Chronic Myeloid Leukemia - The Leukemia Lymphoma Society

Chronic Myeloid Leukemia
Paula, CML survivor
This publication was
supported by a grant from
Revised 2012
A Message From John Walter
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
myeloid leukemia (CML) 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 CML and their families.
We wish you well.
John Walter
President and CEO
Table of Contents
Here to Help
Chronic Myeloid Leukemia
Signs and Symptoms
Diagnosis and Phases of CML
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
The Leukemia & Lymphoma Society gratefully acknowledges for their critical
review and important contributions to the material presented in this publication,
Neil P. Shah, MD, PhD
Associate Professor
Division of Hematology/Oncology
Co-Leader, Hematopoietic Malignancies Program
Helen Diller Family Comprehensive Cancer Center
Edward A. Ageno Distinguished Professor
University of California, San Francisco
Robert J. Arceci, MD, PhD
King Fahd Professor of Pediatric Oncology
Professor of Pediatrics, Oncology and Cellular and Molecular Medicine
Kimmel Comprehensive Cancer Center Johns Hopkins, Baltimore
Chronic Myeloid Leukemia
I page 1
This booklet provides information about chronic myeloid leukemia (CML) for
people who have CML and their families.
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.
A brief description of normal blood and marrow, as well as a glossary of select
medical terms, is provided at the end of the booklet to help readers better
understand the CML-specific information.
Howlader N, Noone AM, et al, eds. SEER Cancer Statistics Review, 1975-2008, National Cancer Institute.
Bethesda, MD,, based on November 2010 SEER data submission, posted
to the SEER website, 2011.
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
people are better able to cope once their treatment plan is established and
they can look forward to recovery.
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.
page 2
I 800.955.4572 I
LLS Has Ways to Help. Treatment for CML will affect your daily life, at least for a
time. You may have questions about your treatment and 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 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 at
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.
InformaciГіn en EspaГ±ol. LLS has a number of resources available in Spanish for
patients, caregivers and healthcare professionals. You can read and download these
resources online at or order printed copies by mail or phone.
Other Helpful Organizations. Our website,,
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
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 TrialCheckВ®, 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
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
Chronic Myeloid Leukemia
I page 3
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
Suggestions From Other People Living With Cancer
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 CML.
{{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:
offers online Blood Cancer Discussion Boards as well as online chats at
{{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 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 Click on “LLS Disease &
Treatment Publications—Survey for Patients, Family and Friends.”
page 4
I 800.955.4572 I
Leukemia is a cancer of the marrow and blood. The four major types of leukemia
are acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic
leukemia and chronic lymphocytic leukemia.
If the cancerous change takes place in a type of marrow cell that forms
lymphocytes, the leukemia is called “lymphocytic” (or “lymphoblastic”). If the cell
change takes place in a type of marrow cell that normally goes on to form red blood
cells, some kinds of white blood cells and platelets, the leukemia is called “myeloid.”
Acute leukemia is a rapidly progressing disease that affects mostly cells that are
partly or completely undeveloped. These immature cells cannot perform their
normal functions. Chronic leukemia typically progresses slowly, and permits the
growth of greater numbers of more developed cells. In general, these more mature
cells can carry out some of their normal functions.
The four main types of leukemia are further classified into subtypes based on
specific features of cells. Knowing the subtype of leukemia can help the doctor
assess how quickly the disease might progress. The subtype is also important
because the treatment approach may vary depending upon the disease subtype.
More general information about leukemia can be found in the free LLS publication
Understanding Leukemia.
Chronic Myeloid Leukemia
Chronic myeloid leukemia (CML) is called by several other names, including
“chronic myelogenous leukemia,” “chronic granulocytic leukemia” and “chronic
myelocytic leukemia.” CML results from a change (mutation) in the DNA of a single
bone marrow cell. The mutation is “acquired” (not present at birth). The mutated
marrow cell multiplies into many cells (CML cells). The CML cells grow and survive
better than the normal cells; if untreated, over time they crowd out the normal
cells. The typical result of an uncontrolled growth of CML cells in the marrow is
an increase in the number of CML cells in the blood. CML does not completely
interfere with the development of mature red cells, white cells and platelets. As a
result, chronic phase myeloid leukemia is generally less severe than acute leukemia.
