Leukemia 2011 June

Chronic Lymphocytic Leukemia
June, CLL Survivor
Revised 2011
A Message From Louis J. DeGennaro, Ph.D.
Interim President and CEO of The Leukemia & Lymphoma Society
The Leukemia & Lymphoma Society (LLS) is committed to bringing
you the most up-to-date blood cancer information. We know how
important it is for you to have an accurate understanding of your
diagnosis, treatment and support options. With this knowledge, you
can work with members of your oncology team to move forward
with the hope of remission and recovery. Our vision is that one day
the great majority of people who have been diagnosed with Chronic
Lymphocytic Leukemia (CLL) will be cured or will be able to manage
their disease with a good quality of life. We hope that the information
in this booklet will help you along your journey.
LLS is the world’s largest voluntary health organization dedicated to
funding blood cancer research, education and patient services. Since
the first funding in 1954, LLS has invested more than $814 million
in research specifically targeting blood cancers. We will continue to
invest in research for cures and in programs and services that improve
the quality of life of people who have CLL and their families.
We wish you well.
Louis J. DeGennaro, Ph.D.
Interim President and CEO
Table of Contents
2
Introduction
2
Here to Help
5
Leukemia
6
Chronic Lymphocytic Leukemia
8
Signs and Symptoms
8
Diagnosis
10
Treatment Planning
13
Treatment
18
Complications: CLL or CLL Treatment
20 Clinical Trials
22 Treatment Response and Follow-Up Care
24 Related Diseases
26 Normal Blood and Marrow
28 The Lymphatic System
29 Medical Terms
41
More Information
Acknowledgement
The Leukemia & Lymphoma Society gratefully acknowledges for his critical
review and important contributions to the material presented in this publication:
John C. Byrd M.D.
D. Warren Brown Chair of Leukemia Research
Professor of Medicine, Medicinal Chemistry, and Veterinary Biosciences
Director, Division of Hematology, Department of Internal Medicine
The Ohio State University
Columbus, OH
Chronic Lymphocytic Leukemia
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Introduction
This booklet provides information about chronic lymphocytic leukemia (CLL) for
patients and their families. Brief descriptions of normal blood, bone marrow and
the lymphatic system are provided to help readers better understand the CLLspecific information in the booklet.
An estimated 105,119 people are living with CLL and 14,5701 people are expected
to be diagnosed with CLL in the United States in 2011. Doctors have learned a
great deal in the last few decades about CLL. In the last several years, new therapies
have been developed, and outcomes for people living with CLL are steadily
improving. Researchers around the world continue to strive to find a cure for CLL.
Howlader N, Noone AM, et al, eds. SEER Cancer Statistics Review, 1975-2008, National Cancer Institute.
Bethesda, MD, www.seer.cancer.gov/csr/1975_2008/, based on November 2010 SEER data submission, posted
to the SEER website, 2011.
1
This publication is designed to provide accurate and authoritative information about the subject matter
covered. It is distributed as a public service by LLS, with the understanding that LLS is not engaged in
rendering medical or other professional services.
Here to Help
The information in this booklet will help you talk to your doctor about the tests
and treatment you need. We encourage you to take the lead in asking questions
and discussing your fears and concerns. These actions will give members of your
healthcare team the opportunity to answer your questions, extend emotional
support and provide any needed referrals.
A diagnosis of CLL is often a shock to the patient, family members and friends.
Denial, depression, hopelessness and fear are some of the reactions people may
have. Keep in mind that
{{Many
people are better able to cope once their treatment plan is established and
they can look forward to recovery.
{{The
outlook for people with CLL is continuing to improve. New approaches
to therapy are being studied in clinical trials for patients of all ages and at every
stage of treatment.
LLS Has Ways to Help. Treatment for CLL will affect your daily life, at least for a
time. During and after treatment, you may want to have friends, family members or
caregivers help you get information.
Making treatment choices, paying for medical care, communicating with healthcare
providers, family members and friends—these are some of the stressors that go
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along with a cancer diagnosis. LLS offers free information and patient services for
individuals and families touched by blood cancers.
Speak to an Information Specialist. Information Specialists are master’s level
oncology professionals. They provide accurate up-to-date disease and treatment
information and are available to speak with callers Monday through Friday, 9 a.m.
to 6 p.m. ET at (800) 955-4572. You can email [email protected] or chat live
with a Specialist at www.LLS.org.
Language Services. Free language services are available when you speak with an
Information Specialist. Let your doctor know if you want a professional healthcare
interpreter who speaks your native language or uses sign language to be present
during your visit. Many times, this is a free service.
Información en Español. LLS has a number of resources available in Spanish for
patients, caregivers and healthcare professionals. You can read and download these
resources online at www.LLS.org/espanol or order printed copies by mail or phone.
Other Helpful Organizations. Our website, www.LLS.org/resourcedirectory,
offers an extensive list of resources for patients and families about financial
assistance, counseling, transportation, summer camps and other needs.
Chapter Programs and Services. LLS chapter offices around the United States
and Canada offer support and education. Your chapter can arrange for peer-topeer support through the Patti Robinson Kaufmann First Connection Program. The
Patient Financial Aid program offers a limited amount of financial aid for qualified
patients. Find your local chapter by calling (800) 955-4572 or by visiting
www.LLS.org/chapterfind.
Co-Pay Assistance Program.This program offers assistance for financially eligible
patients with certain blood cancer diagnoses to help pay for private or public
health insurance premiums and/or co-pay costs for prescription medications.
Check www.LLS.org/copay or call (877) 557-2672 to speak to a Co-Pay Assistance
Program specialist for more eligibility information.
Clinical Trials. Our Information Specialists help patients work with their doctors
to find out about specific clinical trials. Information Specialists conduct clinical-trial
searches for patients, family members and healthcare professionals. You can also
use TrialCheck®, an online clinical-trial search service supported by LLS that offers
patients and caregivers immediate access to listings of blood cancer clinical trials.
Please visit www.LLS.org/clinicaltrials.
Free Materials. LLS publishes many free education and support materials for
patients and healthcare professionals. PDF files can be read online or downloaded.
Free print versions can be ordered. Visit www.LLS.org/resourcecenter.
Chronic Lymphocytic Leukemia
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Telephone/Web Education Programs. LLS provides a number of free,
live telephone and web education programs presented by experts for patients,
caregivers and healthcare professionals. For more information, please visit
www.LLS.org/programs.
Suggestions From Other People Living With Cancer
{{Get
information about choosing a cancer specialist or treatment center.
{{Find out about financial matters: What does your insurance cover?
What financial assistance is available to you?
{{Learn about the most current tests and treatments for your type of CLL.
{{Keep all appointments with the doctor and talk openly about your fears or
concerns or any side effects you experience.
{{Talk with family and friends about how you feel and how they can help.
{{Contact your doctor if you have fatigue, fever, pain or sleep problems so
that any issues can be addressed early on.
{{Get medical advice if you have experienced changes in mood, feelings
of sadness or depression.
Reach Out. You and your loved ones can reach out for support in several ways.
For example:
{{LLS
offers online Blood Cancer Discussion Boards as well as online chats at
www.LLS.org/getinfo.
{{Local or Internet support groups and blogs can provide forums for support.
{{Patients with cancer often become acquainted with one another, and these
friendships provide support.
Depression. Treatment for depression has proven benefits for people living
with cancer. Depression is an illness that should be treated even when a person is
undergoing CLL treatment. Seek medical advice if your mood does not improve
over time—for example, if you feel depressed every day for a 2-week period.
Contact LLS or ask your healthcare team for guidance and referrals to other
sources of help, such as counseling services or community programs. For more
information you can contact the National Institute of Mental Health (NIMH)
at www.nimh.nih.gov and enter “depression” in the search box at the top of the
webpage, or call the NIMH toll-free at (866) 615-6464.
Information for Veterans. Veterans with CLL who were exposed to Agent Orange
while serving in Vietnam may be able to get help from the United States Department
of Veterans Affairs. For more information call the Department of Veterans Affairs at
(800) 749-8387 or visit www.publichealth.va.gov/exposures/agentorange.
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We’d Like to Hear From You. We hope this booklet helps you. Please tell us
what you think at www.LLS.org/publicationfeedback. Click on “LLS Disease &
Treatment Publications—Survey for Patients, Family and Friends.”
Leukemia
Leukemia is a cancer of the marrow and blood. The four major types of leukemia
are chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL),
chronic myeloid leukemia (CML), and acute myeloid leukemia (AML).
Leukemia is called “lymphocytic” (or “lymphoblastic”) if the cancerous change
takes place in a type of marrow cell that forms lymphocytes. Leukemia is called
“myelogenous” (or “myeloid”) if the cell change takes place in a type of marrow cell
that would normally go on to form red cells, some kinds of white cells and platelets.
Chronic leukemia is a slow-growing blood cancer that permits the growth of greater
numbers of more developed cells. In general, these more mature cells can carry out
some of their normal functions. Acute leukemia is a more quickly growing disease
that affects unformed cells or cells that are not yet fully developed. These immature
cells cannot carry out their normal functions.
The four main types of leukemia are further classified into subtypes that are based
on specific features of cells. Knowing the subtype of the patient’s disease may help
the doctor to assess how quickly the disease may progress. The subtype is important
because the treatment approach may vary according to the disease subtype.
Lymphocytic Leukemia and Lymphoma. The World Health Organization
(WHO) includes “lymphocytic leukemias” and “lymphoma” within one
classification. Each of these cancers is the result of a change to a cell that was destined
to be a lymphocyte. However, lymphocytic leukemia and lymphoma originate in
different parts of the body. Lymphocytic leukemia develops in the lymphatic tissue
within the marrow. Lymphoma begins in a lymph node, or another lymphatic
structure in the skin, the gastrointestinal tract, or some other site in the body.
Chronic lymphocytic leukemia (CLL) and small cell lymphocytic lymphoma
(SLL) are often considered to be one disease because they are similar with regard
to incidence, signs and symptoms, genetic features, disease progression and
treatment. The leukemic lymphocytes and tissue abnormalities that are observed
in people with SLL are identical to those observed in patients with CLL. However,
in people with SLL, there is more lymph node and lymphoid tissue involvement
and less marrow and blood involvement; in people with CLL, the marrow and
blood are more strikingly affected. Talk to your doctor if you have questions about
your specific diagnosis and treatment.
More information about leukemia and lymphoma can be found in the free LLS
publications Understanding Leukemia, The Lymphoma Guide—Information for
Patients and Caregivers and Non-Hodgkin Lymphoma.
Chronic Lymphocytic Leukemia
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Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) results from an acquired (not present at
birth) change (mutation) to the DNA of a single marrow cell that develops into
a lymphocyte.
