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Chronic Myeloid Leukemia: This Publication Was Supported by A Grant From
Chronic Myeloid Leukemia: This Publication Was Supported by A Grant From
John Walter
President and CEO
Table of Contents
2 Introduction
2 Here to Help
5 Leukemia
5 Chronic Myeloid Leukemia
9 Signs and Symptoms
10 Diagnosis and Phases of CML
13 Treatment
21 Measuring Treatment Response
24 Stem Cell Transplantation
25 Clinical Trials
27 CML-Related Disorders
28 Normal Blood and Marrow
30 Medical Terms
43 More Information
Acknowledgement
The Leukemia & Lymphoma Society gratefully acknowledges for their critical
review and important contributions to the material presented in this publication,
An estimated 26,359 people in the United States are living with CML in 2011.1
An estimated 5,150 people were expected to be diagnosed with CML in 2011. The
number of people living with CML (prevalence) has doubled since 2001, and this
trend is expected to continue. The growing prevalence of CML reflects important
advances in the treatment of people with CML in the last several years. Since
2001, three new drugs have been approved, and there are now several effective
therapies for people with CML. This progress is expected to continue as a result of
the concerted scientific research effort that is under way and because of patients’
participation in clinical trials.
This publication is designed to provide accurate and authoritative information in regard to the subject
matter covered. It is distributed as a public service by The Leukemia & Lymphoma Society (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 CML 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 CML 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.
Making treatment choices, paying for medical care, communicating with healthcare
providers, family members and friends—these are some of the stressors that go along
with a cancer diagnosis. LLS offers free information and patient services for individuals
and families touched by blood cancers.
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.
Chapter Programs and Services. LLS chapter offices around the United States
and Canada offer support and education. Your chapter can arrange for peer-to-
peer 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.
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.
{{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 CML treatment. Seek medical advice if your mood does not improve
over time—for example, if you feel depressed every day for a two-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 web
page, or call the NIMH toll free at (866) 615-6464.
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.”
Figure 1. I Shown here is the set of chromosomes from a marrow cell of a female patient with chronic myeloid
leukemia (CML). The total number of chromosomes (46) is normal, composed of pairs of chromosomes 1
through 22 and two sex chromosomes, in this instance XX for female. (The sex chromosomes are XY in males.)
The higher the chromosome number, the smaller the chromosome. The arrow in the fourth row indicates the
shortened arm of chromosome 22 (the Ph chromosome), characteristic of the leukemic marrow cells of patients
with CML. The arrow in the second row indicates chromosome 9, which is elongated. These two changes reflect
the translocation of chromosome material between chromosomes 9 and 22.
This figure kindly provided by Nancy Wang, PhD, University of Rochester Medical Center, Rochester, NY.
9 22 9 22 BCR-ABL
oncogene
Piece of 9
BCR
Philadelphia
chromosome
ABL
Piece of 22
{{A portion of the ABL gene from chromosome 9 translocates and fuses
with the remaining portion of the BCR gene on chromosome 22.
The translocated piece of chromosome 9 results in a fusion gene called
BCR-ABL.
{{The BCR-ABL fusion gene directs the production of an abnormal (mutant)
protein, an enzyme called Bcr-Abl tyrosine kinase (see Figure 3).
{{The abnormal enzyme protein is the principal factor in converting the
marrow stem cell from a normal cell into a leukemic cell.
Figure 2. I The process of translocation between the genes on chromosome 9 and chromosome 22.
BCR ABL
BCR ABL
Bcr Abl
Blocked by Bcr-Abl
CML Transformation Tyrosine Kinase
Inhibitors
Figure 3. I The oncogene (cancer-causing gene) shown in the top bar is caused by the fusion of the ABL
gene from chromosome 9 with the BCR gene from chromosome 22. The gene’s DNA sequence is copied into
messenger RNA, shown in the middle bar. The messenger RNA causes the formation of a mutant protein, an
enzyme called “tyrosine kinase,” shown in the lower bar. This enzyme triggers signals that cause the stem cell to
act in an unregulated (leukemic) manner, leading to the formation of too many white cells that live too long.
