Chronic Lymphocytic Leukemia
Definition
Chronic lymphocytic leukemia (CLL) is a cancer of white blood cells. In CLL, mature white blood cells of certain types called lymphocytes function abnormally and cause disease.
Description
Chronic leukemia is a cancer that starts in the blood cells made in the bone marrow. The bone marrow is thespongy tissue found in the large bones of the body. The bone marrow makes precursor cells called “blasts” or “stem cells” that mature into different types of blood cells. Unlike acute leukemias, in which the process of maturation of the blast cells is interrupted, in chronic leukemias, most of the cells do mature and only a few remain as immature cells.
However, even though the cells appear normal, they do not function as normal cells. The different types of cells produced in the bone marrow are red blood cells (RBCs), which carry oxygen and other materials to all tissues of the body, and white blood cells (WBCs), which fight infection. Platelets play a part in the clotting of the blood. The white blood cells can be further subdivided into three main types: the granulocytes, monocytes, and the lymphocytes. The granulocytes, as their name suggests, contain granules (particles). These granules contain special proteins (enzymes) and several other substances that can break down chemicals and destroy microorganisms such as bacteria. Monocytes are the second type of white blood cell. They also are important in defending the body against pathogens. The lymphocytes form the third type of white blood cell. There are two main types of lymphocytes: T lymphocytes and B lymphocytes. They have different functions within the immune system. The B cells protect the
body by making “antibodies.” Antibodies are proteins that can attach to the surfaces of bacteria and viruses.
The occurrence of this attachment sends signals to many other cell types to travel through the blood and destroy the antibody-coated organism. The T cell protects the body against viruses. When a virus enters a cell, it produces certain proteins that are projected onto the surface of the infected cell. T cells recognize these proteins and produce certain chemicals (cytokines) capable of destroying the virus-infected cells. In addition, T cells destroy some types of cancer cells. Chronic leukemias develop very gradually. The abnormal lymphocytes multiply slowly, and in a poorly regulated manner. These lymphocytes live much longer than normal lymphocytes and, thus, their numbers build up in the body. In CLL, lymphocytes accumulate. The enlarged lymphocyte population congregates the blood, bone marrow, lymph nodes, spleen, and liver. The two types of chronic leukemias can be easily distinguished under the microscope. Chronic lymphocytic leukemia (CLL) involves the T or B lymphocytes. B-cell abnormalities are more common than T-cell abnormalities. T cells are affected in only 5% of the patients.
Demographics
Ninety percent of CLL cases are seen in people who
are 50 years or older, with the average age at diagnosis
being 65. Rarely is CLL diagnosed in a patient who is
less than 35 years of age. The incidence of the disease
increases with age. It is almost never seen in children.
According to the estimates of the American Cancer Society
(ACS), approximately 8,100 new cases of CLL were
diagnosed in 2000, 4,600 in men and 3,500 in women.
CLL affects both sexes. Among patients younger
than 65, the disease is slightly more common in men.
However, among patients older than 75 years of age,
CLL appears almost equally in men and women. Within
the United States, CLL affects African-Americans as frequently
as it does Caucasians. However, CLL appears
more frequently among Americans than among people
living in Asia, Latin America, and Africa.
In the United States and Europe, CLL accounts for
more than one-quarter of all diagnosed leukemias. Over
the past 50 years, the rate at which CLL has been appearing
has increased significantly. However, many doctors
think that this increase is not necessarily due to the disease
actually being more common than in the past, but
instead due to the fact that the disease is now more likely
to be diagnosed when it does appear. Fifty years ago,
only one out of ten CLL patients was diagnosed during
the early stages of the disease. Now, half of all CLL
patients are diagnosed during this early stage.
Causes and symptoms
The cause of CLL is unknown. It is certain, however,
that CLL is linked to genetic abnormalities and environmental
factors. For example, close family members of
patients with CLL are twice as likely to seven times as
likely to be diagnosed with CLL as people in the general
population. For another example, exposure to certain
chemicals used in farming and other agricultural occupations
may increase the risk that a person will develop
CLL. In contrast, CLL is not associated with exposure to
radiation known to cause other cancers. As of 2001, doctors
were unsure whether people who have had certain
virus infections are more likely to develop CLL than are
people in the general population. If there does turn out to
be such an association, it would not be with all viruses
but with two human retroviruses (HTLV-I and HTLV-II)
or with Epstein-Barr virus (EBV).
The symptoms of CLL are generally vague and nonspecific.
One out of five patients with CLL has no symptoms
at all, and the disease is discovered only through a
routine blood test. A patient may experience all or some
of the following symptoms:
• chronic fatigue
• weakness
• a general feeling of malaise or of things being not quite
right
• swollen lymph nodes
• an enlarged spleen, which could make the patient complain
of abdominal fullness
• a general feeling of ill health
• fever
• frequent bacterial or viral infections.