In 95 percent of people with CLL, the change occurs in a B lymphocyte. In the
other 5 percent of people with CLL, the cell that transforms from normal to
leukemic has the features of a T lymphocyte or a natural killer (NK) cell. Thus, any
of the three major types of lymphocytes (T cells, B cells or NK cells) can undergo a
malignant transformation that causes diseases related to B-cell CLL
(see Related Diseases on page 24).
Scientists do not yet understand what causes this change. Once the marrow cell
undergoes the leukemic change, it multiplies into many cells. CLL cells grow and
survive better than normal cells; over time, they crowd out normal cells.
The result is the uncontrolled growth of CLL cells in the marrow, leading to an
increase in the number of CLL cells in the blood. The leukemic cells that accumulate
in the marrow in people with CLL do not impede normal blood cell production as
extensively as is the case with acute lymphoblastic leukemia. This is an important
distinction: It is the reason for the generally less severe early course of CLL.
CLL takes different forms. Some people have disease that is slow growing. People
with minimal changes in their blood cell counts (an increase in the number of blood
lymphocytes and little or no decrease in the number of red cells, normal neutrophil
and platelet counts) may have stable disease for years. Other people with CLL have
a faster-growing form of the disease—the CLL cells accumulate in the bone marrow
and blood, and there is a significant decrease in the numbers of red cells and platelets.
People with faster-growing CLL may have
{{Enlarged
lymph nodes that can lead to compression of neighboring organs.
For example, enlarged lymph nodes in the abdomen can interfere with the
functions of the gastrointestinal tract and/or the urinary tract.
{{A
severe immunoglobulin deficiency, sometimes coupled with a low neutrophil
count, which can lead to recurrent infections.
{{An
enlarged spleen which can press on the stomach causing early fullness (satiety)
while eating food and also discomfort in the left upper part of the abdomen.
Causes and Risk Factors. CLL has generally not been associated with any
environmental or external factors. However, the Institute of Medicine of the
National Academy of Sciences issued a report “Veterans and Agent Orange: Update
2002,” which concluded that there was “sufficient evidence of an association”
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between herbicides used in Vietnam and CLL. For Veterans with Agent Orange
exposure, this may provide additional VA benefits.
First-degree relatives of patients with CLL are three to four times more likely to
develop CLL than people who do not have first-degree relatives with the disease.
However, the risk is still small. For example, the 60-year-old sibling or child of
someone with CLL would have three to four chances in 10,000 of developing the
disease, compared with the one chance in 10,000 for a 60-year-old person without
a family history of the disease.
For information on studies about two or more relatives with a hematologic
malignancy, please visit www.LLS.org/diseaseregistries.
Incidence. CLL is more common in people who are 60 years and older (see
Figure 1). The incidence of the disease increases from less than one per 100,000 in
individuals aged 40 to 44 years to more than 30 per 100,000 in individuals aged 80
and older.
Chronic Lymphocytic Leukemia: Age-Specific Incidence Rates (2004-2008)
36
35.6
33
31.3
30
27.5
27
Incidence (per 100,000)
24
21.3
21
18
16.3
15
12
10.9
9
6.3
6
3.3
3
0
n/a
n/a
n/a
n/a
n/a
n/a
n/a
<1
1-4
5-9
10-14
15-19
20-24
25-29
0.1
0.2
0.6
30-34
35-39
40-44
1.8
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
≥85
Age (Years)
Figure 1. I The horizontal axis shows 5-year age intervals. The vertical axis shows the frequency of new cases
of CLL per 100,000 people in a given age-group. Source: SEER Cancer Statistics Review, 1975-2008, National
Cancer Institute. Bethesda, MD, www.seer.cancer.gov/csr/1975_2008/, based on November 2010 SEER data
submission, posted to the SEER website, 2011.
Chronic Lymphocytic Leukemia
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Signs and Symptoms
CLL symptoms usually develop over time. Early in the course of the disease, CLL
often has little effect on a person’s well-being. Some people with CLL do not have
any symptoms. The disease may be suspected because of abnormal results from
blood tests that were ordered either as part of an annual physical or a medical
examination for an unrelated condition. An elevated white cell (lymphocyte) count
is the most common finding that leads a doctor to consider a CLL diagnosis.
People with CLL who do have symptoms may tire more easily, and/or feel short
of breath during day-to-day physical activities—as a result of anemia (low red
cell count). They may lose weight because of decreased appetite and/or increased
use of energy. The lymph nodes and spleen may become enlarged as a result of
an accumulation of CLL cells (leukemic lymphocytes). Infections of the skin,
lungs, kidneys or other sites may occur as result of low immunoglobulin levels and
decreased neutrophil counts.
Diagnosis
Blood Cell Count and Examination. The diagnosis of CLL is usually evident
from the results of blood cell counts and an examination of blood cells. A person
with CLL will have increased numbers of lymphocytes. Low platelet counts and
low red cell counts may also be present; these counts are usually only slightly
decreased in the early stage of the illness.
Bone Marrow Examination. A bone marrow aspiration and biopsy generally are
not needed to make a diagnosis of CLL. However, these tests are recommended
before treatment begins—the test results provide baseline data that can confirm
other diseases are not present and also be used later on to evaluate the effects
of therapy. Repeat marrow biopsies are helpful in distinguishing disease versus
treatment-related causes of low blood cell counts that do not improve within an
expected period of time after treatment.
In people with CLL, a bone marrow examination will show an increase in the
number of lymphocytes in the marrow and often a decrease in the number of
normal marrow cells. The bone marrow biopsy results will also show one of four
patterns characteristic of CLL: nodular, interstitial, mixed or diffuse.
Immunophenotyping. “Immunophenotyping” (or flow cytometry) of
lymphocytes is an important process used to diagnose CLL, and other types of
leukemia and lymphoma, by comparing the cancer cells to normal immune cells.
The test results indicate whether or not the person’s lymphocytes are derived
from a single cancer cell (leukemia) or from other conditions in adults that can,
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infrequently, cause an increase in the number of blood lymphocytes from a
noncancerous origin. This test is especially important if the number of lymphocytes
in the blood is only slightly elevated. Immunophenotyping also determines whether
the CLL cells are from a change in either B-cell or T-cell development (see Figure 2).
Most people with CLL have the B-cell type.
Immunophenotyping is done with an instrument called a “flow cytometer.”
A sample of cells from blood or marrow can be tagged with an antibody that is
specific for a site on the cell surface. The cells go through the flow cytometer,
passing through a laser beam; if they have the antibody-specific surface feature,
the cells light up and they are counted.
Lymphocyte Development
Stem Cells
Other Blood Cells
Lymphocyte Progenitor
Early
Specialized
Lymphocytes
Fully Developed
Specialized
Lymphocytes
B Cells
T Cells
NK Cells
Figure 2. I Mutation of DNA can occur when the early specialized lymphocytes are formed or after the
lymphocyte progenitor has differentiated into one of the three specific types of lymphocytes. The leukemic
cells may be principally B cells, T cells or natural killer (NK) cells. Most patients have a B-cell type of CLL.
Immunoglobulin Levels. The measurement of the concentration of
immunoglobulins (gamma globulins) in the blood is another important test.
Immunoglobulins are proteins called “antibodies” that are made by B cells in
healthy individuals to protect the body from infection. CLL cells do not make
effective antibodies. CLL cells also interfere with the ability of the remaining
normal lymphocytes to make antibodies. As a result, people with CLL often have
low levels of immunoglobulins, which increases their risk of getting infections.
Chronic Lymphocytic Leukemia
I page 9
Treatment Planning
Treatment for CLL is always changing due to new treatments and research from
clinical trials. Therefore, before treatment begins, it is important to consider getting
a second opinion at a center with a CLL-specific expert. Additionally, there are
continuously updated diagnosis and treatment guidelines published by the National
Comprehensive Cancer Network (NCCN) at www.nccn.org, which provide
guidance to doctors.
Staging. Staging for CLL helps doctors to both assess how the disease is expected
to progress over time and also to develop a treatment plan (see Table 1. below).
Staging systems for CLL take into account
{{The
elevation of blood and marrow leukemic lymphocyte counts
{{The
size and distribution of lymph nodes
{{The
spleen size
{{The
degree of anemia and the extent of decreased blood platelet counts.
Table 1. Commonly Used CLL Staging Systems
Rai Staging System
Stage and Signs at Diagnosis
I
Low Risk—0
Abnormal increase in the number of
lymphocytes in the circulating blood and
marrow
I
Intermediate Risk—I & II
Abnormal increase in the number of
lymphocytes in the circulating blood and
marrow and enlarged lymph nodes
or
Abnormal increase in the number of
lymphocytes in the circulating blood and
marrow and enlarged spleen and/or liver
Binet Staging System
Stage and Signs at Diagnosis
A
Abnormal increase in the number
of lymphocytes in the circulating
blood and less than 3 areas of
palpable enlarged lymphoid tissue
I
B
Abnormal increase in the number
of lymphocytes in the circulating
blood and greater than 3 areas of
palpable enlarged lymphoid tissue
High Risk—III & IV
I C
Abnormal increase in the number of
Same as B with anemia
lymphocytes in the circulating blood and
(hemoglobin <11 g/dL in men or
marrow and anemia (hemoglobin <11 g/dL)
hemoglobin <10 g/dL in women)
or
or low platelet count (platelets
Abnormal increase in the number of
<100,000/μL)
lymphocytes in the circulating blood and
marrow and low platelet count (platelets
<100,000/μL)
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Chromosomal Changes. Certain chromosomal changes can help the doctor
to identify those people with CLL who may benefit from closer medical followup or certain types of therapy. About half of the people with CLL have CLL cells
with chromosomal abnormalities when tested with a method called “G-banding
karyotyping.” About 80 percent of the people with CLL have chromosomal
abnormalities when tested with a method called “fluorescence in situ hybridization
(FISH).” The following examples are some of the more common chromosomal
abnormalities:
Del 13q eletions on the long arm of chromosome 13 (del
D
13q) are the most common. Del 13q with no other
chromosomal abnormalities is associated with a relatively
more favorable outcome.
Trisomy 12 bout 10 to 20 percent of patients have CLL cells with
A
three copies of chromosome 12 (trisomy 12) instead of
the expected two chromosomes. Trisomy 12 is associated
with intermediate-risk CLL. Trisomy 12 with other
chromosomal abnormalities is associated with a higher risk
than trisomy 12 alone.
Del 11q p to 20 percent of people with CLL have deletions in
U
CLL cells in the long arm of chromosome 11 (del 11q).
The proportion of CLL patients with del 11q tend to
be younger with large lymph nodes and have high-risk
disease.
Chromosome 14 or
Structural abnormalities of chromosome 14 or
Chromosome 6
chromosome 6 in CLL cells also indicate higher-risk
disease.
Del 17p About 5 percent of people with CLL at diagnosis have
deletions in the short arm of chromosome 17 (del 17p).