This results in the clinical manifestations of CML, such as high white cell counts and low red cell counts. Several
Bcr-Abl tyrosine kinase inhibitors, including imatinib mesylate (Gleevec®), dasatinib (Sprycel®) and nilotinib
(Tasigna®), can bind to the Bcr-Abl tyrosine kinase (protein) and block its effects. The specific drug action on the
protein that leads to CML development is an example of “targeted therapy” (see Treatment on page 13).
Causes and Risk Factors. Scientists do not yet understand why the BCR-ABL
gene that leads to CML is formed in some people and not in others. However,
in a small number of patients, CML is caused by exposure to very high doses of
radiation. This effect has been most carefully studied in the survivors of the atomic-
bomb blast in Japan; their risk of developing leukemia was significantly increased.
A slight increase in risk also occurs in some individuals treated with high-dose
radiation therapy for other cancers, such as lymphoma. Most people treated for
cancer with radiation do not go on to develop CML, and most people who have
CML have not been exposed to high-dose radiation. Exposures to diagnostic dental
or medical x-rays have not been associated with an increased risk of CML.
Incidence. Most cases of CML occur in adults. From 2004 to 2008, the median
age at diagnosis for CML was 66 years. A small number of children develop CML;
the course of the disease is similar in children and adults.
As shown in Figure 4 on page 9, the frequency of CML increases with age, from
about less than 1 in 100,000 people until about 40 years, to about 2 in 100,000
10
Incidence Rate per 100,000 People
0
<1 1-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+
Age in Years
Figure 4. I The horizontal axis shows 5-year age intervals. The vertical axis shows the frequency of new cases
of CML per 100,000 people in a given age-group. Source: 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.
CML signs and symptoms tend to develop gradually. People with CML may
{{Feel tired and be short of breath while doing everyday activities
{{Have an enlarged spleen (leading to a “dragging” feeling on the upper left side of
the abdomen)
{{Be pale from anemia (a decrease in red cells)
{{Experience night sweats, an inability to tolerate warm temperatures and/or
weight loss.
Complete Blood Count (CBC). The CBC measures the number and types of cells
in the blood. With CML, the hemoglobin concentration is decreased and the white
cell count is increased, often to very high levels. The number of platelets may be
increased or decreased, depending on the severity of the person’s CML. Examination
of stained (dyed) blood cells with a light microscope shows a characteristic pattern
of white cells in people with CML: a small proportion of immature cells (leukemic
blast cells and promyelocytes) and a larger proportion of maturing and fully
matured white cells (myelocytes and neutrophils). These blast cells, promyelocytes
and myelocytes are normally not present in the blood of healthy individuals.
Cytogenetic Analysis. This test measures the number and structure of the
chromosomes. Samples from the bone marrow are examined to confirm the blood
test findings and to determine if there is a chromosomal abnormality such as the
Philadelphia chromosome. The bone marrow tests, called “bone marrow aspiration”
and “bone marrow biopsy,” are usually done during the same procedure. For a
bone marrow aspiration, a special needle is inserted through the hip bone into the
marrow to remove a liquid sample of cells. For a bone marrow biopsy, a special
needle is used to remove a core sample of bone that contains marrow. Both samples
are examined under a microscope to look for chromosomal and other cell changes.
The presence of the Ph chromosome (the shortened chromosome 22) in the
marrow cells, along with a high white cell count and other characteristic blood and
marrow test findings, confirms the diagnosis of CML.
Normal Abnormal
Figure 5. I Fluorescence in situ hybridization, or FISH, is a testing method that uses fluorescent molecules
to mark the BCR-ABL gene in CML. In normal cells, two red and two green signals indicate the location of
the normal ABL and BCR genes, respectively. In abnormal cells, the BCR-ABL fusion is visualized through the
fusion of the red and green signals. It is frequently detected as a yellow fluorescence (noted by arrows).
Blood cell counts, bone marrow examinations, FISH and PCR may also be used to
track a person’s response to therapy. Throughout treatment, the number of red cells,
white cells, platelets and CML cells is measured on a regular basis once therapy has
begun (see Measuring Treatment Response on page 21).
For more information about lab tests, see the free LLS publication Understanding
Lab and Imaging Tests.