The Philadelphia Chromosome. Normal cells have 23 pairs of chromosomes
(structures in the nucleus of the cell that contain genes). They consist of 22
numbered pairs, with the sex chromosomes (XX for a female and XY for a male)
constituting the 23rd pair. CML was initially distinguished from other types of
leukemia by the presence of a genetic abnormality of chromosome 22 in CML
Chronic Myeloid Leukemia
I page 5
cells. In 1960, two doctors at the University of Pennsylvania School of Medicine
in Philadelphia were studying chromosomes in cancer cells. They observed that
chromosome 22 in cells from patients with CML was shorter than the same
chromosome in normal cells. The shortened chromosome 22 was named the
“Philadelphia chromosome” and is also called the “Ph chromosome.”
Marrow Cell Chromosomes
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.
The BCR-ABL Cancer-Causing Gene. Further studies of CML leukemia cells
established that two chromosomes, number 9 and number 22, were abnormal.
Portions of these chromosomes actually switch places with each other. A portion
of chromosome 9 moves to the end of chromosome 22; in addition, a portion
of chromosome 22 moves to the end of chromosome 9. This exchange of parts
of chromosomes is called “translocation” (see Figure 1). The translocation of
chromosome 9 and chromosome 22 is found only in the leukemia (CML) cells and
in a proportion of patients with acute lymphoblastic leukemia. One theory that
scientists propose about why this switch occurs is that when the cells are dividing,
chromosomes 9 and 22 are very close to each other, making this error more likely.
page 6
I 800.955.4572 I
Chronic Myeloid Leukemia-Causing Event—How the
BCR-ABL Cancer-Causing Gene (Oncogene) Is Formed
Translocation of chromosomes 9 and 22
Normal Chromosomes
CML Chromosomes
Piece of 9
Piece of 22
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 fusion gene directs the production of an abnormal (mutant)
protein, an enzyme called Bcr-Abl tyrosine kinase (see Figure 3).
abnormal enzyme protein is the principal factor in converting the
marrow stem cell from a normal cell into a leukemic cell.
Figure 2.
The process of translocation between the genes on chromosome 9 and chromosome 22.
The break on chromosome 9 leads to a mutation of a gene called “ABL” (for
Abelson, the scientist who first described this gene). The break on chromosome
22 involves a gene called “BCR” (for breakpoint cluster region). The mutated ABL
gene moves to chromosome 22 and fuses with the remaining portion of the BCR
gene. The result of this fusion is the leukemia-causing fusion gene BCR-ABL.
Genes give cells instructions for making proteins. The BCR-ABL gene produces a
dysfunctional protein called “Bcr-Abl tyrosine kinase.” The Bcr-Abl tyrosine kinase,
which leads to the abnormal regulation of cell growth and survival, is responsible
for the development of CML (see Figure 2). The Bcr-Abl tyrosine kinase is also a
target for specific drug therapies that block its effects in many people with CML
(see Treatment on page 13).
Chronic Myeloid Leukemia
I page 7
Leukemia-Causing Process in a Marrow Stem Cell
Fusion Oncogene (DNA)
Fusion Messenger (RNA)
Fusion Tyrosine Kinase (Protein)
CML Transformation
Blocked by Bcr-Abl
Tyrosine Kinase
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 (GleevecВ®), dasatinib (SprycelВ®) and nilotinib
(TasignaВ®), 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 atomicbomb 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
page 8
I 800.955.4572 I
people at 55 years, to about 9 in 100,000 people at 80 years and older. In coming
years, the incidence of CML may increase. This possibility stems from the fact
that a sizable portion of the US population is made up of people born between
1946 and 1964. These individuals have reached, or are approaching, the age range
associated with increased CML incidence.