The critical gene in this region that is typically deleted is
TP53. People who have CLL with del 17p tend to have
higher-risk disease and usually do not respond as well to
standard initial therapy. Their CLL treatment needs to be
approached in a different manner.
Chronic Lymphocytic Leukemia
I page 11
Other factors may be signs of faster-growing disease (higher-risk CLL) and indicate
the need for closer follow-up with the doctor. For example:
Blood lymphocyte People with CLL whose lymphocyte number doubles in
doubling
one year have higher-risk CLL and need closer followup; a lymphocyte number that remains stable indicates a
relatively lower risk.
CD38
CD is an abbreviation for “cluster designation,” a term
used with a number to identify a specific molecule on the
surface of an immune cell. The expression of CD38 on
CLL cells may be an indicator of higher-risk CLL.
B2M A higher level of serum beta2-microglobulin, (B2M) a
protein that is shed from CLL cells, is associated with a
greater extent of disease. Several studies have found that
B2M and other serum markers, such as CD23, may help
predict survival or progression-free survival. Tests for these
markers need to be standardized, and further study in
clinical trials is needed to evaluate their relative value in
managing the treatments of people with CLL.
Unmutated IgHv The unmutated immunoglobulin heavy chain variable
region gene (IgHv) suggests the likelihood of higher-risk
disease. Forty percent of CLL patients at diagnosis will
have this whereas 60 percent will have the more favorable
IgHv mutated disease.
ZAP-70 ZAP-70 (zeta-associated protein 70), when increased, may
be associated with higher-risk disease. It should be noted
that further study in clinical trials is needed to standardize
the assessment of ZAP-70. The National Comprehensive
Cancer Network (NCCN) guidelines state that the
evaluation of ZAP-70 expression by flow cytometry can
be challenging and is not recommended outside of a
clinical trial.
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Treatment
Current therapies do not offer patients a cure for CLL, but there are treatments that
help manage the disease. Treatments for CLL include
{{Watch
and wait
{{Single
or combination drug therapy
{{White
cell (neutrophil) growth factors
{{Radiation
therapy (rarely used)
{{Splenectomy
{{Treatment
{{
Drug
(rarely used)
in a clinical trial (see page 20).
therapy with new drugs or new drug combinations
{{
High-dose
chemotherapy and allogeneic stem cell transplantation.
The goals of CLL treatments are to
{{Slow
the growth of the CLL cells
{{Provide
long periods of remission (when there are no signs of CLL and/or
people feel well enough to go about their day-to-day activities)
{{Improve
{{Help
survival
people to feel better if they have infections, fatigue or other symptoms.
Some people with CLL can be managed with a watch and wait approach for years
before the disease progresses. The decision to treat a person with CLL is based on a
number of factors (see Table 2).
Table 2. S
ome Factors That Influence the Decision
to Treat Patients Who Have CLL*
Enlarging lymph nodes
Enlarging spleen
Worsening anemia
Absolute lymphocyte count (>300)**
Falling platelet count
CLL symptoms (such as fatigue, night sweats, weight loss, fever, etc.)
* Several of these factors are often present at the same time.
** Rapidly rising lymphocyte count in asymptomatic patients may not be an independent factor to begin treatment.
Chronic Lymphocytic Leukemia
I page 13
A person with CLL is usually treated by a hematologist or an oncologist. People are
advised to consult with a doctor who specializes in treating patients with leukemia
and to discuss their most appropriate treatment options—including whether or not
participation in a clinical trial is recommended.
Watch and Wait. People with CLL who have minimal changes in their blood
counts and no symptoms are usually managed with observation alone. This
approach includes medical examinations and periodic testing to determine whether
the disease is stable or beginning to progress. People with CLL being treated with a
watch and wait approach are counseled by their doctors to seek medical assistance
if they develop fevers or other signs of infection or illness. When, or if, the disease
begins to progress, active treatment is started.
People are often concerned when they receive a diagnosis of CLL and then learn
that they will not begin treatment right away. It is important to know that the
watch and wait approach is the current standard of care for people with CLL who
have minimal changes in their blood counts and no symptoms. Many studies have
compared the watch and wait approach to an early treatment approach for people
with low-risk CLL. To date, no benefits of early treatment for people with low-risk
CLL have been shown. Several studies have confirmed that the use of alkylating
agents in patients with early-stage disease does not prolong survival. There are also
risks of early treatment including potential side effects and treatment complications.
Patients may build up a resistance to the drugs used and would not be able to use
them again when treatment for progressive disease is necessary. Deferred treatment
versus early treatment for people with CLL who are symptom-free is an area of
ongoing study in clinical trials.
Many patients take alternative medicines during this time period. The active
ingredient of green tea (EGCG) has been studied preliminarily as a therapy to
prevent CLL progression and has shown very modest results but reasonable safety.
Other agents have not been studied extensively in this area. Patients should discuss
taking such alternative medications with their doctors. For more information
about alternative therapies, see the free LLS publication Integrative Medicine &
Complementary and Alternative Therapies as a Part of Blood Cancer Care.
Drug Therapies. Patients who have symptomatic, intermediate- and high-risk
disease are usually treated with chemotherapy and/or monoclonal antibody therapy.
The choice of recommended treatment generally depends on the patient’s overall
health status, genetic markers in the leukemia cells and the stage of his or her
disease. Age may be a factor for certain types of therapy. Given the importance of
genetics in picking the correct therapy for CLL, it is important that FISH studies
are done to look for del (17p) and del (11q) prior to starting treatment for CLL.
The following therapies may be used to treat people with newly diagnosed CLL,
relapsed CLL or refractory CLL (see Relapsed or Refractory CLL on page 17).
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Chemotherapy. Chlorambucil (Leukeran®) is a long-used form of chemotherapy
for CLL. It is a pill (oral) and remains one standard therapy for older patients (65
years or older). Fludarabine (Fludara®) is considered to be one of the most effective
types of chemotherapy for CLL in younger patients. Drug combinations, including
fludarabine and cyclophosphamide (Cytoxan®) were shown to improve response
and remission time of CLL patients. Fludarabine and cyclophosphamide (FC)
combination therapy is most important for treating the genetic group of CLL with
del (11q). Combination of fludarabine with rituximab (Rituxan®) (FR), a CD20
antibody, (see Monoclonal Antibody Therapy below) or FC with Rituxan (FCR) is
called “chemoimmunotherapy.” Studies comparing treatment with chemotherapy
(fludarabine or FC) with chemoimmunotherapy (FR or FCR) have shown that FR or
FCR treatment significantly improve the frequency of complete response, remission
duration, and overall survival in previously untreated people with CLL (see Treatment
Response and Follow-Up Care on page 22).
While it is clear that FCR is the best treatment for CLL patients with del (11q), the
benefit of this (versus FR) is not as clear in other genetic groups and is currently being
studied in clinical trials. The hesitancy of some doctors to use cyclophosphamide in
FCR, in part, comes from a higher risk that may arise of both short and long-term
complications, such as chronic heart failure. Trials using fludarabine in patients 65
years or older, have not shown as much benefit. Additionally, patients with del (17p)
do not respond as well or for as long to fludarabine-based therapies. Therefore, if del
(17p) is present on a FISH test, it is important for patients to be evaluated early for
consideration of reduced-intensity allogeneic stem cell transplantation or to strongly
consider participating in a clinical trial.
Bendamustine (Treanda®) is another type of chemotherapy that is approved for
the treatment of CLL. Combination therapy with Treanda and Rituxan in both
untreated and previously treated CLL patients have shown promising results and
are commonly being administered as second-line therapy. A randomized trial is
comparing Treanda and Rituxan to FCR in previously untreated CLL patients.
Patients with del (17p) generally do not respond well or for long to Treanda therapy
as initial therapy.
Monoclonal Antibody Therapy. Monoclonal antibodies are proteins that are
bioengineered in the laboratory. Each monoclonal antibody therapy is designed to
recognize a specific molecule on a cell. The monoclonal antibody therapy targets
the molecule and attaches to the cell, causing the cell to die.
The monoclonal antibody therapies rituximab (Rituxan®), ofatumumab (Arzerra®)and
alemtuzumab (Campath®) are used to treat people with CLL (see Table 3 on page 17).
Rituxan and Arzerra target CD20 on the CLL cell’s surface; Campath targets CD52.
Rituxan is FDA approved for combination with fludarabine and cyclophosphamide
in symptomatic, previously untreated and treated CLL. Arzerra is FDA approved for
the treatment of patients with CLL that is refractory to fludarabine and alemtuzumab.
Campath is FDA approved as a single agent for CLL treatment.
Chronic Lymphocytic Leukemia
I page 15
These therapies continue to be studied in clinical trials in combination with
chemotherapy and other biologic therapies such as lenalidomide (Revlimid®).
(see Clinical Trials on page 20).
Whereas most chemotherapy affects normal tissue cells as well as CLL cells,
monoclonal antibody therapy may affect some normal lymphocytes but spare most
other cells. This is particularly true for CD20 antibodies (Rituxan and Arzerra).
Even though the infusion of a monoclonal antibody into a patient’s vein may cause
a short period of fever, chills or low blood pressure, generally people experience less
troubling side effects with monoclonal antibody therapy than with chemotherapy.
The drugs most commonly used to treat CLL are shown in Table 3 on page 17.
White Cell (neutrophil) Growth Factors. Treatment for CLL may include
administering blood cell growth factors to improve low white cell counts.
Treatment with white blood cell growth factors may help people with CLL to
tolerate the side effects of higher doses of chemotherapy (see Complications: CLL or
CLL Treatment on page 18).
Radiation Therapy. Radiation is sometimes used to shrink large lymph node
masses or masses in locations that interfere with the function of a neighboring body
part, such as the kidney, the gastrointestinal tract or the throat. This treatment is
rarely used in CLL.
Splenectomy. CLL cells can accumulate in the spleen and become problematic in
some people with CLL. Surgical removal (splenectomy) of a very enlarged spleen
may improve blood cell counts. This approach is used selectively because it is only
beneficial if the patient’s spleen is affected by CLL.
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Table 3. Some Drugs Used to Treat Chronic Lymphocytic Leukemia
Chemotherapy
(Treanda®)
{{Chlorambucil (Leukeran®)
{{Cladribine (Leustatin®)
{{Cyclophosphamide (Cytoxan®)
{{Doxorubicin (Adriamycin®)
{{Fludarabine (Fludara®)
{{Prednisone
{{Bendamustine
Monoclonal Antibody Therapy
(Campath®)
{{Ofatumumab (Arzerra®)
{{Rituximab (Rituxan®)
{{GA101*
{{Xm5574*
{{TRU-016*
{{Alemtuzumab
Other Drugs
{{PCI-32765 (BTK kinase inhibitor)*
{{CAL-101 (PI3-kinase inhibitor)*
{{Flavopiridol (CDK kinase inhibitor)*
{{Dinaciclib (CDK kinase inhibitor)*
{{Lenalidomide (Revlimid®)*
[immunomodulator]
* Under study in clinical trials
Relapsed or Refractory CLL. “Relapsed CLL” is the term for disease that
responded to therapy but, after six or more months, stopped responding.