The Phases of CML. CML has three phases. Most often, CML is diagnosed in
the “chronic” phase, although some patients are diagnosed in the “accelerated”
phase and others in “blast crisis.” A small proportion of patients who are diagnosed
and treated in the chronic phase of CML nonetheless progress to the accelerated
phase of CML. The progression from chronic phase, which can usually be well
Chronic Phase. People with chronic phase CML may have no symptoms in
this phase, or CML symptoms may be present prior to treatment due to changes
in blood cell counts or spleen enlargement (see Signs and Symptoms on page 9).
If present, chronic phase symptoms resolve promptly when people are treated.
Effective therapy initially lowers the total white cell count to near-normal
levels. The improved white cell count is accompanied by a reduction in spleen
enlargement, improvement in the hemoglobin concentration and a return to
general well-being. Bleeding and infectious complications are uncommon in the
chronic phase. Once treated, people with chronic phase CML are typically able to
fully participate in their usual activities.
Accelerated Phase. Anemia may develop or progress and cause fatigue, the white
cell count may either fall to very low levels or rise because of the accumulation of
blast cells, and platelet counts generally decrease. The blast count often increases
in the blood and bone marrow in the accelerated phase (and is further elevated
in blast crisis). The spleen may become enlarged; the patient may lose his or her
sense of well-being (in this phase, individuals more commonly feel ill), and other
complications may follow.
Blast Crisis. In this phase, the number of blast cells increases in both bone
marrow and blood; the red cell, platelet and neutrophil counts can be very
low, and patients may experience episodes of infection and bleeding as a result.
Other symptoms commonly encountered include fatigue, shortness of breath,
abdominal pain, bone pain and/or spleen enlargement. Unfortunately, blast crisis
is similar to acute leukemia in its effects on the patient. In about 25 percent of
people, the transformation in the blast crisis takes on the appearance of acute
lymphoblastic leukemia, while in the majority it takes on the appearance of acute
myeloid leukemia.
Leukapheresis. Some patients may have extraordinarily high white cell counts at
the time of diagnosis. This can create viscosity problems and impair blood flow to
the brain, lungs, eyes and other sites and also cause damage in small blood vessels.
Patients can be treated initially with the removal of white cells by a machine that
is similar to a dialysis machine. The process is called “leukapheresis.” Hydroxyurea
is often used as well to initially decrease the white cell count. Leukapheresis can
be used if chronic phase CML is diagnosed during the first months of pregnancy,
when other treatments may be harmful to fetal development. For more information
about pregnancy and CML, see page 19.
Other Treatments
{{Bosutinib†
{{Ponatinib (AP24534)†
{{Interferon alfa (Roferon®-A, Intron® A)
{{Pegylated interferon alfa
{{Hydroxyurea (Hydrea®)
{{Cytarabine (Cytosar-U®)
{{Busulfan (Myleran®)
Table 1. I Some of the drugs that are currently used to treat chronic phase CML are listed in this table. Interferon,
hydroxyurea, cytarabine and busulfan were used prior to the introduction of Gleevec and may continue to be used
to treat selected patients, sometimes in combination with a Bcr-Abl tyrosine kinase inhibitor.
Side Effects of Treatment. The following describes possible side effects from
TKI treatment.
Accelerated Phase and Blast Crisis Phase. The goal in treating accelerated
or blast crisis phase CML is, as with the chronic phase, to eliminate all cells that
contain the BCR-ABL gene, thus leading to remission. If this is not possible,
the goal is to return the disease to the chronic phase. Gleevec is commonly used
as an initial treatment for people diagnosed in accelerated phase CML. Sprycel
and Tasigna are drug treatment options for Gleevec-resistant patients with CML
that progresses to accelerated or blast crisis phase in the course of treatment with
Gleevec. Prior to the availability of Gleevec, Sprycel and Tasigna, allogeneic stem
cell transplantation was the principal means of successful treatment for patients of
an appropriate age, in generally good health and with an available donor.
