect of obinutuzumab (Gazyva), ofatumumab (Arzerra), and rituximab (Rituxan) therapy. People may not know that they have HBV because a healthy immune system can force the virus to hide without causing noticeable symptoms. Treatment with the CD20- directed monoclonal antibodies can wake up the virus. If unchecked, this restart of HBV infection can cause acute liver failure and possibly death. To prevent this, patients are screened for HBV before monoclonal antibody treatment. People who have the virus are closely monitored during and after treatment. Patients should be mindful of signs of an active HBV infection, such as increasing fatigue and yellowing of the skin or eyes.

Serious, sometimes deadly, infections have been reported in patients treated with alemtuzumab (Campath). Because of this, patients are treated with anti-infection medications against bacterial pneumonia and herpes virus before the start of treatment with alemtuzumab.

Tumor Lysis Syndrome

TLS occurs when an anticancer drug triggers the quick death of a large number of tumor cells, making them break apart and spill their contents into the blood. The spilled cellular material floating in the blood can damage kidneys and other organs. If not properly treated, TLS may lead to kidney failure and damage to the heart and nervous system.

To prevent TLS, patients may receive extra fluids and medications such as allopurinol (Zyloprim). If TLS develops, it can be treated with medications such as rasburicase (Elitek).

What Side Effects Are Caused by Ibrutinib?

The most common side effects caused by ibrutinib are decreased platelets and neutrophils, anemia, diarrhea, upper respiratory tract infections/inflammation, feeling unusually tired or weak, muscle and bone pain, swelling of the hands, feet, ankles, and lower legs, nausea, bruising, difficulty breathing, constipation, rash, stomach pain, vomiting, sinus infection, and decreased appetite. Rarer but serious side effects include bleeding problems, infections, kidney problems, and secondary cancers (such as skin cancer).

Patients on ibrutinib should notify their doctor if they are considering any surgical procedure or if they have undergone any emergency procedure because ibrutinib treatment will have to be stopped for a short period of time before and after these procedures because of an increased risk of bleeding.

What Side Effects Are Caused by Idelalisib?

The most common side effects caused by idelalisib are diarrhea, fever, fatigue, nausea, cough, pneumonia, abdominal pain, chills, and rash. Rarer but serious side effects include severe skin reactions, life-threatening allergic reaction (anaphylaxis), and low neutrophil count (neutropenia). Idelalisib can also cause very serious and potentially life-threatening side effects such as liver problems, severe diarrhea, lung or breathing problems, and tears in the intestinal wall (perforation). However, this medication is well tolerated by most patients.

Before and during idelalisib treatment, the doctor will order blood tests to check for liver problems. Patients should notify their doctor if they experience:

  * Any symptoms of liver problems (yellow skin, dark or brown urine, pain in the upper-right side of the stomach, bleeding or bruising more easily than normal)

  * An increase in the number of bowel movements to six or more per day

  * A new or worsening cough, shortness of breath, difficulty breathing, or wheezing

  * A new or worsening pain in the stomach area, chills, fever, nausea, or vomiting

What Side Effects Are Caused by Allogeneic Stem Cell Transplantation?

Patients treated with chemotherapy and/or radiation before undergoing an allogeneic stem cell transplant are at increased risk for developing infection, bleeding, and other side effects as described previously (see "What Side Effects Are Caused by Chemotherapy?" and "What Side Effects Are Caused by Radiation Therapy?" )

These patients are also at risk of developing graft-versus-host disease (GVHD), a condition where the donated bone marrow attacks the patient's tissues. GVHD can happen at any time after the transplant. Drugs can be used to reduce the risk of developing GVHD or to treat the problem once it develops.

More information about stem cell transplantation and its effects can be found at www.bethematch.org.

When Should a Patient's Doctor Be Contacted?

As a general rule, a patient's doctor should be contacted if:

  * The patient experiences a side effect that is unexpected or lasts longer than expected.

  * The patient experiences a medical problem—such as high fever, shortness of breath, prolonged or constant nausea and vomiting, chest pains, and/or dizziness—that cannot wait for a regularly scheduled appointment.

If the patient's doctor or nurse cannot be reached, go to the hospital emergency room for a medical assessment and place another call to the doctor so that they know the location of the hospital where treatment is being provided.