“Refractory disease” is the term for CLL that does not result in a remission (but
may be stable) or disease that gets worse within six months of the last treatment.
People who are treated for relapsed or refractory CLL often have good quality years
of remission after more treatment. Treatment guidelines for people with relapsed
CLL are generally the same as treatment for newly diagnosed people.
People who have refractory CLL with a short time to progression after the first
treatment and/or CLL cells with del 17p often do not respond to standard
chemotherapy. These people are advised to speak to their doctors about whether
or not treatment in a clinical trial is a good option for them. Investigative clinical
protocols for drug therapies or allogeneic stem cell transplantation may offer
appropriate treatment options (see Clinical Trials on page 20).
Chronic Lymphocytic Leukemia
I page 17
Complications: CLL or CLL Treatment
Infection. Infections are a common complication for people with CLL.
Because of this high risk of infections, immediate vaccination for pneumococcal
pneumonia with Prevnar 13® (repeated every 5 years) and a yearly flu vaccine is
recommended. CLL patients do not respond well to vaccines due to their immune
system depression. CLL patients should never receive live vaccines (such as the
shingles vaccine).
A higher risk of infection is caused by
{{The inability of the person’s CLL cells to make antibodies needed to fight infections
{{The effect of chemotherapy, which causes reduced cell counts for certain infection-
fighting white cells in the blood, specifically neutrophils and monocytes.
Antibiotic therapy is usually required to treat bacterial or fungal infections during the
course of the disease. People who get recurrent infections may also receive injections
of immunoglobulin (gamma globulin) on a regular basis to correct the immune
deficiency. While immunoglobulin is expensive, it does have benefit in decreasing
the frequency of infections in CLL patients with low levels of this in the blood.
CLL-related low blood counts are often efficiently corrected by CLL therapy.
However, the use of white cell growth factors may benefit patients who experience
prolonged low white cell counts after treatment. Examples of white cell growth
factors are
{{Granulocyte-colony
stimulating factor (G-CSF) (filgrastim [Neupogen®] or
pegfilgrastim [Neulasta®]) that can increase the number of neutrophils
{{Granulocyte-macrophage
colony-stimulating growth factor (GM-CSF)
(sargramostim [Leukine®]) that can increase the number of neutrophils and
monocytes.
Anemia. Anemia (low numbers of red cells) is a common side effect of
chemotherapy. Some people with CLL may need blood transfusions.
Richter Transformation. In about 3 to 5 percent of people with CLL, the disease
transforms into an aggressive lymphoma because of a change in the characteristics
of the CLL cells. This is much more common in IVgH-unmutated CLL. This
pattern is referred to as a “Richter transformation” or “large cell transformation.”
People with this type of CLL may have significantly enlarged lymph nodes, and
may have fevers and weight loss. Tumors of lymphocytes may also develop in
parts of the body other than the lymph nodes. Richter transformation is treated
with aggressive chemotherapy and reduced-intensity allogeneic transplantation if
feasible. Outcome for patients with Richter transformation is generally poor unless
it is diagnosed prior to receiving a lot of treatment for CLL.
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Prolymphocytes. About 15 percent of people with CLL have leukemia cells that
are a mix of lymphocytes and another type of white cell, called a “prolymphocyte”
(see Figure 3, Panel D). Most people with this type of CLL follow a similar
course to that of other people with CLL. However, for a relatively small subset of
patients with this type of CLL, the blood cells may become mainly composed of
prolymphocytes; the spleen may enlarge further, and the disease may become less
responsive to treatment. In these cases, individuals are encouraged to talk to their
doctors about the potential benefits of treatment in a clinical trial.
Lymphocytes
Panel A
Panel B
Panel C
Panel D
Figure 3. I Panel A shows a normal lymphocyte in the blood film of a healthy person. Panel B shows the
increased frequency of lymphocytes in the blood film of a patient with CLL. Panel C shows the appearance
of large granular lymphocytes in a patient with large granular lymphocytic leukemia (the arrows point to the
cluster of granules in the cells), and Panel D shows the cells of prolymphocytic leukemia, which are larger than
those in Panels A and B and have a light area in their nucleus, called a “nucleolus” (see arrow). This structure in
the nucleus is a sign of a more immature or primitive cell.
Autoimmune Hemolytic Anemia. Some people with CLL produce a type of
antibody that works against their own cells. These “autoantibodies” are usually
directed against the patient’s red cells and causes them to be removed rapidly
from the blood. This condition, called “autoimmune hemolytic anemia,” can
worsen the effects of already low red cell counts. The “antiglobulin test” or
“Coombs’ test” is used to identify the autoantibodies. Less often, the antibody
works against the platelets. This condition, called “immune thrombocytopenia,”
Chronic Lymphocytic Leukemia
I page 19
results in significantly decreased platelet counts. The drugs prednisone, Rituxan
and cyclosporine are sometimes used to treat autoimmune hemolytic anemia and
immune thrombocytopenia.
Second Cancers. People with CLL have a higher risk than the general population
of developing a second cancer. The second cancers that are seen most frequently
are melanoma, soft tissue sarcoma, colorectal cancer, lung cancer, squamous cell
skin cancer and basal cell carcinoma. The recurrence rate of basal cell carcinoma
after treatment is also higher for people with CLL compared to that of the general
population. Both treated and untreated people with CLL can develop acute
myeloid leukemia or myelodysplastic syndromes. This complication is more
common after treatment with fludarabine and cyclophosphamide (FC or FCR).
Further evaluation is needed to determine whether treatment with fludarabine
may increase the risk of second solid tumor cancers. It is important to follow up
with your oncologist on a regular basis. More information about long-term and
late effects can be found in the free LLS publication Long-Term and Late Effects of
Treatment in Adults.
Clinical Trials
New approaches to treatment in clinical trials, many of which are being supported
by LLS research programs, hold the promise of increasing the rate of remission and
finding a cure for CLL.
Clinical Trials. Every new drug or treatment regimen goes through a series of
studies called “clinical trials” before it becomes part of standard therapy. Clinical
trials are carefully designed and rigorously reviewed by expert clinicians and
researchers to ensure as much safety and scientific accuracy as possible. Participation
in a carefully conducted clinical trial may be the “best available” therapy. Patient
participation in clinical trials in the past has resulted in the therapies we have today.
LLS Information Specialists, at (800) 955-4572, can offer guidance on how
patients can work with their doctors to determine if a specific clinical trial is an
appropriate treatment option. Information Specialists will conduct individualized
clinical-trial searches for patients, family members and healthcare professionals.
This service is also available at www.LLS.org/clinicaltrials.
Research Approaches. There are clinical trials for newly diagnosed patients and
patients with relapsed or refractory disease. A number of approaches are under
study in clinical trials for the treatment of patients with CLL, as follows:
New Drug Treatments. Specific new drug therapies under study in clinical trials
for people with CLL include
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Kinase Inhibitor Therapy. Kinases are enzymes that are found in both normal
cells and cancer cells. Some cancer cells can be targeted by kinase inhibitor drugs
that destroy the cancer cells. Kinase inhibitor drugs may be associated with fewer
side effects than some other chemotherapy agents. There are many different
kinases in CLL cells, including a phosphatidylinositol 3-kinase (PI3-kinase) and
Bruton’s tyrosine kinase (BTK).
Examples of kinase inhibitor therapy include
{{PCI-32765.
PCI-32765 is an orally administered BTK inhibitor that is in
phase II clinical trials for CLL where significant durable remissions have
been observed with single agent activity and it has shown a very favorable
side-effect profile. Efforts to combine PCI-32765 with other agents such as
bendamustine (Treanda®) or ofatumumab (Arzerra®) are ongoing. Phase III
studies are being planned for this agent. This agent does cause temporary
lymphocytosis (high lymphocyte count) when given by itself but this has not
been shown to have any significant clinical consequence.
{{CAL-101.
CAL-101 is an orally administered PI3-kinase inhibitor that is in
phase II clinical trials for CLL where significant durable remissions have been
observed with single agent activity. Efforts to combine CAL-101 with other
agents such as Treanda, rituximab (Rituxan®), or Arzerra are ongoing. Phase
III studies are being planned for this agent. This agent also causes temporary
lymphocytosis (high lymphocyte count) when given by itself but this has not
been shown to have any significant clinical consequence.
{{Flavopiridol.
Flavopiridol is a CDK inhibitor being studied in people with
high-risk genetic features whose CLL has responded to few, if any, standard
treatments. It is being studied to treat CLL or prolymphocytic leukemia
arising from CLL that is refractory to fludarabine.
{{Dinaciclib.
Dinaciclib is a second-generation CDK inhibitor being studied
in patients with relapsed CLL who are not responsive to other therapies. It
has shown activity in this group including patients with high-risk genetic
features.
Monoclonal Antibody. Xm5574 is an antibody that targets CD19 on the
surface of CLL cells. It is being studied in phase I/II clinical trials in CLL.
Immunomodulatory Drug. Lenalidomide (Revlimid®) is an oral drug that
is used to treat patients with myeloma. It stimulates a person’s own immune
system to attack cancer cells. This drug is being evaluated in several CLL trials,
including a phase III study, to determine if Revlimid, given as a maintenance
therapy, is safe and effective in further improving the quality and duration of
the response to treatment. This study will compare the effects of Revlimid with
the effects of a placebo. Revlimid is also being studied as a possible treatment for
people with CLL following second-line therapy. Other studies include Revlimid
with Rituxan or Arzerra; Revlimid, fludarabine and Rituxan combined for
minimally treated and untreated CLL patients; and Revlimid, fludarabine and
cyclophosphamide combined for patients with advanced-relapsed or refractory
Chronic Lymphocytic Leukemia
I page 21
CLL. One problem that has emerged in patients with long-term (maintenance)
use of Revlimid in multiple myeloma has been the occurrence of secondary
cancers. The relevance of this finding to CLL is uncertain although the current
trials with Revlimid are being monitored very carefully for this complication.
Improvements in Stem Cell Transplantation. New procedures for allogeneic
stem cell transplantation are being studied in clinical trials. Research teams are now
trying novel ways to reduce the toxicity of transplantation and make it a possible
therapy for more people with CLL.
Allogeneic stem cell transplantation is an investigational treatment option for
people with high-risk CLL that has not responded to other standard therapies. It
may be an appropriate therapy for carefully selected younger people with CLL who
can be matched with a stem cell donor.
A modified form of allogeneic stem cell transplantation called a “reduced-intensity”
or “nonmyeloablative” allogeneic stem cell transplantation may be another
transplant option for CLL patients who do not respond to other treatments.