• unusually severe response to insect bites
• night sweats
• weight loss not due to dieting or exercise
Diagnosis
There is no screening test for CLL. If the doctor has
reason to suspect leukemia, he or she will conduct a very
thorough physical examination to look for enlarged
lymph nodes in the neck, underarm, and pelvic region. In
addition, the doctor will look to see whether the liver and
spleen are enlarged. Urine and blood tests may be
ordered to check for microscopic amounts of blood in the
urine and to obtain a complete differential blood count.
This count will give the numbers and percentages of the
different cells found in the blood. An abnormal blood test
might suggest leukemia. Some authorities state that CLL
may be diagnosed if the number of lymphocytes in the
blood exceeds a certain level.
The doctor may perform a bone marrow aspiration
and biopsy to confirm the diagnosis of leukemia. During
the bone marrow biopsy, a cylindrical piece of bone and
marrow is removed. The tissue is generally taken out of
the hipbone. These samples are sent to the laboratory for
examination. In many CLL patients, more than onefourth
of the bone marrow is made up of mature lymphocytes.
In addition to diagnosis, bone marrow biopsy is
also conducted during the treatment phase of the disease
to see if the leukemia is responding to therapy.
Some CLL patients have a condition called
hypogammaglobulinemia. Immunoglobulins are normal
parts of the body’s immune system, the system used to
fight off infection. Patients with hypogammaglobulinemia
have very low levels of all of the various types of
immunoglobulins.
The doctor may also conduct immunophenotyping.
This involves taking a sample of the blood and looking at
what types of cells of the immune system are being
affected by the CLL. Approximately 19 out of 20 CLL
patients have the B-cell type of CLL. Far more rare is the
T-cell type of CLL. In addition, the doctor may look for
abnormalities in the chromosomes of the affected cells.
Chromosomes are a unit of genetic material within cells.
Patients exhibiting no chromosomal abnormalities have a
better prognosis than those who do have such abnormalities.
If the abnormalities become more complex over
time, the patient’s prognosis may worsen.
Standard imaging tests such as x rays, computed
tomography scans (CT scans), and magnetic resonance
imaging (MRI) may be used to check whether the
leukemic cells have invaded other organs of the body,
such as the bones, chest, kidneys, abdomen, or brain.
Clinical staging, treatments, and prognosis
Staging
Usually one of two systems are used to stage CLL.
One of these is the Binet system and the other the Rai
system. According to the Rai system, patients at low risk
have no enlargement of lymph nodes, spleen or liver. The
occurrence of these marks entry into the intermediate
stage, according to Rai. High risk patients have, in addition,
anemia and a significant decrease in the number of
blood platelets in their blood. Blood platelets help blood
to clot. According to the Binet system, a patient’s stage
depends upon how much hemoglobin (part of red blood
cells that carry oxygen) and how many platelets are in
the blood, as well as how many other areas the disease
has affected. According to both systems, patients at low
risk usually survive more than ten years. Patients at intermediate
risk usually survive about six years. Patients at
high risk usually survive about 2 years. Other factors
with important implications for prognosis include the
pattern at which bone marrow is being affected by the
CLL and the amount of time it takes for the number of
lymphocytes to double.
Treatment
Because the long-term prognosis for many patients
with CLL is excellent, many patients receive no treatment
at all at first. Many patients go for years before
developing aggressive disease that requires treatment.
Treatment for early stage CLL should be started only
when one of the following conditions appears:
• Symptoms of the disease are growing worse, for example,
there is a greater degree of fever, weight loss, night
sweats, and so forth.
• The spleen is enlarging or enlargement of the spleen
has become painful.
• Disease of the lymph nodes has become more severe.
• The condition of the bone marrow has deteriorated and
there is anemia and a marked reduction in the number
of blood platelets.
• There is anemia or reduction in the number of blood
platelets for reasons not specifically related to the condition
of the bone marrow.
• The population of lymphocytes is rapidly growing.
• The patient is experiencing numerous infections
caused by bacteria.
Therapy for CLL usually starts with chemotherapy.
Depending on the stage of the disease, single or multiple
drugs may be given. Drugs commonly prescribed include
fludarabine, cladribine, chlorambucil and cyclophosphamide.
Studies have also provided evidence that a
combination of fludarabine and cyclophosphamide is
effective. However, this combination has not yet been
evaluated over periods of ten years or more. Another
combination now being studied involves fludarabine and
mitoxantrone (Novantrone). Yet another involves fludarabine
and anthracyclines. Low-dose radiation therapy
may be given to the whole body, or it may be used to
alleviate the symptoms and discomfort due to an
enlarged spleen and lymph nodes. The spleen may be
removed in a procedure called a splenectomy.
Bone marrow transplantation (BMT) has produced
some positive outcomes in patients with CLL,
although it has not been the subject of sufficient systematic
study to permit doctors to know how effective it is.