### Chapter 8: Managing Life During and After Treatment

This chapter discusses some general issues that patients may encounter while they live their life during and after treatment.

Coping Strategies

Each person's experience with cancer is different, and how he or she copes with the physical and emotional impact of having CLL/SLL is unique to a patient's personality and situation. Here are some suggestions for how to cope with some issues that patients may face.

Table 8.1. Coping Strategies

The Importance of Pain Control

In some situations, patients may experience pain from the cancer itself or from their treatments and procedures. Cancer pain is very treatable, and there is no reason for a patient to endure this pain without help. Patients should tell their doctors and nurses if they have any pain because they can offer advice regarding medications and other ways to relieve the pain, as some medications may not be appropriate for their disease.

Different types of pain are best controlled by different types of pain relievers. Patients should ask their healthcare team what options are best to help manage their pain.

Managing Pain

  * Tell your doctor or nurse about your pain. Be specific when you describe it.

    * Where do you feel the pain?

    * When did the pain start?

    * What type of pain is it (sharp, dull, throbbing)?

    * Does it come and go, or is it steady?

    * How strong is it? How long does it last?

    * Does anything make the pain feel better or worse?

    * Which drugs have you taken for the pain? Do they help? If so, for how long?

  * Take your pain medication on a regular schedule even if the pain seems to be better. Do not skip doses.

  * Tell your family and friends about your pain so they can help you and understand why you may be acting differently.

  * Try deep breathing, yoga, or other ways to relax.

  * Ask to meet with a pain specialist or palliative care specialist to help you find better ways to control your pain.

  * Tell your doctor or nurse of any changes in your pain.

Maintain a Healthy Lifestyle

Regular physical activity helps keep the cardiovascular system strong and body muscles flexible. Exercise can also help alleviate breathing problems, constipation, and mild depression. It also helps reduce stress and fatigue. Patients should talk to their doctor before starting an exercise program and consider visiting a physical therapist for advice.

Several types of exercise are particularly helpful:

  * General physical activity, such as swimming, dancing, household chores, and yard work

  * Aerobic activity to improve cardiovascular fitness, such as walking, jogging, and bicycling

  * Resistance training to strengthen muscles, protect joints, and help remedy osteoporosis by building bone mass

  * Flexibility exercises such as stretching and yoga to improve range of motion, balance, and stability

Eating a healthy diet is especially important during treatment for CLL/ SLL because it will help patients keep up strength and energy, tolerate treatment-related side effects, decrease risk of infection, and heal and recover more quickly. Patients should aim for a diet high in fruits and vegetables, protein (poultry, fish, and eggs), and whole grains. During chemotherapy and after a stem cell transplant, the patient may be asked to temporarily avoid raw fruits and vegetables that may increase the risk of infection if they have a low white blood cell count ("neutropenic diet"). The healthcare team can help develop an eating plan that is appropriate. Patients should talk to their doctor before taking any dietary supplements such as multivitamins or individual vitamin supplements, as well as any herbal or "natural" supplements, because they may interfere with treatments or have unexpected side effects.

The Importance of Follow-up Care

At the first visit following the completion of treatment, patients should discuss their follow-up schedule with the doctor. This will be different from patient to patient depending on their disease stage, age, and general health. Patients should adhere to their schedule of follow-up visits—these are very important for monitoring disease recurrence and detecting and treating any health problems that might have been caused by the treatment.

During these follow-up visits, the doctor will ask about any medical changes since the last appointment and give a physical examination. The doctor may also prescribe blood, molecular diagnostic, imaging, or other laboratory tests.

Be Proactive in Healthcare Decisions

To stay proactive in healthcare decisions, patients should write out their questions and bring them to their appointments, take notes during their visit, and obtain the following information from their medical team:

  * Copies of all medical records and a written summary of treatment(s) in case the patient switches oncologists or needs to see a primary care physician for routine medical care

  * A list of signs of disease recurrence and late side effects from treatment

At the follow-up care appointments, patients should inform their doctor of:

  * Any new symptoms

  * Pain

  * Physical problems that disrupt their daily life such as fatigue, insomnia, sexual dysfunction, and weight gain or loss

  * Any new health problems such as heart disease, diabetes, and high blood pressure

  * Any new medications and vitamins they are taking

  * Emotional problems such as anxiety and depression

  * Any other questions or concerns

### _Part 4 - Clinical Trials and Advances in Treatment_

### Chapter 9: Overview of Clinical Trials

There are hundreds of CLL/SLL clinical trials now underway in hospitals, cancer centers, and doctors' offices around the country. The government, pharmaceutical and biotechnology companies, universities, and doctor groups often sponsor clinical trials.