Patients being prepared for a reduced-intensity transplant receive lower dosages
of chemotherapy drugs and/or radiation in preparation for the transplant,
compared to the dosages given to patients receiving an allogeneic transplant.
Immunosuppressive drugs are used to prevent rejection of the donor stem cells, and
the engraftment of donor immune cells may allow these cells to attack the CLL
cells (called “graft-versus-tumor effect”). The theory being tested with a reducedintensity transplant is that by undergoing less-toxic procedures prior to the stem
cell transplant, the body is better able to withstand the infusion of donor cells.
However, full donor engraftment would still take place, and the desired graftversus-tumor effect would still occur. This type of transplant is generally done for
high-risk CLL patients with del (17p) early in the course of CLL and also relapsed
patients who have received multiple therapies. Even if transplant is not eventually
pursued, it is important for patients with del (17p) who require therapy and
patients with relapsed CLL to be referred to a transplantation expert relatively early.
We encourage you to contact our Information Specialists and visit www.LLS.org
for more information about specific treatments under study in clinical trials.
Treatment Response
and Follow-Up Care
Treatment Outcomes. Treatment outcomes for people with CLL vary widely,
and expected outcomes are influenced by the stage of the disease, the presence or
lack of various factors associated with higher-risk disease, the overall health of the
patient and other factors. Studies suggest that newer treatment combinations and
approaches may improve the length of survival. People with CLL should consult
with their doctors to discuss individual potential outcomes.
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The National Cancer Institute-sponsored Working Group has recommended
criteria to describe responses to CLL therapy. A summary of this information is
presented in Table 4; it may help people with CLL who want to discuss the results
of drug studies with their doctors and to make informed treatment decisions.
Table 4. Responses to CLL Therapy
Complete Response (CR)
{{No
evidence of clinical disease for at least two months after the completion
of treatment, including normal blood count (at least 1,500 neutrophils,
100,000 platelets, and <4,000 lymphocytes per microliter (μL) of blood)
{{Hemoglobin >11 g/dL without transfusions
{{No CLL symptoms or enlarged lymph nodes, enlarged spleen or bone
marrow involvement
Partial Response (PR)
{{At
least a 50 percent reduction in the number of blood lymphocytes and in
lymph node and spleen enlargement
{{One or more of the following must also be maintained for at least two
months: platelets greater than 100,000/μL; hemoglobin >11 g/dL; or a
50 percent improvement over pretreatment red cell or platelet counts
without transfusions
{{Same
Nodular Partial Response
as CR but with persistent lymphocytic nodules in the marrow
Progressive Disease
At least one of the following:
{{Increase of at least 50 percent in absolute lymphocyte count or
transformation to higher-risk disease. Lymphocytosis (high lymphocyte
count) can be temporarily seen with the kinase inhibitors PCI-32765 and
CAL-101 and do not indicate progression in absence of other signs
{{Increase of at least 50 percent in liver or spleen size or new appearance of
enlarged liver or spleen
{{Increase of at least 50 percent in the sum of the products of at least two
lymph nodes on two consecutive exams performed two weeks apart
{{New appearance of enlarged lymph nodes
Stable Disease
{{Absence
of CR or PR, without progressive disease
Chronic Lymphocytic Leukemia
I page 23
Follow-Up Care. People with CLL need regular medical follow-up after they have
completed treatment. It is important to assess the full effect of therapy as well as to
identify any return of progressive disease that may require additional therapy.
Minimal Residual Disease. Some people with CLL have such a low level of
remaining CLL cells after treatment that these cells cannot be detected by the
usual clinical tests, such as blood and marrow examinations. The term used for
this condition is “minimal residual disease” (MRD). More sensitive tests may be
performed to detect the presence of abnormal cells. The methods generally used to
detect MRD in people with CLL are four-color cell flow cytometry and polymerase
chain reaction (PCR). The benefit of flow cytometry is its widespread reproducible
use that now is standard as part of clinical trials. These techniques may provide
information that can help the doctor to recognize a disease relapse and to start
treatment again. However, treating asymptomatic patients with MRD remains a
research question and should not be pursued outside of clinical trials.
People who have been treated for CLL and/or other cancers are encouraged to keep
a record of the treatments they have received. It is a good idea to share these records
with the doctors who monitor general health problems, both during treatment and
after treatment ends. Regular screening and monitoring for skin, colorectal, breast
and other types of cancer is advisable.
Related Diseases
The diseases mentioned in this section result from the cancerous transformation of
a type of lymphocyte; the accumulation of these cancer cells occurs mainly in the
marrow, the blood and the spleen (see Table 5 on page 25).
There are distinguishing characteristics that enable the hematology oncologist
to identify each disease, including the appearance and the immunophenotype
of the cancer cells; the cells’ varying effects on normal marrow and blood cell
development; and the cells’ varying effects on other parts of the body, such as the
kidneys, bowels and nervous system.
The diseases represent a range of clinical severity. At one end of the range, there are
the diseases that may be stable and may not advance in severity for some months or
years, or occasionally indefinitely. At the other end of the range, there are diseases
associated with difficulties that may be present at diagnosis and possibly get worse,
requiring immediate treatment and frequent observation.
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Table 5. CLL and Related Diseases
Less rapidly progressive
Chronic lymphocytic leukemia
Hairy cell leukemia*
Large granular lymphocytic leukemia
Small cell lymphocytic lymphoma**
Waldenström macroglobulinemia*
More rapidly progressive
Prolymphocytic leukemia
Mantle cell lymphoma*
Most rapidly progressive
Acute lymphoblastic leukemia*
* For more information, please see the free LLS publication about this disease.
** F
or more information about small cell lymphocytic lymphoma, please see the free LLS publication
Non-Hodgkin Lymphoma.
Large Granular Lymphocytic (LGL) Leukemia. LGL leukemia is another type
of chronic leukemia of the lymphocytes. It is characterized by larger lymphocytes
containing noticeable granules, which can be seen when the blood is examined
under a microscope (see Figure 3, Panel C, on page 19). These are not features of
cells in other types of CLL. LGL leukemia is either T-cell type or NK-cell type. The
blood lymphocyte count is always elevated in CLL. However, it is often normal
or low in LGL leukemia. Although the liver and spleen may be enlarged in LGL
leukemia, the lymph nodes are not. This is another feature that distinguishes it
from CLL.
For patients with T-cell LGL leukemia, chemotherapy, if required, with lowdose methotrexate or cyclophosphamide, or treatment with cyclosporine, an
immunomodulatory drug, may be helpful in improving the neutrophil count and
the red cell count. Granulocyte-colony stimulating factor (G-CSF) may also be
part of therapy to improve neutrophil counts, especially if an infection is present.
Alemtuzumab (Campath®), which destroys large granular lymphocytes, is being
studied in clinical trials as a potential treatment. NK-cell LGL leukemia is very
resistant to therapy.
Prolymphocytic Leukemia. This disease can be a B-cell or a T-cell type and
features large numbers of lymphocytes in the blood. These lymphocytes are
a mixture of small lymphocytes akin to CLL cells and large, more immatureappearing lymphocytes akin to acute lymphoblastic leukemia cells.
Chronic Lymphocytic Leukemia
I page 25
In general, prolymphocytic leukemia develops more rapidly than the chronic
form of lymphocytic leukemia, but more slowly than the acute form. It is treated
with the same drugs that are used for other types of lymphocytic leukemia. In
addition, there are a number of clinical trials to study new treatment approaches for
prolymphocytic leukemia.
Normal Blood and Marrow
Blood is composed of plasma and cells suspended in plasma. The plasma is largely
made up of water in which many chemicals are dissolved. These chemicals include
{{Proteins
{{
Albumin,
the most common protein in blood
{{
Blood-clotting
proteins, made by the liver
{{
Erythropoietin,
cell production
a protein made by the kidneys that stimulates red
{{
Immunoglobulins,
antibodies made by plasma cells in response to infections
including those we develop from our vaccinations (such as poliovirus
antibodies, which are made by normal plasma cells in the bone marrow)
{{Hormones
(such as thyroid hormone and cortisol)
{{Minerals
(such as iron and magnesium)
{{Vitamins
(such as folate and vitamin B12)
{{Electrolytes
(such as calcium, potassium and sodium).
The cells suspended in plasma include red cells, platelets and white cells
(neutrophils, monocytes, eosinophils, basophils, and lymphocytes).
{{The
red cells make up a little less than half the volume of the blood. They are
filled with hemoglobin, the protein that picks up oxygen in the lungs and
delivers it to the organs all around the body; hemoglobin then picks up carbon
dioxide from the body’s cells and delivers it back to the lungs, where it is
removed when we exhale.
{{The
platelets are small cells (one-tenth the size of red cells) that help stop
bleeding at the site of an injury in the body. For example, when a person has a
cut, the vessels that carry blood are torn open. Platelets stick to the torn surface
of the vessel, clump together and plug up the bleeding site with the help of
blood-clotting proteins such as fibrin and electrolytes such as calcium. Later, a
firm clot forms. The vessel wall then heals at the site of the clot and returns to its
normal state.
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{{The
neutrophils and monocytes are white cells. They are called “phagocytes”
(eating cells) because they can ingest bacteria or fungi and kill them. Unlike red
cells and platelets, the monocytes can leave the blood and enter the tissue, where
they can attack the invading organisms and help combat infection. Eosinophils
and basophils are types of white cells that respond to allergens or parasites.
{{Most
lymphocytes, another type of white cell, are found in the lymph nodes,
the spleen and the lymphatic channels, but some enter the blood. There are
three major types of lymphocytes: T lymphocytes (T cells), B lymphocytes
(B cells) and natural killer (NK) cells. Each of these cells is a key part of the
immune system.
Marrow is a spongy tissue where blood cell development takes place. It occupies
the central cavity of bones. In newborns, all bones have active marrow. By the time
a person reaches young adulthood, the bones of the hands, feet, arms and legs
no longer contain functioning marrow. In adults, the spine (vertebrae), hip and
shoulder bones, ribs, breastbone and skull contain the marrow that makes blood
cells. The process of blood cell formation is called “hematopoiesis.” A small group
of cells, the stem cells, develop into all the blood cells in the marrow by the process
of differentiation (see Figure 4).
Blood Cell & Lymphocyte Development
Stem Cells
Multipotential
Hematopoietic Cells
Multipotential
Lymphoid Cells
Differentiate & mature into
six types of blood cells
Differentiate & mature into
three types of lymphocytes
Red Cells
Neutrophils
Eosinophils
Figure 4.
I
Basophils
Monocytes
Platelets
T Lymphocytes
B Lymphocytes
Natural Killer Cells
Stem cells develop into blood cells (hematopoiesis) and lymphocytic cells.
In healthy individuals, there are enough stem cells to keep producing new blood cells
continuously. Blood passes through the marrow and picks up the fully developed and
functional red and white cells and platelets for circulation in the blood.
