Chronic Myelocytic Leukemia
Definition
Chronic myelocytic leukemia (CML) is a cancer of white blood cells in which too many white blood cells are made in the bone marrow. Chronic myelogenous leukemia and chronic myeloid leukemia are other names for CML and refer to the identical disease. In CML, there is an increased proliferation of white blood cells called granulocytes.
Description
Chronic leukemia is a cancer that starts in the bloodcells made in the bone marrow. The bone marrow is the spongy 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, 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; white blood cells (WBCs), which fight infection; and platelets, which 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, have granules (particles) inside them. These granules contain special proteins (enzymes) and several other substances that can break down chemicals and destroy microorganisms such as bacteria. Monocytes are also 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 functionswithin 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. This attachment sends signals to many other cell types to come 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. The T cells can recognize these proteins and produce certain chemicals (cytokines) that are capable of destroying the virus-infected cells. In addition, the T cells can destroy some types of cancer cells. Chronic leukemias develop very gradually. The abnormal lymphocytes multiply slowly, but in a poorly regulated manner. They live much longer than normal cells and thus their numbers build up in the body. The two types of chronic leukemias can be easily distinguished under the microscope. Chronic lymphocytic leukemia (CLL) involves the T or B lymphocytes. In chronic myelocytic leukemia (CML), the cells affected are the granulocytes.
In addition, CML involves abnormalities of both the blood platelets, structures that help blood to clot, and the red blood cells, the blood cells that carry oxygen. Very rarely will CML appear in children. Juvenile CML is a distinct disease of children younger than 14 years of age. There is a decrease in the number of blood platelets, substances that help the blood to clot. And there is an increase in certain white blood cells.
Demographics
Slightly more men than women are affected by
CML. The average patient is between 50 and 60 years of
age. However, CML can affect people of any age. Chronic
leukemias account for 1.2% of all cancers. Chronic
myelocytic leukemia is generally seen in people in their
mid-40s. According to the estimates of the American
Cancer Society (ACS), approximately 4,400 new cases
of leukemia were diagnosed in the year 2000, 2,600 in
men and 1,800 in women. Between 1973 and 1991, the
rate at which CML appeared in the United States
decreased slightly.
Causes and symptoms
People exposed to nuclear and other radiation are at
increased risk for CML. Thus, people who have had
higher exposure to radiation for medical reasons are at
increased risk of developing this cancer. Parents with
CML do not have children who are more than normally
likely to develop CML. However, it is possible that people
whose immune system exhibits certain characteristics
are at increased risk for the disease.
CML develops in a two- or three-stage progression.
First, the chronic phase appears. Between 60 and 80 percent
of patients next exhibit the symptoms of what is
called the accelerated phase. The final stage of CML is
the terminal blastic phase.
Symptoms of chronic phase CML appear in
60%–85% of patients. This means 15% to 40% of all the
people diagnosed with CML have no symptoms at all
and are diagnosed with the disease only because of the
results of a routine blood test. Patients who do have
symptoms most frequently find themselves to have
fatigue, weight loss, or pain. Some patients have a mass
of tissue or an enlarged liver that the doctor is able to
feel. Some patients experience strokes, visual problems,
a lowering of alertness or responsiveness, priapism, and
ringing in the ear. Many patients in accelerated phase
CML have no specific symptoms. However, fever,
weight loss, and night sweats may appear.
Patients with terminal, blastic phase CML often
experience symptoms. There may be fever, weight loss,
night sweats, and bone pain. Many patients develop
infections. Many have anemia (low counts of red blood
cells) and many bleed easily.
Diagnosis
There are no screening tests available for chronic
leukemias. The detection of these diseases may occur by
chance during a routine physical examination.
People who have CML have an unusually high number
of white blood cells. Somewhat less than half of
these people also have high numbers of blood platelets.
Most patients have mild anemia. The composition of the
bone marrow in CML patients also differs from that of a
healthy person. The marrow is described as being hypercellular.
This means that the number of cells present in
the bone marrow is unusually great.