Chronic Myeloid Leukemia: Age-Specific Incidence Rates 2004-2008
Incidence Rate per 100,000 People
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,,
based on November 2010 SEER data submission, posted to the SEER website, 2011.
Signs and Symptoms
People with CML may not have any symptoms at the time of diagnosis. These
individuals can be diagnosed following a medical examination for another
condition or as part of a periodic checkup.
CML signs and symptoms tend to develop gradually. People with CML may
tired and be short of breath while doing everyday activities
an enlarged spleen (leading to a “dragging” feeling on the upper left side of
the abdomen)
pale from anemia (a decrease in red cells)
weight loss.
night sweats, an inability to tolerate warm temperatures and/or
Chronic Myeloid Leukemia
I page 9
Diagnosis and Phases of CML
Diagnosis. In most cases, blood and marrow cells are examined to make a CML
diagnosis. Various laboratory tests are used to examine the blood and marrow cells;
for example:
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.
Fluorescence In Situ Hybridization (FISH). The bone marrow cells of about
90 percent of people with CML have Ph chromosomes detectable by cytogenetic
analysis. A small percentage of people with clinical signs of CML do not have
cytogenetically detectable Ph chromosomes, but they almost always test positive
for the BCR-ABL fusion gene on chromosome 22. FISH is a more sensitive
method for detecting CML than the standard cytogenetic tests that identify the Ph
chromosome. FISH is a quantitative test that can identify the presence of the BCRABL gene (see Figure 5). Genes are made up of DNA segments. FISH uses DNAbinding agents that are specific for selected pieces of DNA—in this case, ABL
and BCR. The probes for both BCR and ABL are labeled with chemicals that each
release a different color of light. The color shows on the chromosome that contains
the gene—normally chromosome 9 for ABL and chromosome 22 for BCR—so
FISH can detect the piece of chromosome 9 that has moved to chromosome 22
in CML cells. Since FISH can detect BCR-ABL in cells found in the blood, it can
be used to determine if there is a significant decrease in the number of circulating
CML cells as a result of treatment.
page 10
I 800.955.4572 I
Identifying the BCR-ABL Gene Using FISH
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).
Polymerase Chain Reaction (PCR). The BCR-ABL gene is also detectable by
molecular analysis. A quantitative PCR test is a molecular testing method that
can be applied to either blood or bone marrow cells. It is the most sensitive test
to identify and measure the BCR-ABL gene. The PCR test essentially increases or
“amplifies” small amounts of specific pieces of either RNA or DNA to make them
easier to detect and quantify. Thus, the BCR-ABL abnormality can be detected even
when present in a very low number of cells. About one abnormal cell in one million
cells can be detected by PCR testing. Quantitative PCR is used to determine the
relative number of cells with BCR-ABL in the blood; this has become the most used
and relevant type of PCR test, based on its high degree of sensitivity and its ability
to quantify the amount of disease present.
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 Myeloid Leukemia
I page 11
managed, to accelerated phase or blast crisis results from additional genetic
alterations in the leukemic stem cells. Some of the additional chromosome
abnormalities are identifiable by cytogenetic analysis. However, there appear to
be other genetic changes in the CML stem cells that cannot be identified by the
laboratory tests that are currently available.
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.
page 12
I 800.955.4572 I
CML is not highly curable with current drug therapies, but there have been many
significant treatment advances in recent years, and treatment options continue
to evolve. With current drug therapies, most people diagnosed with chronic
phase CML can expect to live good-quality lives. The goals of CML research are
to develop curative therapies and to decrease the side effects of treatment. The
approach for treating each patient is customized, based on the phase of CML
at diagnosis, test results and age, particularly if stem cell transplantation is a
consideration. People are advised to consult with a doctor who specializes in treating
patients with CML and to discuss the most appropriate treatment options for their
situation. A person with CML is usually treated by a hematologist or an oncologist.