What Is a Clinical Trial?

A _clinical trial_ is a carefully designed research study that involves people who volunteer to participate. Clinical trials are also sometimes referred to as clinical studies. However, the term "clinical study" is broadly used to describe many different sorts of studies in addition to those described in this chapter.

The purpose of clinical trials in cancer is to answer questions about new ways to treat, diagnose, prevent, or manage a disease or the side effects caused by treatments. Strict rules and oversight procedures make sure that clinical trials are designed and run in a way that protects the right and safety of the people who volunteer to participate.

In the United States, a new drug must pass through a strict approval process governed by the Food and Drug Administration (FDA) before it can become a standard therapy for use in people. The FDA- regulated approval process for drugs includes preclinical studies (done in laboratories) and clinical trials (done in hospitals and clinics).

As shown in the following table, there are four main types (or phases) of clinical trials. The first three are usually required before a drug is considered for approval by the FDA. Phase IV studies are performed after a drug has received FDA approval; these trials are sometimes called post-marketing studies. Patients may be eligible to take part in different types of clinical trials depending on their health status, stage of CLL/SLL, and type of treatment, if any, they previously received.

Table 9.1. The Four Main Types (or Phases) of Clinical Trials

Why Is a Placebo Sometimes Used in Phase III Trials?

**In cancer clinical trials, patients are never given a placebo in place of an effective standard therapy**. They would be given a placebo only if there were no standard therapies. Placebo-controlled trials are NEVER DONE in a manner that would deny patients an effective therapy.

A _placebo_ , or sugar pill, is an inactive ingredient that is used as a comparator in some clinical trials. The placebo will be made to look and taste the same as the experimental pill. The patients and the doctors and nurses treating them may not know what type of treatment is being given.

Should a Patient Participate in a Clinical Trial?

Clinical trials are not a "last resort" for patients. Patients with all stages of CLL/SLL can participate in clinical trials, whether at the time of initial diagnosis or at relapse. Clinical trials offer patients exciting new therapies that are not otherwise available to all patients. Another advantage of clinical trials is that the health of enrolled patients is monitored very carefully. In many cases, patients can benefi more from participation in clinical trials than from receiving standard therapies.

Some professional organizations, like the National Comprehensive Cancer Network (which develops guidelines for doctors to use in treating patients with all types of cancers), actively encourage the participation of patients with cancer in clinical trials because they provide the best management for any cancer patient.

What Is Informed Consent?

_Informed consent_ is a process through which people learn all about the clinical trials they are interested in joining. During this process, members of the clinical trial research team will explain:

  * The purpose of the study

  * The factors used to decide if a patient is allowed to participate in the study

  * The tests, procedures, and visits participants will be expected to agree to

  * The type of treatment provided in the study

  * The possible risks and benefits

  * The rights of patients to decide whether or not to participate and to leave the study at any time

The research team will answer questions and provide written information about the trial. If patients agree to participate in a clinical trial, they will be asked to read and sign an informed consent form that details all the trial information discussed and describes how their records will be kept private.

Remember that even after signing the consent form, patients can leave the study at any time.

Questions to Ask About a Clinical Trial

  * What is the purpose of this clinical trial?

  * Why are you recommending this clinical trial for me?

  * Who is sponsoring this trial (the National Cancer Institute, a cancer center, a pharmaceutical/biotechnology company)?

  * Who has reviewed and approved this clinical trial?

  * Does this clinical trial include the use of a placebo (sugar pill)?

  * How long will the study last? Where will it take place?

  * What are the risks involved?

  * What are the possible benefits?

  * If I benefit from the intervention, will I be allowed to continue receiving it after the trial ends?

  * What are my responsibilities during the clinical trial?

  * What kinds of tests, procedures, or treatments will be performed? How many and how often?

  * Will I be in any discomfort or pain?

  * Will I be able to see my own doctor during the clinical trial?