Stem cell transplantation is still a treatment option for some patients who
are first diagnosed in, or progress to, advanced phases of CML (see Stem Cell
Transplantation on page 24). In these situations, patients are counseled by
their doctors to consider the benefits and risks of having an allogeneic stem cell
transplant while in remission after treatment with Gleevec and particularly after
second-line treatment with Sprycel. Although not approved for newly diagnosed
blast phase CML, both Sprycel and Tasigna can be effective in such patients, and
can achieve initial remissions that can facilitate transplantation. At the present time,
the outlook for patients with blast phase CML who do not undergo transplantation
while in remission is quite poor.
Patients should consider checking in with a CML specialist from time to time to
make sure they are meeting treatment milestones. Patients can go for a consultation
on their own or can ask their doctor to work in consult with a CML specialist.
Patients who belong to HMOs typically have more restrictions on their ability to
seek consultation with academic medical centers. Speak to your insurance company
to know what is covered under your plan.
The patient’s doctor can send the patient’s blood sample for BCR-ABL testing
(which requires specialized equipment and expertise) to a reference laboratory
(used for specialized tests that are ordered only occasionally or require specialized
equipment), an academic center or an NCI (National Cancer Institute) center
laboratory. There are commercial tests available for Bcr-Abl kinase domain
mutation assessment. Many employee health insurance plans require that you use
a specific lab, which is often indicated on your insurance card. Sometimes, if the
insurance company will not cover the test, providing clarification or justification
for the testing may help your case. The National Comprehensive Cancer Network
(NCCN) and the European LeukemiaNet (ELN) have suggestions for when to
assess for mutations. Some insurance carriers consider mutation assessment a
“genetic” test and will only authorize a single such test per lifetime. Talk to your
doctor and your healthcare team to be sure that, if needed, the mutation testing will
be covered.
For information about the CML mutation testing guidelines from the NCCN,
please visit www.nccn.org.
Children and Young Adults with CML. A small percentage of patients diagnosed
with CML are children and young adults. CML represents about 3 percent of newly
diagnosed childhood leukemias.
CML has the same disease course in children as it does in adults. The features of
disease at diagnosis and the response to therapy in children seem to be identical
to that in adults. Specific guidelines for CML treatment in children have yet to be
determined. However, imatinib mesylate (Gleevec®) is the primary treatment used
The next treatment option for children who have CML that does not respond
well to Gleevec is stem cell transplantation. Patients can also be treated with drugs
such as Sprycel® or Tasigna®. Complications of a transplant remain challenging,
so treatment with Gleevec continues to be the first choice for younger patients in
chronic phase.
With oral medications, it is important to follow the doctor’s directions and keep
taking the medication for as long as prescribed. This can be overwhelming for
parents of children and young adults because remembering to take the drug can
be hard.
Talk to your child’s doctor about the best treatment for him or her. It is important
for your child to be seen by a doctor who specializes in pediatric leukemia. See the
free LLS publications Choosing a Blood Cancer Specialist or Treatment Center and
Coping With Childhood Leukemia and Lymphoma for more information.
Pregnancy and TKIs. A growing number of women with CML who are in stable
remission with ongoing treatment are showing increasing interest in becoming
pregnant. Data are available from a limited number of pregnancies that have
occurred accidentally in women who were taking Gleevec. While a substantial
proportion of children who were exposed to Gleevec in the uterus have been born
healthy and without apparent abnormalities, there have been a few abnormalities
noted in children and in aborted fetuses. It thus cannot be convincingly
stated or assumed that Gleevec can be safely taken during pregnancy. Current
recommendations include counseling so that potential parents understand the
{{Need for women to stop treatment during preconception and pregnancy
{{Risk of relapse if therapy is stopped based on the depth and duration of response
{{Risk for fetal effects from Gleevec (probably greatest during the first trimester)
{{Need for women on Gleevec to refrain from breast-feeding
{{Uncertainty about treatment options and restoration of stable response during
and after pregnancy.
Early reports of treatment cessation for pregnancy have been discouraging; risk
of relapse and the chance of regaining response remain unknown. With a larger
proportion of patients in stable remission and promising results from early trials
of deliberate treatment cessation among a nonpregnant population, hope remains
that women with CML who want to become pregnant can be better managed with
lower risk to both mother and child if treatment is interrupted after achieving a
deep and stable molecular response. See Treatment Cessation on page 20.