Chronic Phase CML. The goal in treating people with chronic phase CML is to
restore blood counts to normal levels, dramatically reduce or eliminate CML cells
altogether, and preserve an acceptable quality of life. Treatment usually returns the
blood cell counts to normal values and maintains them either at or close to normal
levels (mild reductions in blood cell counts are not uncommon). The size of the
spleen decreases until it approaches its normal dimensions. Infections and abnormal
bleeding are unusual. Patients are able to resume their previous levels of day-today activities. However, they will need to receive periodic health checks, including
blood cell counts and other tests to determine the extent and stability of cytogenetic
and molecular remission (see Measuring Treatment Response on page 21). Periodic
bone marrow examinations are necessary early in treatment and can often be done
less frequently over time; periodic blood-based monitoring of treatment response
continues indefinitely. Individuals also need to have their tolerance to drugs assessed
from time to time and may need dosage adjustments.
Three drugs, imatinib mesylate (GleevecВ®), dasatinib (SprycelВ®) and nilotinib
(TasignaВ®), have been approved as initial therapy for chronic phase CML and all
three are reasonable options for newly diagnosed patients.
Gleevec. The oldest of the three treatments is imatinib mesylate (GleevecВ®), which
has been the standard initial therapy for chronic phase CML since 2001 (see Table
1 on page 14). Gleevec is a type of drug called a “Bcr-Abl tyrosine kinase inhibitor”
(TKI); it works by blocking the Bcr-Abl tyrosine kinase. It is a highly effective oral
drug therapy that, for the majority of people treated, brings about a stable remission.
Studies have shown that Gleevec can keep the chronic phase of CML under control
for at least 10 years, the length of the observation period since this drug’s approval
(in 2001). Gleevec is approved by the US Food and Drug Administration (FDA)
to treat newly diagnosed chronic, accelerated or blast crisis phase CML in adults, as
well as chronic phase CML after failure of interferon-alfa therapy. It is also approved
for use in children with chronic phase CML who are newly diagnosed or whose
disease has recurred after stem cell transplantation, and in patients with disease
that is resistant to interferon-alfa therapy. The drug is generally well tolerated by
the majority of both younger and older people taking it, although most patients
Chronic Myeloid Leukemia
I page 13
experience some side effects. For some people with CML, the side effects of Gleevec
are significant and prevent them from taking this drug. In addition, some CML
patients develop disease that no longer responds to Gleevec, and therefore require
other therapies.
Sprycel and Tasigna. In 2010, the oral drug therapies dasatinib (SprycelВ®)
and nilotinib (TasignaВ®) were approved for newly diagnosed chronic phase CML
patients, based upon superior cytogenetic and molecular response rates compared
with response rates for Gleevec. Neither Sprycel nor Tasigna has been shown to result
in longer survival at this point in follow-up. However, findings from studies of each
drug show faster complete cytogenetic response (CCyR) and molecular response
(MR), which may prove to be associated with better long-term outcomes.
People being treated with Sprycel or Tasigna should note that it is important to
follow the instructions for taking these drugs, as these may differ from instructions
for Gleevec, which is typically taken with a meal once daily. Sprycel is taken once
daily, with or without food. Tasigna is taken twice daily on an empty stomach.
Table 1. Some Drugs Used to Treat Chronic Myeloid Leukemia (CML)
Approved for Newly Diagnosed Patients
{{Imatinib mesylate (GleevecВ®)
{{Dasatinib (SprycelВ®)*
{{Nilotinib (TasignaВ®)*
Other Treatments
{{Bosutinib†{{Ponatinib (AP24534)†{{Interferon alfa (Roferon®-A, Intron® A)
{{Pegylated interferon alfa
{{Hydroxyurea (HydreaВ®)
{{Cytarabine (Cytosar-UВ®)
{{Busulfan (MyleranВ®)
* Also used to treat patients who are intolerant of or resistant to Gleevec.
†Currently under study in clinical trials.