Chronic Lymphocytic Leukemia
I page 27
Some stem cells also enter the blood and circulate. They are present in such small
numbers that they cannot be counted or identified by standard blood count tests.
Their presence in the blood is important because they can be collected by a special
technique. There are also methods to induce more stem cells to leave their home in
the marrow and circulate in the blood, allowing a greater number of stem cells to be
collected. If enough stem cells are harvested from a compatible donor, they can be
transplanted into a recipient.
Stem cell circulation, from marrow to blood and back, also occurs in the fetus.
After birth, placental and umbilical cord blood can be collected, stored and used as
a source of stem cells for transplantation.
The Lymphatic System
The marrow is really two organs in one. The first is the blood cell–forming organ.
The second is the lymphocyte-forming organ and is a part of the immune system.
The marrow produces three main types of lymphocytes:
{{B
lymphocytes (B cells), which make antibodies in response to foreign antigens,
especially microbes
{{T
lymphocytes (T cells), which mature in the thymus. The T lymphocytes
have several functions, including assisting B lymphocytes to make antibodies
against invading bacteria, viruses or other microbes. The antibody attaches to
the microbe, making it possible for other white cells to recognize the antibody
and pull it into the cell (ingest it) along with its attached microbe. The white cell
then kills and digests the microbe
{{Natural
killer (NK) cells, which attack virus-infected cells without requiring an
antibody or other mediation. T cells and NK cells have other functions as well
and are important elements in research efforts to design immunotherapies to
treat lymphoma and other cancers.
The lymphocytes circulate through channels called “lymphatics,” which connect the
lymph nodes to each other throughout the body. The lymphatic channels collect
into large ducts that empty into blood vessels. Lymphocytes enter the blood via
these ducts. Most lymphocytes are found in the lymph nodes and other parts of
the lymphatic system such as the skin; spleen; tonsils and adenoids (special lymph
nodes); intestinal lining; and, in young people, the thymus.
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Medical Terms
Allogeneic Stem Cell Transplantation. A treatment that uses donor stem cells
to restore a patient’s marrow and blood cells. First, the patient is given conditioning
therapy (high-dose chemotherapy or high-dose chemotherapy with total body
radiation) to treat the leukemia and to “turn off” the patient’s immune system
so that the donor stem cells will not be rejected. A type of transplant called a
“nonmyeloablative” or “reduced-intensity” transplant is under study. It uses lower
doses of conditioning therapy and may be safer, especially for older patients. For more
information, see the free LLS booklet Blood and Marrow Stem Cell Transplantation.
Anemia. A decrease in the number of red cells and, therefore, the hemoglobin
concentration in the blood. This results in a diminished ability of the blood to carry
oxygen. If severe, anemia can cause a pale complexion, weakness, dizziness, fatigue
and shortness of breath on exertion.
Antibodies. Proteins released by plasma cells (derived from B lymphocytes) that
recognize and bind to specific foreign substances called “antigens.” Antibodies
coat, mark for destruction or inactivate foreign particles, such as bacteria, and
viruses or harmful toxins. Antibodies can also be made in the laboratory, in two
ways. Material from species is injected into a different species; the receiving species
recognizes the materials as foreign and make antibodies to it. These antibodies are
usually polyclonal antibodies; that is, they react to multiple targets (antigens). The
second method involves monoclonal antibodies, which react to only one target
(antigen) and can be used in several important ways. They can be used to identify
and classify types of blood cancers or they can be altered to make them useful in
antibody-mediated immunotherapy.
Apheresis. The process of removing certain components of a donor’s blood and
returning the unneeded parts to the donor. The process, also called “hemapheresis,”
circulates blood from a donor through a specialized machine, and then back to the
donor. Apheresis makes it possible to remove desired elements from large volumes
of blood. Platelets, red cells, white cells and plasma can be removed separately. This
procedure is also used to remove circulating blood stem cells, which can be frozen,
stored and later used for transplantation instead of marrow stem cells. See Platelet
Transfusion.
Autologous Stem Cell Transplantation. A treatment that uses a patient's
own stem cells to delay the progression of certain blood cancers. The autologous
transplantation process takes place after the patient achieves a complete response
(remission), or a good partial response, to induction drug therapy. In this treatment
1) the patient’s stem cells are harvested, usually from the blood; 2) the stem cells
are frozen for later use and the patient receives conditioning drug therapy; and
3) the stem cells are thawed and infused back into the patient through an
indwelling catheter (central line). Patients receive supportive care to help prevent
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and/or manage the side effects. Generally, after 10 to 14 days, blood counts begin
to normalize and the side effects of the conditioning therapy begin to resolve. This
therapy is generally not performed for CLL. For more information about all types
of stem cell transplantation, see the free LLS publication Blood and Marrow Stem
Cell Transplantation.
Banding of Chromosomes. The staining of chromosomes with dyes that
highlight transverse bands or regions on the chromosome. The bands give the
chromosomes more specific features, allowing individual distinctions to be made
among them. This technique permits more precise identification of chromosomes.
See Fluorescence In Situ Hybridization.
Basophil. A type of white cell that participates in certain allergic reactions.
Beta2-Microglobulin (B2M). A protein that is shed from CLL cells. The degree
of elevation of serum B2M appears to correlate with IgHv mutation status and
ZAP-70. A patient with a high ZAP-70 or an unmutated IgHv gene status is more
likely to have a high B2M level. This test to measure B2M is available in most
laboratories in the United States.
Blast Cells. The earliest marrow cells identified by the light microscope. Blasts
represent about 1 to 5 percent of normally developing marrow cells. They are
largely myeloblasts, which are cells that will develop into neutrophils. In normal
lymph nodes, blasts are usually lymphoblasts; that is, cells that are part of
lymphocyte development. In acute leukemias, and in some cases of myelodysplastic
syndromes (MDS), abnormal blast cells (abnormal myeloblasts) accumulate in the
marrow. This accumulation is associated with decreased function of the normal
marrow, leading to decreased numbers of red cells, neutrophils, and platelets in the
blood. The reduced number of cells, particularly of red cells, is responsible for the
symptoms of MDS and acute myeloid leukemia (AML).
Bone Marrow. A spongy tissue in the hollow central cavity of the bones that
is the site of blood cell formation. After puberty, the marrow in the spine, ribs,
breastbone, hips, shoulders and skull is most active in blood cell formation. In
adults, the bones of the hands, feet, legs and arms do not contain blood-forming
marrow. In these sites the marrow is filled with fat cells. When marrow cells have
matured into blood cells, they enter the blood that passes through the marrow and
are carried throughout the body.
Bone Marrow Aspiration. A test to examine marrow cells to detect abnormalities.
A marrow sample is usually taken from the patient’s hip bone. After medication
is given to numb the skin, the liquid sample is removed using a special needle
inserted through the bone into the bone marrow. The sample is looked at under
a microscope and assessed not only for the presence of leukemia, but also for how
much of it there is. The cells obtained can also be used for cytogenetic analysis, flow
cytometry and other tests.
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Bone Marrow Biopsy. A test to examine marrow cells for the presence of
abnormalities. This test differs from a bone marrow aspiration in that a small
amount of bone filled with marrow is removed, usually from the hip (pelvic) bone.
After medication is given to numb the area, a special hollow biopsy needle is used
to remove a core of bone containing marrow. The marrow is examined under a
microscope to determine if abnormal cells are present. Bone marrow aspiration and
biopsy may be done in the doctor’s office or in a hospital. The two tests are almost
always done together. Both tests are also done after treatment to determine the
proportion of blood cancer cells that have been killed by therapy.
Bone Marrow Transplantation. See Allogeneic Stem Cell Transplantation and
Autologous Stem Cell Transplantation.
CD38. An antigen on CLL cells and other cells. The expression of CD38 may be a
marker to assist in predicting CLL progression.
Central Line. A special tube inserted into a large vein in the upper chest. The
central line, sometimes referred to as an “indwelling catheter,” is tunneled under
the skin of the chest to keep it firmly in place. The external end of the catheter can
be used to administer medications, fluids or blood products or to withdraw blood
samples. With meticulous care, central lines can remain in place for long periods
of time (many months) if necessary. They can be capped and remain in place in
patients after they leave the hospital, and be used for outpatient chemotherapy or
blood product administration. Several types of catheters (for example, Groshong®,
Hickman®, and Broviac®) can be used for patients receiving intensive chemotherapy
or nutritional support. There are essentially two types of central lines: the one
described above, in which the tube is outside the skin and requires daily care, and
one called a “port,” which is implanted completely under the skin. A port can be
left in place indefinitely and can be removed when no longer needed. Ports must be
flushed periodically. Patients and/or caregivers are given instructions about caring
for the port. See Port.
Chemotherapy. The use of chemicals (drugs or medications) to kill cancer cells.
Numerous chemicals have been developed for this purpose; most act to injure
the DNA of the cancer cells. When the DNA is injured, the cells cannot grow
or survive. Successful chemotherapy depends on the fact that malignant cells
are somewhat more sensitive to the chemicals than normal cells. However, cells
of the marrow are also sensitive to these chemicals, and injury to the cells of the
gastrointestinal tract, skin and hair follicles causes the most common side effects of
chemotherapy, such as mouth sores and hair loss.
Chromosome. Any of the 46 structures (in 23 pairs) in the nucleus of all cells in
the human body (except the red cells) that contain a strand of DNA. This strand is
made up principally of genes, which are specific stretches of the DNA. “Genome”
is the term for an organism’s complete set of DNA. The human genome has been
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estimated to contain about 30,000 genes. The genes on the X and Y chromosomes
are the determinants of our gender: two X chromosomes produce a female and an
X and a Y chromosome produce a male. Each chromosome has a long arm (called
“q”) and a short arm (called “p”). The number or size of chromosomes may be
altered in blood cancer cells as a result of chromosome breakage and rearrangement
(translocation). See Translocation.
Clonal. The designation for a population of cells derived from a single transformed
parent cell. Virtually all cancers are derived from a single cell with an injury
(mutation) to its DNA and thus are monoclonal. Leukemia, lymphoma, myeloma
and myelodysplastic syndromes are examples of clonal cancers; that is, cancers
derived from a single abnormal cell.
Cluster Designation (CD). A term used with a number to identify a specific
molecule on the surface of an immune cell. It is commonly used in its abbreviated
form, for example, “CD20” (the target of the monoclonal antibody therapy
rituximab [Rituxan®] and “CD52” (the target of the monoclonal antibody therapy
alemtuzumab [Campath®]).
Colony-Stimulating Factor. See Growth Factor.
Cytogenetic Analysis. The process of analyzing the number and size of the
chromosomes of cells. Chromosome alterations can be detected, and in some cases
it is possible to identify the actual genes that have been affected. These findings
are very helpful in diagnosing specific types of blood cancers, in determining
treatment approaches and in following the response to treatment. The individual
who prepares and examines the chromosomes and interprets the results is called a
“cytogeneticist.”