For Sprycel and Tasigna, experience has been even more limited, and, like
Gleevec, these agents are considered unsafe to take during pregnancy at the
present time. Women who are on Sprycel or Tasigna should not breast-feed.
There is hope that by achieving deep molecular responses in a higher proportion
of patients, these new agents may facilitate more treatment interruptions, but this
issue is not yet resolved.
Treatment Cessation. Although many patients with chronic phase CML develop
deep and lasting remission with drugs such as Gleevec, Sprycel and Tasigna, at the
present time CML is not generally believed to be curable with current medical
therapies. PCR testing shows that most patients with deep remissions still have
evidence of residual CML cells. Even in patients who test negative for the BCR-
ABL gene by PCR testing, PCR is not capable of sampling every last cell in the
blood and bone marrow. When PCR does not detect any evidence of BCR-ABL
after initiating treatment, CML drug therapy is still used to treat the disease that
presumably remains.
Limited reports in the medical literature about treatment cessation in the past
demonstrated that relapse is common or even expected. Careful clinical trials have
begun to examine whether individuals who have deep remissions while taking
therapy are able to sustain stable remissions after they stop therapy (see Measuring
Treatment Response on page 21). Interestingly, some patients with undetectable
disease have interrupted treatment without evidence of disease recurrence during
the subsequent two to three years, but it is not known if any of these patients
are cured of their CML. More research is required in this area before any change
can be confidently made to the current recommendation to maintain therapy
indefinitely. There have been rare individuals who were treated with Gleevec alone
and remained free of detectable disease for several years despite discontinuing this
medication and in the absence of any CML therapy. However, it remains formally
possible that interruption of the tyrosine kinase inhibitor (TKI) even in patients
with undetectable disease may increase the likelihood of developing resistant disease;
therefore, prolonged TKI interruption should only be performed under special
circumstances such as a clinical trial. For Gleevec-responsive individuals, the risk
of losing response—or moving to a more advanced phase of the disease—appears
greatest during the first four years after initiating treatment. After this early period,
the risk appears to decrease to very low levels. Available evidence suggests that people
who receive TKIs may remain in remission for very long periods.
Blood and Marrow Tests. During CML drug therapy, a complete blood count
(CBC) is routinely performed to measure the numbers of white cells, red cells and
platelets. Hemoglobin and hematocrit levels are also measured. After an initial
diagnosis of CML, blood counts may be performed every two to four weeks. When
blood counts return to normal, blood tests are generally performed every three to
six months.
Certain changes can occur in CML cells in the bone marrow that cannot be
detected by blood tests. Bone marrow assessments are generally recommended
every six months during the first 18 months of therapy until a complete
cytogenetic response is documented. After achievement of a complete cytogenetic
response, bone marrow testing can be performed infrequently. Anytime there is
a substantial change in response to oral CML drug therapy as measured in the
blood, a bone marrow test is recommended to determine if there are specific cell
and chromosome changes that cannot be detected by blood tests (see Table 2).
Note that the same individual may have a deep remission with stable, low levels
of BCR-ABL (e.g., complete molecular response) according to one laboratory’s
test results and yet still have detectable BCR-ABL levels according to another
Chronic Myeloid Leukemia I page 21
laboratory’s test results. Efforts to standardize quantitative PCR reporting are
ongoing in an effort to more uniformly report test results.
Blood or bone marrow may be used for FISH or PCR tests (see pages 10 and 11).
In general, FISH offers little in comparison to bone marrow chromosome studies
and quantitative PCR testing, and is therefore not commonly used to track disease
response. Quantitative PCR testing is generally performed at diagnosis and every
three months after initiation of therapy.
Sprycel and Tasigna have produced high rates of hematologic and cytogenetic
responses in patients with chronic phase CML who either cannot tolerate or are
resistant to therapy with Gleevec. Both drugs are effective for treating people with
accelerated phase CML, either to restore chronic phase or to induce hematologic
and/or cytogenetic response. Such responses occur less often in the advanced phases
than in the chronic phase. Sprycel is approved to treat myeloid and lymphoid blast
phase CML (as well as Ph-positive acute lymphoblastic leukemia) when Gleevec
response is insufficient or lost. If a patient is resistant to Sprycel or Tasigna, testing
for drug-resistant mutations would be important; this information guides treatment
and helps the doctor choose the best therapy for each patient. See Mutation Testing
on page 18 for more information.