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.
page 14
I 800.955.4572 I
Side Effects of Gleevec. Gleevec therapy may bring about a variety of side
effects; for most people, these side effects can be managed without stopping
therapy. The more common Gleevec side effects include fluid retention (edema),
collection of fluid in the chest (pleural effusion), puffiness around the eyes, nausea
and vomiting, muscle cramps, diarrhea and rash. Some patients experience chronic
fatigue. Gleevec primarily affects three of the 90 human tyrosine kinases. In most
patients the principal effect of the drug is on the mutant Bcr-Abl tyrosine kinase
in CML cells. However, the possibility of effects on normal cells exists and may
account for these and other side effects. Side effects are medically manageable in
most cases, and the benefit of CML remission generally outweighs the risk of side
effects. There do not appear to be any troubling late-occurring side effects with
Gleevec, at least within the first 10 years of treatment (see Other Effects of Gleevec
on page 16).
Side Effects of Sprycel. Results of studies to date indicate that treatment with
Sprycel may lead to low white cell and platelet counts, collection of fluid in the
chest (pleural effusion), diarrhea, headache, fluid accumulation (edema), low
blood calcium levels and slight abnormalities in liver function test results.
In the head-to-head comparison with Gleevec, most side effects were reported
less commonly in patients treated with Sprycel. Sprycel may increase the risk of a
serious condition called “pulmonary arterial hypertension” (PAH). This side effect
appears to be rare, however.
Side Effects of Tasigna. Studies have revealed that Tasigna treatment is
associated with risk of low white cell and platelet counts; pancreatic enzyme
abnormalities and occasionally pancreatitis; low blood phosphorus levels;
abnormalities in liver enzymes, including increased bilirubin levels; hyperglycemia;
rash; nausea; headache; itching; tiredness; diarrhea; and constipation.
In the head-to-head comparison with Gleevec, most side effects were reported less
commonly in patients treated with Tasigna. Tasigna may be associated with an
increased risk of vascular events (disease relating to blood vessels), such as a rare
but serious condition called “peripheral arterial occlusive disease” (PAOD).
It is important for researchers to continue to evaluate the long-term safety of all
three approved TKIs. For more information about Gleevec, Sprycel or Tasigna’s
side effects, speak to your doctor and see the full prescribing information for
Gleevec, Sprycel and Tasigna.
Cardiac Effects. Uncommonly, patients treated with Gleevec, Sprycel and
Tasigna have developed severe congestive heart failure (a weakness of the heart
that leads to a buildup of fluid in the lungs and surrounding body tissues) and left
ventricular dysfunction (difficulty emptying blood from the left lower chamber
of the heart). To date, most of these patients had other health problems and
risk factors, including older age and previous medical history of cardiac disease.
A possible side effect of Tasigna that needs to be regularly monitored is a heart
rhythm condition called QT prolongation. Gleevec and Sprycel may occasionally
cause QT prolongation as well in some individuals. Some other medications are
Chronic Myeloid Leukemia
I page 15
also known to cause QT prolongation, and should be avoided whenever possible.
Your doctor will give you a list of medications to avoid, and will monitor you for
these conditions as needed.
Other Effects of Gleevec. A “late effect” of treatment is a medical problem
that does not show up or get noticed until years after treatment is initiated. A
potential late effect of Gleevec therapy is the loss of the mineral phosphorus from
bone. If such loss proves to be an actual concern, it could lead to osteoporosis.
Osteoporosis is a condition in which the normal balance of bone buildup and
breakdown (an ongoing process in the body) shifts slightly towards more bone
breakdown than bone buildup. Whether or not this late effect would occur is still
under study.
Animal models demonstrated cardiac effects, resulting in heart failure. However,
little risk, if any, of heart failure was noted after an extensive review of heart-related
complications in large databases of people with CML who were on Gleevec therapy.
Treatment for Gleevec-Intolerant or Gleevec-Resistant Patients. Over time,
some people initially treated with Gleevec will either
side effects that limit their ability to take the drug or require them to stop
Gleevec treatment (intolerance), or
achieve adequate response or lose their response to treatment with
Gleevec (resistance).