  * What type of long-term follow-up care is part of this trial?

  * What costs will I be responsible for?

  * What happens if my health gets worse during the clinical trial?

What Is the Cost of Participating 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 patient's health insurance coverage.

The March 2010 Affordable Care Act (ACA) states that all healthcare plans (offered through an employer or purchased through an ACA exchange) that were newly issued or renewed on or after January 1, 2014 are not allowed to limit or deny coverage for people who decide to participate in an approved clinical trial. However, this patient protection provision does not apply to healthcare plans that existed before January 1, 2014. Some of these "grandfathered" plans do pay for the basic medical procedures associated with the trial, such as laboratory tests, scans, and hospitalization when required, while others may define clinical trials as "experimental" or "investigational" and not cover some of the routine costs, such as doctor visits, tests, or treatments. Medicare provides coverage for patient care associated with most 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.

Patients should ask their doctor what clinical trials may be most appropriate for them. Here are some additional sources of clinical trial information:

  * The _Lymphoma Helpline_ at the Lymphoma Research Foundation at (800) 500-9976

  * Cancer centers in the area

  * The Coalition of Cancer Cooperative Groups website at www.cancertrialshelp.org

  * The NIH websites at www.cancer.gov and www.clinicaltrials.gov

### Chapter 10: Advances in Treatment of Patients With CLL/SLL

Doctors and scientists around the world are working very hard to improve currently available treatment options and find better and safer drugs to treat patients with CLL/SLL. Advances are being made in different areas including genetics, molecular biology, immunology, treatments, and supportive care. In particular, recent developments have provided a better understanding of the biology of the disease.

Drugs that are not yet approved for sale by the Food and Drug Administration (FDA) are said to be investigational. Some of these investigational drugs are being studied in laboratory experiments using tissue culture cells and laboratory animals. This is often referred to as the preclinical phase. The drugs in more advanced stages of research are being studied in patients in clinical trials and are then referred to as being in the clinical phase of development.

The most common way for a patient to receive an investigational drug is through a clinical trial. To find out more about getting access to investigational drugs, visit the NCI website at www.cancer.gov and search for "access to investigational drugs." Alternatively, visit the website at www.clinicaltrials.gov to search for trials using a particular drug or to find clinical trials nearby.

Remember that today's science is moving very fast. Please check with your doctor or the Lymphoma Research Foundation for additional information and recent updates.

For detailed discussion of currently approved treatment options, please see "Treatments for CLL/SLL."

Chemotherapy

Researchers are trying to develop new chemotherapy drugs, make improved versions of existing drugs, and find better ways to combine different doses and sequences of existing drugs. The goal is to make drugs that are better at killing CLL/SLL cells while leaving healthy cells alone (decreasing the chance of side effects).

Monoclonal Antibodies

Monoclonal antibodies are drugs that mimic our own immune proteins that are designed to recognize and stick to specific target molecules on cancer cells. When a monoclonal antibody attaches itself to a cancer cell it can stop or slow down its growth, or it can make it easier for the immune system to recognize and kill it. The success of the monoclonal antibody rituximab (Rituxan) inspired researchers to develop other monoclonal antibodies to treat patients with various types of non-Hodgkin lymphoma (NHL), including CLL/ SLL. This research led to the FDA approvals of the monoclonal antibodies alemtuzumab (Campath), obinutuzumab (Gazyva), and ofatumumab (Arzerra) for the treatment of patients with CLL/SLL. New combinations of some of these monoclonal antibodies and other drugs are being investigated in clinical trials.

Targeted Therapies

In addition to monoclonal antibodies that target molecules on cell surfaces, many drugs are in development that target molecules inside cancer cells. A better understanding of the biology and genetics of CLL/SLL is helping researchers identify specific molecules in lymphoma cells that may be good targets for new drugs. These molecules usually have important roles in controlling the growth and survival of lymphoma cells. The drugs that target these molecules are broadly called targeted or biologic therapies. These drugs may kill the lymphoma cells or slow down or stop their growth. Targeted therapies attack cancer cells in a more specific way than chemotherapy drugs and are less likely to kill or damage healthy cells. This makes it less likely that these agents will cause serious side effects.