In BMT, the patient’s diseased bone marrow is replaced
with healthy marrow. There are two ways of performing
a bone marrow transplant. In an allogeneic bone marrow
transplant, healthy marrow is taken from another person
(donor) whose tissue is either the same or very closely
resembles the patient’s tissues. The donor may be a twin,
a sibling, or a person who is not related at all. First, the
patient’s bone marrow is destroyed with very high doses
of chemotherapy and radiation therapy. To replace the
destroyed marrow, healthy marrow from the donor is
given to the patient through a needle in the vein.
In the second type of bone marrow transplant, called
an autologous bone marrow transplant, some of the
patient’s own marrow is taken out and treated with a
combination of anticancer drugs to kill all the abnormal
cells. This marrow is then frozen to save it. The marrow
remaining in the patient’s body is then destroyed with
high-dose chemotherapy and radiation therapy. Following
that, the patient’s own frozen marrow is thawed and
given back to the patient through a needle in the vein.
The use of this mode of bone marrow transplant for the
treatment of CLL is currently being investigated in clinical
trials.
Allogeneic BMT has been successfully used with
younger patients with CLL who have not responded positively
to chemotherapy. Autologous BMT has produced
some positive results in older CLL patients. However,
BMT is generally not considered an option in treating
most patients with CLL because they are too old to be
considered good candidates for the procedure.
Other CLL therapies that are being investigated
include monoclonal antibody-targeted therapy and interferons.
Monoclonal antibodies (MoAbs) are laboratorymanufactured
chemicals that closely resemble parts of the
body’s natural immune system. Studies of MoAbs-targeted
therapies have shown some positive results in CLL,
although definitive studies have not been performed at the
time of this writing in 2001. Interferon is a chemical normally
made in the cells of the body. It helps protect the
body against viruses and also seems to have some effect
against certain cancers. The interferon used as medicine is
a laboratory-manufactured copy of the interferon produced
by the body. As of this writing in 2001, interferon
therapy has produced some response in CLL patients.
However, interferon therapy has not as yet been shown to
be associated with prolongation of remission.
Radiation therapy is very effective for approximately
one in three of those CLL patients for whom it is considered
appropriate.
Because leukemia cells can spread to all the organs
via the blood stream and the lymph vessels, surgery is
not considered an option for treating leukemias.
Treatment of CLL and its complications
During therapy for CLL, complications frequently
appear. Many patients develop infectious illnesses. Sometimes,
two or more infectious diseases attack a patient at
the same time. These infections should be treated with
great care. Most people whose death has been directly
attributed to CLL have actually died from bacterial infections.
The patient should be involved in identifying symptoms
of infection and reporting these to the doctor without
delay. Doing so may save the patient’s life.
Many patients develop anemia, which is treated with
the drug prednisone. Patients who do not respond to
prednisone therapy may have their spleen removed and
may receive therapy with immunoglobulin, a component
of the blood.
Treatment after transformation of CLL
Between three and ten out of every hundred patients
with CLL experiences transformation of the disease into
large-cell lymphoma (LCL). When this happens it is
called Richter’s transformation. Its occurrence is often
marked by fever, weight loss, and night sweats. Treatments
for LCL are being studied, although outcomes
have not been very good. Very infrequently, CLL may
transform into another disease, called prolymphocytic
leukemia. Attempts to develop adequate therapies for this
disease are ongoing.
Prognosis
For many CLL patients, the prognosis is excellent.
Using the Binet and Rai staging systems, patients at low
risk usually survive more than ten years. Patients at intermediate
risk usually survive about six years. Patients at
high risk usually survive about two years. The average
patient survives approximately nine years following
diagnosis. Factors with important implications for prognosis
that are not included in the Binet or Rai systems are
the pattern at which bone marrow is being affected by the
CLL and the amount of time it takes for the number of
lymphocytes in the blood to double. It is uncertain
whether BMT may prolong the lifespan of CLL patients.
Many of the chemotherapy agents used to treat disease
do effectively control the leukemia and its effects but, as
yet, the more established chemotherapy agents have not
been shown to increase the life span of patients.
Coping with cancer treatment
Since many CLL patients die from infection, it is
essential that patient be very alert to the signs of infection.
If patients perform this role and seek medical attention
as soon as symptoms of infection appear, then treatment
can be started early. This may save a life.
It is very difficult for some patients to be not only
informed that they have leukemia but then to also be told
that they do not need treatment. This may be very confusing,
unless the patient realizes that treatment may be
necessary at some future time and that starting therapies
too soon may be counterproductive.
Because nutritional alteration, weight loss, and psychosocial
problems may accompany CLL, it may be prudent
for patients to consult with a registered dietitian.
Cancer patients need supportive care to help them
come through the treatment period with physical and
emotional strength in tact. Many patients experience
feelings of depression, anxiety, and fatigue, and many
experience nausea and vomiting during treatment. Studies
have shown that these can be managed effectively if
discussed with the attending physician.
Prevention
Although some cancers are related to known risk
factors, such as smoking, in leukemias, there are no
known risk factors. Therefore, at the present time, there
is no way known to prevent the leukemias from developing.
Everyone should undergo periodic medical
checkups.
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