Fortunately, there are other approved therapies that help those with CML who are
Gleevec intolerant or Gleevec resistant. Doctors decide, with their patients, which
treatment is best after Gleevec, based on specific knowledge about the person’s
pattern of resistance and the potential side effects of each drug. In addition to
Gleevec, Sprycel is approved to treat adults in all phases of CML with resistance
or intolerance to prior therapy including Gleevec, and Tasigna is approved to treat
chronic and accelerated phases of CML in adults who are resistant to or intolerant
of prior therapy that included Gleevec. Like Gleevec, Sprycel and Tasigna work by
blocking the Bcr-Abl tyrosine kinase. However, these two drugs bind to the Bcr-Abl
tyrosine kinase more easily, making them effective for many patients whose disease
is resistant to Gleevec therapy.
More than 50 percent of Gleevec resistance is thought to result from the presence
of subtle mutations in the Bcr-Abl protein, which affects Gleevec’s ability to bind
to the protein and shut off its activity. Both Sprycel and Tasigna can be effective in
many of these resistance situations. Identifying the type of mutations a patient has
can help a doctor decide which drug to prescribe. This is the case because CML
patients with certain mutations may not respond to Sprycel, while patients with
other mutations may not respond to Tasigna. For instance, patients with Gleevecresistant mutations V299 and F317 are not likely to respond to Sprycel and should
be treated with Tasigna instead. Similarly, patients with Gleevec-resistant mutations
G250, Y253, E255 and F359 are not likely to respond to Tasigna and should be
treated with Sprycel. See Mutation Testing on page 18.
page 16
I 800.955.4572 I
Other CML Drug Therapies. There are specific Gleevec-resistant mutations that
predict the advantages of one drug over the other. However, a mutation called
T315I changes the Bcr-Abl enzyme in such a way that none of the approved
TKIs—Gleevec, Sprycel or Tasigna—are effective. A significant ongoing research
effort is under way to develop treatments to overcome the T315I mutation, and it
appears that there may soon be effective treatments for CML patients who develop
this mutation (see Clinical Trials on page 25).
Interferon, an injectable medication, and the oral medication hydroxyurea
(HydreaВ®) were used to treat people with CML prior to the availability of Gleevec.
These drugs are still options to treat people who are either intolerant of, or resistant
to, all of the approved TKIs. TKIs have a lower frequency of severe side effects than
optimal doses of interferon, especially when interferon is given to older patients.
This medication often cannot be tolerated and can induce flulike side effects: fever,
muscle aches and weakness. Some patients, such as those with prolonged fatigue
and weight loss, for example, may need a reduction in their dosage. Hair loss,
diarrhea, depression, ulceration of the lining of the mouth, cardiac effects and other
side effects occasionally occur. Interferon continues to be studied in combination
with TKIs and may offer some benefit; a small but finite proportion of patients
who had deep remissions on interferon 20 years ago remain free of CML despite
ceasing interferon after a few years. However, the side effects of interferon make its
use not practical for the majority of CML patients.
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.
Chronic Myeloid Leukemia
I page 17
Mutation Testing. Patients should talk to their doctor about ordering a mutation
test if there is
{{Failure to meet a treatment milestone
of hematologic or cytogenetic response despite taking an adequate dose of
Gleevec (at least 300 mg)
confirmed rise in quantitative PCR level by a factor of 5 to10
about the medication being effective (working).
A mutation test does not need to be done in a patient who is switching medication
as a result of side effects.
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
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 (GleevecВ®) is the primary treatment used
page 18
I 800.955.4572 I
for children diagnosed with CML. More than 80 percent of children with chronic
phase disease treated with Gleevec achieve complete cytogenetic remission.
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 SprycelВ® or TasignaВ®. 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
for women to stop treatment during preconception and pregnancy
of relapse if therapy is stopped based on the depth and duration of response
for fetal effects from Gleevec (probably greatest during the first trimester)
for women on Gleevec to refrain from breast-feeding
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.