Many targeted therapies for CLL/SLL are being studied in laboratories and in clinical trials. The first targeted therapy approved by the FDA for CLL/SLL was ibrutinib (Imbruvica), a tyrosine kinase inhibitor, which stops signals from BTK, a molecule inside B cells that is important for sending signals that are critical for the CLL/SLL cells to survive. Duvelisib (IPI-145) is a phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma inhibitor in clinical trials for the treatment of patients with CLL/SLL and other types of lymphoma. PI3K-delta and PI3K-gamma have non- overlapping roles in key functions in the cell. Idelalisib was the first drug in this class to receive approval from the FDA.

Another drug currently in clinical trials for CLL/SLL is ABT-199, an inhibitor of Bcl2 (a molecule that helps cancer cells survive and become resistant to treatments).

Stem Cell Transplantation

Ongoing research in stem cell transplantation is focused on finding better ways to collect stem cells from the bone marrow or peripheral blood; eliminating graft-versus-host disease in allogeneic (donor) transplantations; and developing more effective non-myeloablative (reduced-intensity) stem cell transplantations.

Genetically Engineered T Cells

Researchers have treated a small number of patients with CLL with genetically engineered immune cells, or T cells. T cells are removed from patients and genetically modified to produce special receptors on their surface called chimeric antigen receptors (CARs), which allow them to recognize and kill CLL cells. The genetically engineered T cells that produce CARs are grown in the laboratory until they number in the billions and then are infused back into the patient. The CARs on the surface of T cells allow them to recognize a specific protein (antigen) on the tumor cells called CD19, so that the patient's own immune system can selectively kill them. CD19 is an ideal tumor target for CAR therapy because it is expressed on almost all CLL cells.

Once infused into the body, the genetically modified cells can grow to large numbers and amplify the anti-tumor response, persisting for long periods of time and providing ongoing tumor control and possible protection against recurrence. Some patients have had very good responses, with no malignant tumor cells detected after treatment.

However, this therapy can also result in significant side effects such as tumor lysis syndrome or "cytokine release syndrome" after treatment. Although this treatment approach looks very promising, much more research needs to be done to investigate the long-term effects of this kind of therapy.

### ABOUT THE LYMPHOMA RESEARCH FOUNDATION

The Lymphoma Research Foundation (LRF) is the nation's largest lymphoma-focused nonprofit organization devoted exclusively to funding lymphoma research and providing patients and healthcare professionals with the most current information on the disease. The Foundation's mission is to eradicate lymphoma and serve those touched by this disease.

The Foundation remains dedicated to finding a cure for lymphoma through an aggressively funded research program and by supporting the development of improved therapies for people living with lymphoma. LRF provides a comprehensive series of programs and services for people with lymphoma, their loved ones, and caregivers.

### How the Lymphoma Research Foundation Serves the Lymphoma Community

Research

LRF remains dedicated to finding a cure for lymphoma through an aggressively funded research program. LRF supports innovative research through Clinical Investigator Career Development Awards, Fellowships, and several disease-specific research initiatives. These focused initiatives include a Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Initiative.

The Foundation's volunteer Scientific Advisory Board, comprised of more than 45 world-renowned lymphoma experts, guides the Foundation's research activities, seeking out the most innovative and promising lymphoma research projects for support.

Professional Education

LRF is committed to educating healthcare professionals on the latest developments in lymphoma diagnosis and treatment. The Foundation offers a wide range of lymphoma-focused continuing education activities for nurses, physicians, and social workers, including workshops, conference symposia, and webcasts.

Programs and Services

LRF provides a comprehensive series of programs and services for the lymphoma community, including:

  * Clinical Trials Information Service

  * Community Volunteer Network

  * Disease-Specific Publications and Websites

  * Financial Assistance Grants

  * Focus on Lymphoma Mobile App

  * In-Person Workshops and Educational Forums

  * Lymphoma Helpline

  * Lymphoma Support Network

  * Public Policy and Advocacy

  * Teleconferences

  * Webcasts/Podcasts

Contact Information

LRF National Headquarters

115 Broadway, Suite 1301

New York, NY 10006

Phone: (212) 349-2910

Fax: (212) 349-2886

Email: LRF@lymphoma.org

Website: www.lymphoma.org

LRF Helpline

Phone: (800) 500-9976

Email: helpline@lymphoma.org