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. Swollen gums, an enlarged liver or
spleen, bruises, or pinpoint red rashes all over the body
are among the signs of leukemia. 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.
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.
Many doctors consider the presence of the Philadelphia
(Ph) chromosome to be a crucial factor in the diagnosis
of CML. The Ph chromosome is formed if some of
the genetic material in two specific parts of two specific
genetic units, called chromosomes, have exchanged
some content in a particular way and created an arrangement
of genetic material characteristic of CML patients.
Laboratory findings indicate when a patient enters
the accelerated phase of CML. There may be more than
15% blasts (immature cells) in the blood. Alternately, the
accelerated phase has started when more than 30% of the
blood may be composed of a combination of blasts and
promyelocytes. Promyelocytes are immature granulocytes.
Another marker for the start of the accelerated
phase is when the blood contains more than 20% of
another white blood cell, called a basophil. Finally, the
accelerated phase may be heralded by there being more
than 100,000,000,000 platelets per liter of blood. The terminal,
blastic phase of CML is heralded by measurements
of 30% or more of blasts in either the bone marrow
or the blood.
Clinical staging, treatments, and prognosis
Staging
Several different staging systems are in use. Most of
these make use of the fact that a number of factors relevant
to patients with CML say something about the
patient’s prognosis. Among these factors are the patient’s
age, the white blood cell count, the platelet count, the
percentage of blast cells and basophil cells in either the
blood or the bone marrow, the size of the liver, the size of
the spleen, population of red blood cells that have a central
portion called a nucleus, and the evolution of certain
cell clones.
Treatment
It is very fortunate that several years ago the American
Society of Hematology convened an Expert Panel on
Chronic Myeloid Leukemia. This panel reviewed available
therapies and published its findings in 1999. The
findings were rigorously based upon evidence provided
by the best research. The panel, comprised of top doctors
from around the world, carefully sifted through all of the
studies on treatment for CML and put aside all those
studies performed with questionable methodology. This
is a most important document relevant to CML therapy.
Since the publication of the findings of the expert
panel, however, a new medicine has demonstrated great
success in studies. This new medicine is known as STI571,
Imatinib mesylate, or Gleevec. Since Gleevec was such a
new drug in 2001, few studies have been conducted to
evaluate its long-term effects. Furthermore, researchers
have not had an opportunity to view the effects of imatinib
mesylate over a period of five, 10, or 20 years.
In terms of CML therapy, the situation in 2001 was
the following: physicians have the reliable report of the
Expert Panel and a little bit of new information about a
new medication. How the Expert Panel’s findings and
this new information should be integrated with the
results of recent studies of imatinib mesylate is an issue
that cancer doctors are currently resolving.
The Expert Panel looked at treatment of the chronic
phase of CML. One therapy examined by the panel is
busulfan (BUS). Another is hydroxyurea (HU). Both
BUS and HU are chemotherapy medications. Studies
have demonstrated that CML patients in chronic phase
given HU live longer than patients given BUS.
Another therapy examined by the expert panel is
interferon-alpha. 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. The Expert Panel concluded that patients in
chronic phase CML who have received interferon live
longer than those given HU or BUS. This conclusion
applies, in particular, to patients who have had little prior
treatment for CML, who start interferon treatment soon
after diagnosis, and who have certain other characteristics.
However, side effects of interferon therapy are
greater than those of therapy with HU or BUS. Patients
who develop the side effects of interferon may feel like
they have the flu. Patients receiving interferon seem to do
better if they also receive chemotherapy with either HU
or a medicine called Ara-C, or cytarabine.
Bone marrow transplantation (BMT) is an effective
treatment for CML. In BMT, the patient’s diseased
bone marrow is replaced with healthy marrow. There are
two ways of doing 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.
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 marrow that was frozen is
thawed and given back to the patient.