Table 3. G
eneral Guidelines for Chronic Myeloid Leukemia (CML)
Drug Therapy Responses
Table 3. I Patients respond differently to CML drug therapy. These are general guidelines for CML drug therapy.
An individual’s CML drug therapy response is measured against that person’s results at the start of therapy, called
“baseline” results. Thus, if a person has a high white cell count at the beginning of therapy, a “complete hematologic
response and some cytogenetic improvement” may occur later than “after 3 months of therapy.” A complete
molecular response is optimal, but only some patients attain this. Even without a complete molecular response,
CML may be well controlled by drug therapy.
For more information about all types of stem cell transplantation, see the free LLS
publication Blood and Marrow Stem Cell Transplantation. See Clinical Trials on
page 25 for more information about other types of transplants under study.
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.
Research Approaches. There are clinical trials for newly diagnosed patients and
for patients with advanced phase disease or who are intolerant of or resistant to
their current treatment. The following are some approaches under study in clinical
trials for the treatment of patients with CML.
Vaccine Therapy. Various forms of vaccine therapy are being studied. Proteins on
the surface of CML cells may be well-suited targets for such vaccines, which could
employ a patient’s immune cells to attack his or her own CML cells. See the free
LLS publication Immunotherapy Facts for information about the development of
blood cancer vaccines.
Other drugs are being tested in clinical trials to enhance the graft-versus-tumor
effect of stem cell transplantation and to reduce the risks of high-grade graft-versus-
host disease. In addition, research is under way using umbilical cord blood as a
source of stem cells for transplantation in children and adults. Cord blood provides
another potential source of matched, unrelated stem cells for those patients without
a matched, related stem cell donor. Results from cord-blood stem cell transplants
have been promising, and there appears to be a reduced risk of acute graft-versus-
host disease in younger cord-blood transplant patients. For more information
about all types of stem cell transplantation, see the free LLS publication Blood and
Marrow Stem Cell Transplantation.
In general, CMML, JMML and CNL create more severe disturbances in blood
cell counts early in the course of the disease; these disturbances are not as well
controlled with current drug treatments. People with some signs and symptoms of
CML who are BCR-ABL negative and do not fit the diagnostic criteria for CMML
are sometimes designated as having “atypical CML” because their disease cannot
be adequately described by the criteria for CMML or CML. Also, a small number
of people with the clinical signs of CML do not, in fact, show evidence of the
Philadelphia chromosome and are sometimes designated as having “Ph-negative
CML.” In these rare instances, there is most likely another alteration or cancer
gene that mimics the effects of BCR-ABL. Patients with disease that is caused by
alterations other than BCR-ABL are not expected to (and have been proven not to)
respond to therapies such Gleevec, Sprycel, or Tasigna.
Albumin,
{{ the most common protein in blood
Blood-clotting
{{ proteins, made by the liver
Erythropoietin,
{{ a protein made by the kidneys that stimulates red cell
production
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 cells 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
discharged 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.
{{The neutrophils and monocytes are white cells known as “phagocytes” (eating
cells) because they can ingest bacteria or fungi and kill them. Unlike the red cells
and platelets, the monocytes can leave the blood and enter the tissues, where
they can attack invading organisms and help combat infection. Eosinophils and
basophils are 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.
Stem Cells
Multipotential Multipotential
Hematopoietic Cells Lymphoid Cells
Figure 6. I Stem cells develop into blood cells (hematopoiesis) and lymphoid cells.
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 have functioning marrow. The spine (vertebrae), hip and shoulder bones,
ribs, breastbone and skull contain the marrow that makes blood cells in adults.
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 6).
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.
Some stem cells 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 called “apheresis.” 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.
Bilirubin. A brownish yellow substance that is produced mainly when the liver
breaks down old red cells. It can be measured in a blood sample.
Blast Cells. The earliest marrow cells identified by the light microscope. Blasts
represent about 1 to 5 percent of normally developing marrow cells.
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
then they are carried throughout the body.
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.
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.