Differentiation. The process by which stem cells give rise to functional cells of
a single blood cell line. Differentiation of stem cells forms red cells, platelets and
white cells (neutrophils, monocytes, eosinophils, basophils and lymphocytes). See
Hematopoiesis.
Eosinophil. A type of white cell that participates in allergic reactions and helps
fight certain parasitic infections.
Erythrocytes. See Red Cells.
Flow Cytometry. A test that permits the identification of specific cell types within
a sample of cells. The test may be used to examine blood cells, marrow cells or
cells from a biopsy. A diluted suspension of cells from one of these sources can be
tagged with an antibody specific for a site on the cell surface. The antibody has a
chemical attached that will emit light when activated by a laser beam. The cells flow
through the instrument called a “flow cytometer”; when the cells pass through its
laser beam, those with the antibody-specific surface feature light up and then can
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be counted. One use of flow cytometry is to determine whether a sample of cells is
composed of T cells or B cells. This permits the doctor to determine if the leukemia
or lymphoma is of the B- or T-cell type. Flow cytometry is also used to select stem
cells from a mixed-cell population so that they can be used later in a stem cell
transplant.
Fluorescence In Situ Hybridization (FISH). A technique for studying
chromosomes in tissue using DNA probes tagged with fluorescent molecules that
emit light of different wavelengths (and different colors). The probes match to the
chromosomes within the cells, and the chromosomes fluoresce in color. FISH can
be helpful in assessing risk and treatment needs, and for monitoring treatment
effectiveness, by providing a sensitive test to see abnormal cells, such as cells with
deletions of 17p.
G-Banding Karyotyping. A testing method that makes a certain characteristic
of chromosomes easier to see. A “karyotype” is the systematic arrangement,
using images, of the 46 human chromosomes of a cell. Karyotypes are examined
for deviations from the expected arrangement, number, size, shape or other
characteristics of the chromosomes. Each chromosome pair has a characteristic
banding pattern. To make the banding pattern easier to see, a dye called “Giemsa”
may be used as a stain. This process is also referred to as “G-banding.” Certain
chromosomal abnormalities are associated with specific CLL subtypes. G-banding
karyotyping and other cytogenetic tests provide doctors with information that
contributes to determining the best treatment approach for an individual patient.
This test can take several weeks after samples are obtained from a bone marrow
aspiration, since the cells have to be grown in a laboratory and then stained and
examined individually. Thus, the test takes longer than the FISH test, but has the
advantage of being able to detect any changes that are visible because it does not
rely on specific probes. Usually, both tests are done on samples from the marrow,
especially at the time of diagnosis.
Graft-Versus-Host Disease (GVHD). The immune attack by lymphocytes in
a donor’s marrow or blood cell suspension (the graft) against the tissues of the
recipient (the host). The immune cells most engaged in this reaction are donor T
lymphocytes, which are present in the donor’s blood or marrow, the source of stem
cells. The principal sites of attack are the skin, the liver and the gastrointestinal tract.
The reaction does not occur in identical-twin transplants. The reaction may be
minimal in closely matched individuals or severe in less well-matched individuals.
These reactions are mediated in part by antigens that are not in the major HLA
system and cannot be matched prior to transplantation. For example, in the case
of a female stem cell donor and a male recipient, factors that are produced by
genes on the male recipient’s Y chromosome may be seen as foreign by the female
donor’s cells, which do not share the genes on the Y chromosome. This fact does
not prohibit female donors and male recipients, but it makes the risk of immune
reaction higher.
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Graft-Versus-Tumor Effect (Graft-Versus-Leukemia Effect). The potential
immune reaction of transplanted (donor) T lymphocytes to recognize and
attack the malignant cells of the recipient. This effect was noted when 1) disease
recurrence after transplant was seen to be more likely if the donor and recipient
were identical twins than if they were nonidentical siblings; 2) disease recurrence
was less likely the more pronounced the graft-versus-host disease was; and
3) the removal of donor T lymphocytes decreased the incidence of graft-versushost disease (GVHD) but also resulted in a higher frequency of disease relapse.
Each of these observations could be explained best as an immune attack by
donor lymphocytes against recipient tumor cells that, along with the intensive
conditioning treatment, serve to keep the disease in check. This effect seems to be
most active in types of myeloid leukemia, although it may also occur in patients
with other blood cancers.
Granulocyte. A type of white cell that has a large number of granules in the cell
body. Neutrophils, eosinophils and basophils are types of granulocytes.
Growth Factor. A chemical used to stimulate the production of neutrophils and
shorten the period of low neutrophil counts in the blood after chemotherapy.
Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage
colony stimulating factor (GM-CSF) are examples of growth factors that are made
commercially. GM-CSF can also stimulate monocytes.
Hemapheresis. See Apheresis.
Hematologist. A doctor who specializes in the treatment of blood cell diseases.
This person is either an internist who treats adults or a pediatrician who treats
children.
Hematopathologist. See Pathologist.
Hematopoiesis. The process of blood cell development in the marrow. The
most undeveloped cells in the marrow are stem cells. They start the process of
blood cell development. The stem cells begin to develop into young or immature
blood cells, such as red cells or various types of white cells. This process is called
“differentiation.” The young or immature blood cells then further develop into
fully functional blood cells. This process is called “maturation.” The mature
cells leave the marrow, enter the blood and circulate throughout the body.
Hematopoiesis is a continuous process that is active normally throughout life.
The reason for this activity is that most blood cells live for short periods and must
be replaced continuously. Red cells live for months, platelets live for a week or two
and white cells live for a few days. About 500 billion blood cells are made each
day. When the marrow is invaded with cancer cells, the constant demand for new
blood cells cannot be met, resulting in a severe deficiency in blood cell counts.
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HLA. The abbreviation for “human leukocyte-associated antigen(s).” These antigens
are proteins on the surface of most tissue cells, and they give an individual his or
her unique tissue type. HLA factors are inherited from mother and father, and
the greatest chance of having the same HLA type is between siblings. On average,
one in four siblings is expected to share the same HLA type. The testing for HLA
factors is referred to as “tissue typing.” There are six major groups of HLA: A, B,
C, D, Dr, and Dq. These proteins on the cell surface act as antigens when donated
(transplanted) to another individual, the recipient. If the antigens on the donor cells
are identical (as in identical twins) or very similar (as in HLA-matched siblings), the
transplant (donated stem cells) is more likely to survive (engraft) in the recipient.
In addition, the recipient’s body cells are less likely to be attacked by the donated
immune cells (a result called “graft-versus-host disease”).
Immunoglobulin Heavy Chain Variable Region (IgHv) Gene Status. A
marker that can distinguish between CLL subtypes (unmutated IgHv and mutated
IgHv). People with CLL with unmutated IgHv gene status may have a more
progressive form of the disease.
Immunophenotyping. A method that uses the reaction of antibodies with cell
antigens to determine a specific type of cell in a sample of blood cells, marrow cells
or lymph node cells. The antibodies react with specific antigens on the cell. A tag is
attached to an antibody so that it can be detected. The tag can be identified by the
laboratory equipment used for the test. As cells carrying their array of antigens are
tagged with specific antibodies, they can be identified.
Indwelling Catheter. See Central Line.
Karyotype. The systematic arrangement, using images, of the 46 chromosomes in
the human cell in 22 matched pairs (maternal and paternal member of each pair)
by length from longest to shortest and other features, with the sex chromosomes
shown as a separate pair (either XX or XY). These 22 pairs are referred to as
“autosomes.” See Fluorescent In Situ Hybridization.
Leukocytes. See White Cells.
Leukopenia. A decrease below normal in the concentration of blood leukocytes
(white cells).
Lymphadenopathy. Enlargement of lymph nodes.
Lymphatic System. The system comprising the lymph nodes, the thymus gland
(in the first several decades of life), the lymphatic channels, the lymphatic tissue of
the marrow, the gastrointestinal tract, the skin and the spleen, along with the T, B
and Natural Killer (NK) lymphocytes contained in those sites.
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Lymph Nodes. Small structures, the size of beans that contain large numbers
of lymphocytes and are connected with each other by small channels called
“lymphatics.” These nodes are distributed throughout the body. Enlarged lymph
nodes can be seen, felt or measured by computed tomography (CT) scan or
magnetic resonance imaging (MRI) depending on their location and the degree of
enlargement. In patients with lymphoma and some types of lymphocytic leukemia,
the malignant lymphocytes grow and expand the lymph nodes so that they may
become enlarged.
Lymphocyte. A type of white cell that is the essential cell type in the body’s
immune system. There are three major types of lymphocytes: B lymphocytes,
which produce antibodies to help combat infectious agents such as bacteria, viruses
and fungi; T lymphocytes, which have several functions, including assisting B
lymphocytes in making antibodies; and natural killer (NK) cells, which can attack
virus-infected cells or tumor cells.
Macrophage. See Monocyte/Macrophage.
Minimal Residual Disease (MRD). The small amounts of cancer cells that may
remain after treatment, even when blood and marrow may appear to be normal.
These residual cells can only be identified by sensitive molecular techniques.
Monoclonal. See Clonal.
Monocyte/Macrophage. A type of white cell that represents about 5 to 10
percent of the cells in normal human blood. The monocyte and the neutrophil
are the two major microbe-eating and microbe-killing cells in the blood. When
monocytes leave the blood and enter the tissue, they are converted to macrophages.
The macrophage is the monocyte in action: It can combat infection in the
tissue, ingest dead cells (in this function it is called a “scavenger cell”) and assist
lymphocytes in their immune functions.
Multidrug Resistance (MDR). A characteristic of cells that makes them resistant
to the effects of several different classes of drugs. There are several forms of drug
resistance. They are each determined by genes that govern how the cell will respond
to the chemical agents. One type of multidrug resistance involves the ability to
force several drugs out of cells. The outer wall of the cell contains a pump that ejects
chemicals, preventing them from reaching a toxic concentration. The resistance
to drugs can be traced to the expression of genes that direct the formation of high
amounts of a protein that prevents the drugs from affecting the malignant cells. If
the gene or genes involved are not expressed or are weakly expressed, the cells are
more sensitive to the drug’s effect. If the genes are highly expressed, the cells are less
sensitive to the drug’s effect.
Mutation. An alteration in a gene that results from a change to a part of the
stretch of DNA that represents the gene. A “germ cell mutation” is present in the
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egg or the sperm and can be transmitted from parent(s) to offspring. A “somatic
cell mutation” occurs in a cell and can result in the growth of that specific tissue
cell into a tumor. Most cancers start after a somatic mutation. In leukemia,
lymphoma or myeloma, a primitive marrow (blood-forming) or lymph node
cell undergoes a somatic mutation (or mutations) that leads to the formation of
a tumor. If a mutation results from a major abnormality of chromosomes, such
as a translocation, it can be detected by cytogenetic examination. Sometimes the
alteration in the gene is more subtle and requires more sensitive tests to identify the
original mutated cell (oncogene).