Allogeneic BMT may be used soon after diagnosis
or after a patient has been treated with interferon or
chemotherapy. The Expert Panel found that carefully
designed, well-controlled, randomized studies have not
been conducted on BMT therapy for CML. In the studies
that do exist, scientists performed BMT on a group of
patients and then observed the results. These studies
show that BMT may lead to long-term remission. Remission
is achieved if the disease becomes diminished for a
period. Patients appear to live longer if they received
chemotherapy followed by BMT. But the Expert Panel
cautions that the results of these observational studies
cannot be relied upon. One problem with them might be,
for example, that the patients chosen to receive BMT
might have started out being healthier than patients who
did not receive BMT. The side effects of BMT may be
severe, and a large number of CML patients receiving
BMT die as a direct result of the BMT.
Therefore, one important consideration when BMT
is being considered is whether the conditions under
which the individual patient might receive BMT are
favorable. In other words, is a very suitable marrow
donor available? Is the patient within two years of CML
diagnosis? It is important that patients understand clearly
the ptential benefits and risks of BMT. One comment
made by the Expert Panel is that younger patients who
hope to live a very long time after CML diagnosis are
more likely to benefit from allogeneic BMT. Autologous
BMT has not achieved superior long-term results.
The recent studies of imatinib mesylate found it very
effective in two groups of CML patients. One group was
made up of patients who had unsuccessful results with
interferon alfa therapy. The other group of CML patients
studied were in the blast phase of the disease. Both studies
found the medication to be effective and well tolerated.
However, studies reporting on the effectiveness of
imatinib mesylate over periods of five years or longer
were not yet available in 2001.
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 the leukemias.
The Expert Panel was careful to state that patient preferences
should be taken into account as a treatment plan is
developed. No approach to CML therapy is perfect. Each
provides some benefit and is accompanied by certain side
effects and risks. Which therapy or therapies is best for
each individual patient depends upon on certain facts, such
as the age of the patient and whether the patient is suffering
from illnesses other than CML. In addition, the Expert
Panel explains that the personal preferences of each
patient are an important consideration. For example, some
patients would rather avoid potential severe side effects
and would be willing to give up the potential of living
another few months or years. Other patients would be
entirely unwilling to accept this way of looking at risks
and benefits. It is important that health care professionals
educate patients as to what treatment options are available
and the perfections and imperfections associated with
each. The opinions of each patient should be an important
factor in deciding which treatment is best for that patient.
In the accelerated and blastic phase of CML, aggressive
chemotherapy may be given. Combination chemotherapy,
in which multiple drugs are used, is more effective
than using a single drug for the treatment. Interferon
and BMT may be used, although results are not as good
as for patients in the chronic phase of CML.
It should be mentioned that during treatment the
doctor may order a procedure called leukapheresis. This
lowers the numbers of white blood cells circulating in the
patient’s body. Also, either before or after therapy, it may
be necessary to provide the patient with a transfusion of
blood platelets. In addition, antibiotics are often used to
help prevent infection in leukemia patients.
Prognosis
The most important factor in determining the likelihood
that a patient receiving interferon therapy will
achieve long-term survival is whether there is a positive
response to interferon-alfa. Although experience with
imatinib mesylate is being gathered in studies, this drug
remains so new that doctors do not know what effect it
will have on the prognosis of CML patients. Once the
threat of transplantation-related complications has
passed, patients receiving BMT may achieve longer survival
than patients receiving interferon therapy.
Before the discovery of modern therapies, patients
often spent between three-and-a-half and five years in the
chronic phase. Then some patients entered an accelerated
phase, from which most died within 18 months. Once
patients were in the terminal, blastic phase most died
within six months. However, all of this has changed with
the arrival of newer therapeutic techniques. Just as many
patients used to die from heart attack while similar
patients may now live for decades, so cancer patients are
achieving longer lives.
Coping with cancer treatment
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 doctor.
Prevention
Although some cancers are related to known risk
factors, such as smoking, in leukemias, there are no
definitive risk factors. Therefore, at the present time,
there is no way known to prevent the leukemias from
developing. People who are at an increased risk for
developing leukemia because of proven exposure to ionizing
radiation, the organic liquid benzene, or people
who have a history of other cancers of the lymphoid system
(Hodgkin’s lymphoma) should undergo periodic
medical checkups.
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