Computed Tomography (CT) Scan. A technique for imaging body tissues and
organs. X-ray transmissions are converted to detailed images using a computer to
synthesize x-ray data. The images are displayed as a cross-section of the body at any
level from the head to the feet. A CT scan of the chest, abdomen or pelvis permits
detection of an enlarged lymph node, liver or spleen. A CT scan can be used to
measure the size of these and other structures before, during and after treatment.
Cord-Blood Stem Cells. Stem cells that are present in blood drained from the
placenta and umbilical cord. These stem cells have the capability to repopulate the
marrow of a compatible recipient and produce blood cells. Frozen cord blood is a
source of donor stem cells for transplantation to HLA-matched recipients. Most
cord-blood transplants are given by matched or nearly matched unrelated donors.
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.”
Eosinophil. A type of white cell that participates in allergic reactions and helps
fight certain parasitic infections.
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 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.
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.
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 steadily replaced. Red cells die in four months, platelets in 10 days and
most neutrophils in one to three days. About 100 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.
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.
Lymphocyte. A type of white cell that is an essential part of the body’s immune
system. There are three major types of lymphocytes: B lymphocytes, which
produce antibodies to help combat infectious agents like bacteria, viruses and fungi;
T lymphocytes, which have several functions, including assisting B lymphocytes to
make antibodies; and natural killer (NK) cells, which can attack virus-infected cells
or tumor cells.
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.
Mutation. An alteration in a gene that results from a change to some part of the
DNA that represents the gene. A “germ cell mutation” is present in the egg or the
sperm and can be transmitted from parent to offspring. A “somatic mutation”
occurs in a specific tissue cell and can result in the growth of that 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 one or more
somatic mutations that lead 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. See Oncogene.
Oncogene. A mutated gene that is the cause of a cancer. Several subtypes of acute
myeloid leukemia, acute lymphoblastic leukemia and lymphoma, and nearly all
cases of chronic myeloid leukemia are associated with an oncogene. See Mutation.
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.
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.
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
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.
Salvage Therapy. Treatment for a person who has cancer that has not responded
to other primary treatments.
More Information
Free LLS publications include
Choosing a Blood Cancer Specialist or Treatment Center
The CML Guide: Information for Patients and Caregivers
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
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Gambacorti-Passerini C, Antolini L, Mahon FX, et al. Multicenter independent
assessment of outcomes in chronic myeloid leukemia patients treated with imatinib.
Journal of the National Cancer Institute. 2011;103(7):553-561.
Hiwase DK, Yeung DT, White DL. Optimizing the selection of kinase inhibitors
for chronic myeloid leukemia patients. Expert Review of Hematology.
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Howlader N, Noone AM, Krapcho M, 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 January 20, 2012.
Ibrahim AR, Paliompeis C, Bua M, et al. Efficacy of tyrosine kinase inhibitors
(TKIs) as third-line therapy in patients with chronic myeloid leukemia in chronic
phase who have failed 2 prior lines of TKI therapy. Blood. 2010;116(25):5497-5500.
Epub 2010 Sept 10.
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Jiang Q, Xu LP, Liu DH, et al. Imatinib mesylate versus allogeneic hematopoietic
stem cell transplantation for patients with chronic myelogenous leukemia in the
accelerated phase. Blood. 2011;117(11):3032-3040. Epub 2011 Jan 20.
Lee JW, Chung NG. The treatment of pediatric chronic myelogenous leukemia
in the imatinib era. Korean Journal of Pediatrics. 2011;54(3):111-116.
Epub 2011 Mar 31.
Liesveld JL, Lichtman MA. Chapter 90. Chronic myelogenous leukemia and
related disorders. Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K, Prchal, JT.
Williams Hematology. 8th ed. AccessMedicine. Accessed January 23, 2012.
Mahon FX, Réa D, Guilhot J, et al. Discontinuation of imatinib in patients with
chronic myeloid leukaemia who have maintained complete molecular remission for
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Lancet Oncology. 2010;11(11):1029-1035. Epub 2010 Oct 20.
National Comprehensive Cancer Network. Practice Guidelines in
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professionals/physician_gls/f_guidelines.asp. Accessed January 20, 2012.
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Annual Meeting. Teleconference of The Leukemia & Lymphoma Society, Past
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