Myelocyte. A cell of the marrow that is a precursor of the mature granulocytes of
the blood. Myelocytes are not present in the blood of healthy individuals.
Neutropenia. A decrease to a below-normal concentration of neutrophils, a type
of white cell.
Neutrophil. The principal phagocyte (microbe-eating cell) in the blood. The
neutrophil is the main cell that combats infections. Patients with certain blood
cancers or patients who have undergone chemotherapy often do not have sufficient
quantities of neutrophils circulating in their bloodstream. A severe deficiency of
neutrophils increases the patient’s susceptibility to infection. A neutrophil may be
called a “poly” (polymorphonuclear neutrophil) or “seg”(segmented neutrophil)
because its nucleus has several lobes.
Nonmyeloablative Allogeneic Stem Cell Transplantation. See ReducedIntensity Stem Cell Transplantation.
Oncologist. A doctor who diagnoses and treats patients with cancer. Oncologists
are usually internists who treat adults or pediatricians who treat children. Radiation
oncologists specialize in the use of radiation to treat cancer. Surgical oncologists
specialize in the use of surgical procedures to diagnose and treat cancer. These
doctors cooperate and collaborate to provide the best treatment plan (surgery,
radiation therapy, chemotherapy or immunotherapy) for the patient.
Pancytopenia. A decrease to a below-normal concentration of all three of the
major blood cell types: red cells, white cells and platelets.
Pathologist. A doctor who identifies disease by studying tissues under a
microscope. A hematopathologist is a type of pathologist who studies diseases
of blood cells by looking at peripheral blood smears, bone marrow aspirates and
biopsies, and lymph nodes and other tissues and uses his or her expertise to identify
diseases such as CLL. In addition to the microscope, a hematopathologist also uses
laboratory values, flow cytometry and molecular diagnostic tests to make the most
accurate diagnosis. The hematopathologist works closely with the hematologist or
oncologist who sees the patient and decides on the best treatment based upon the
diagnosis. See Hematopathologist.
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Petechiae. Pinhead-sized sites of bleeding in the skin. This type of bleeding results
from a very low platelet count. The small hemorrhages are frequently seen on the
legs, feet, trunk and arms. They evolve in color from red to brown, and eventually
disappear. They stop developing when the platelet count increases.
Phagocytes. Cells that readily eat (ingest) microorganisms such as bacteria and
fungi and kill them as a means of protecting against infection. The two principal
phagocytes are neutrophils and monocytes. They leave the blood and enter tissue
in which an infection has developed. A severe decrease in the concentrations of
these cells is the principal cause of susceptibility to infection in patients treated with
intensive radiation therapy and/or chemotherapy. Treatment may suppress blood
cell production in the marrow, resulting in deficiencies of these phagocytic cells.
Platelets. Blood cells (about one-tenth the volume of red cells) that stick to the
site of blood vessel injury, aggregate and then seal off the injured blood vessel
to stop bleeding. “Thrombocyte” is another word for platelet and a form of
this word is often used as the prefix in describing disorders of platelets, such as
thrombocytopenia (too few) or thrombocythemia (too many).
Platelet Transfusion. Transfusion of donor platelets, which may be needed to
support some patients treated for blood cancer. The platelets can be collected from
several unrelated donors and given as pooled, random-donor platelets. The platelets
from about six single-unit blood donors are required to significantly raise the
platelet count in a recipient. Sufficient platelets can be obtained from one donor
by a procedure known as “apheresis.” Platelets are skimmed from large volumes of
blood passing through a specialized machine. The red cells and plasma are returned
to the donor. The advantage of single-donor platelets is that the patient is not
exposed to the different antigens on platelets from many different people and thus
is less likely to develop antibodies against donor platelets. HLA-matched platelet
transfusion can be given from a related donor who has an identical or very similar
HLA tissue type.
Polymerase Chain Reaction (PCR). A technique to expand trace amounts
of DNA or RNA so that the specific type of the DNA or RNA can be studied
or determined. This technique has become useful in detecting a very low
concentration of residual blood cancer cells, too few to be seen using a microscope.
PCR can detect the presence of one blood cancer cell among 500,000 to one
million blood cancer cells. PCR requires a specific DNA (or RNA) abnormality
or marker, like an oncogene, in cancer cells to be used for identifying residual
abnormal cells.
Port. A small device that is used with a central line that allows access to a vein.
The port is placed under the skin of the chest. After the site heals, no dressings are
needed and no special home care is required. To give medicines or nutrition, or to
take blood samples, the doctor or nurse inserts a needle through the skin into the
port. A numbing cream can be put on the skin before the port is used.
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Promyelocyte. A cell that is formed in the transition from an immature cell to a
mature cell during the development cycle for certain types of white cells.
Red Cells. Blood cells (erythrocytes) that carry hemoglobin, which binds oxygen
and carries it to the tissues of the body. Red cells make up about 40 to 45 percent of
the volume of the blood in healthy individuals.
Reduced-Intensity Stem Cell Transplantation. A form of allogeneic
transplantation, now in clinical trials. In reduced intensity transplantation (also
called "nonmyeloablative stem cell transplantation"), patients receive lower
doses of chemotherapy drugs and/or radiation in preparation for the transplant.
Immunosuppressive drugs are used to prevent rejection of the graft (donor
tissue). The engraftment of donor immune cells may allow these cells to attack
the disease (graft-versus-leukemia effect). More study is needed to determine the
effectiveness of this treatment for CLL patients. Studies to determine the usefulness
of reduced-intensity stem cell transplantation in older patients are also under way.
For more information about all types of stem cell transplantation, see the free LLS
publication Blood and Marrow Stem Cell Transplantation.
Refractory CLL. The term used to describe CLL that does not go into remission or
improve substantially after treatment with standard therapy for the disease. Newly
diagnosed patients or relapsed patients may have refractory disease.
Relapsed CLL. The term used to describe CLL that responded to therapy but,
after six or more months, stopped responding.
Remission. The disappearance of evidence of a disease, usually as a result of
treatment. The words “complete” and “partial” are sometimes used to further define
the term “remission.” Complete remission means that all evidence of the disease is
gone. Partial remission means that the disease is markedly improved by treatment,
but residual evidence of the disease is present.
Resistance to Treatment. The ability of cells to grow despite exposure to a
chemical that ordinarily kills cells or inhibits their growth. Refractory disease is the
condition in which a proportion of malignant cells resist the damaging effects of a
drug or drugs. Cells develop drug resistance in several different ways. See Multidrug
Resistance (MDR).
Richter Transformation. In a small number of patients, a progression in their
CLL in which their disease becomes more characteristic of an aggressive lymphoma
such as large cell lymphoma, prolymphocytic transformation, or Hodgkin
lymphoma. This change is not a second cancer, but a transformation of the CLL cells.
Spleen. An organ located in the left upper portion of the abdomen just under
the left side of the diaphragm. It contains clusters of lymphocytes and also filters
old or worn-out cells from the blood. It is often affected in CLL and lymphoma.
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Enlargement of the spleen is called “splenomegaly.” Surgical removal of the spleen
is known as “splenectomy.” Certain diseases are treated by removing the spleen.
Most of the functions of the spleen can be performed by other organs, such as the
lymph nodes and liver, but a person whose spleen has been removed is at higher
risk for infection. He or she is given antibiotic therapy immediately at the first sign
of infection, such as a fever.
Stem Cells. Primitive cells in the marrow that are essential to the formation of red
cells, white cells and platelets. Stem cells are largely found in the marrow, but some
leave the marrow and circulate in the blood. Using special techniques, the stem cells
in the blood can be collected, preserved by freezing and later thawed and used for
stem cell therapy. See Hematopoiesis.
Stem Cell Transplantation. See Allogeneic Stem Cell Transplantation;
Autologous Stem Cell Transplantation.
Thrombocytopenia. A decrease to a below-normal concentration of platelets in
the blood.
Translocation. An abnormality of chromosomes in the marrow or lymph node
cells that occurs when a piece of one chromosome breaks off and attaches to
the end of another chromosome. In a balanced translocation, genetic material is
exchanged between two different chromosomes with no gain or loss of genetic
information. When a translocation occurs, the gene at which the break occurs is
altered. This is one form of somatic mutation that may transform the gene into an
oncogene (cancer-causing gene). See Mutation.
White Cells. Any of the five major types of infection-fighting white cells in the
blood: neutrophils, eosinophils, basophils, monocytes and lymphocytes. White cells
are also called “leukocytes.”
ZAP-70. An abbreviation for the cell protein “zeta-associated protein 70.” A high
level of ZAP-70 expression on the cells of patients with B-cell CLL is one of several
factors that may predict more progressive disease. Outside of a research laboratory
this test is generally not very reliable and should not be used.
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More Information
Free LLS publications include
Blood Transfusion
Choosing a Blood Cancer Specialist or Treatment Center
The CLL Guide—Information for Patients and Caregivers
Cancer-Related Fatigue Facts
Understanding Clinical Trials for Blood Cancers
Understanding Drug Therapy and Managing Side Effects
Understanding Lab and Imaging Tests
Visit “Suggested Reading” at www.LLS.org/resourcecenter to see helpful books on a
wide range of topics.
References
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and
treatment of chronic lymphocytic leukemia: a report from the International
Workshop on Chronic Lymphocytic Leukemia updating the National Cancer
Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456.
Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to
fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia:
a randomized, open-label, phase 3 trial. Lancet. 2010;376:1164-1174.
Howlader N, Noone AM, et al, eds. SEER Cancer Statistics Review, 1975-2008,
National Cancer Institute. Bethesda, MD, www.seer.cancer.gov/csr/1975_2008/,
based on November 2010 SEER data submission, posted to the SEER website, 2011.
Accessed November 9, 2011.
Jaglowski SM, Alinari L, Lapalombella R, et al. The clinical application
of monoclonal antibodies in chronic lymphocytic leukemia. Blood.
2010;116(19):3705-3714.
Kipps TJ. Chapter 94. Chronic lymphocytic leukemia and related diseases. In:
Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K, Prchal, JT: Williams
Hematology, 8e. Available from: AccessMedicine. Accessed November 9, 2011.
National Comprehensive Cancer Network. Practice Guidelines in
Oncology—v.1.2011. Non-Hodgkin Lymphoma. www.nccn.org/professionals/
physician_gls/f_guidelines.asp. Accessed November 9, 2011.
Chronic Lymphocytic Leukemia
I page 41
Woyach JA, Ruppert AS, Heerema NA, et al. Chemoimmunotherapy with
fludarabine and rituximab produces extended overall survival and progression-free
survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study
9712. Journal of Clinical Oncology. 2011;29(10):1349-1355.
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Chronic Lymphocytic Leukemia
I page 43
Notes
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