Chronic Myeloid Leukemia
I page 19
Data are limited on men who father children while taking Gleevec, but to date do
not reveal any obvious causes for concern. Nonetheless, Gleevec cannot be presumed
safe in this setting.
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 BCRABL 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.
page 20
I 800.955.4572 I
Measuring Treatment Response
Measuring the response to therapy with blood and bone marrow testing is a
critically important part of treatment for people with CML. In general terms, the
greater the response to drug therapy, the longer the disease will be controlled. Other
factors that affect a person’s response to treatment include the stage of the disease
and the features of the individual’s CML at the time of diagnosis.
Nearly all people with chronic phase CML have a “complete hematologic response”
with Gleevec therapy; most of these people will eventually achieve a “complete
cytogenetic response.” Patients who have a complete cytogenetic response often
continue to have a deeper response and achieve a “major molecular response.”
Additionally, a growing proportion of patients achieve a “complete molecular
response.” (For an explanation of these terms, see Table 2 on page 22.)
People who are taking Gleevec can feel confident and be encouraged to continue
therapy based on the safety data from more than 10 years of clinical trials. Sprycel
and Tasigna are also FDA approved following results on safety and effectiveness
from carefully controlled clinical trials. Longer-term safety data have been reported
for Sprycel (since 2006) and Tasigna (since 2009) in patients with Gleevec
resistance or intolerance. In addition, for all three therapies the ongoing, careful
watch for long-term or late effects is reassuring thus far.
Treatment for CML has changed since 2001 with the introduction of oral
therapies. It is important for patients to continue taking their medication to get
the best response. Unless they are following their doctor’s instructions, stopping
medication or taking less than the amount prescribed can impact the effectiveness
of the medication and may result in a loss of response.
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.
Table 2. Chronic Myeloid Leukemia (CML) Treatment Responses
Complete hematologic response (CHR)
Immature CML cells are eliminated from detection in the blood, the
white cell count is no longer elevated, the platelet count is at or near
normal values (no longer elevated) and spleen enlargement is resolved.
Overall, the number of CML cells is usually decreased to one-tenth of the
level at the start of treatment.
Complete cytogenetic response (CCyR)
There are no CML cells (measured numbers of cells with the Philadelphia
chromosome and the BCR-ABL cancer gene) in the blood or marrow
that can be detected by FISH testing. The number of CML cells is now
estimated at less than 1/100 of the level at the start of treatment.
Major molecular response (MMR)
Quantitative PCR testing reveals a “3-log” or greater reduction in BCR-ABL
RNA or DNA in the blood or marrow. A 3-log reduction is a 1/1,000 or
1,000-fold reduction of the level at the start of treatment.
Complete molecular response (CMR)
Quantitative PCR testing reveals no evidence of the BCR-ABL RNA
or DNA in the blood or marrow. This is generally considered to be a
reduction in leukemia burden to 1/10,000 or less below the level at the
start of treatment.
Table 2.
page 22
This table describes the range of responses to CML treatment.
I 800.955.4572 I
For people who experience a loss of response to Gleevec or who do not achieve
the expected response within a given period of time (see Table 3), options include
increasing the dose of Gleevec, switching to another approved TKI or participating
in a clinical trial.
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
Time Frame Response(s)
After 3 to 6 months of therapy
Complete hematologic response and
After 6 to 12 months of therapy
Cytogenetic response defined as a
After 12 to 18 months of therapy
Complete cytogenetic response and
some cytogenetic improvement
two-thirds reduction in the number
of Philadelphia chromosomes in
the marrow
partial molecular response
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.
Chronic Myeloid Leukemia
I page 23
Stem Cell Transplantation
Allogeneic Stem Cell Transplantation. Allogeneic stem cell transplantation
(infusion of donor stem cells into a patient) is the best-documented curative
treatment for CML at this time. The transplant patient receives drug therapy first
to induce a remission or, in advanced phase cases, a return to chronic phase CML
before having high-dose conditioning chemotherapy and then the transplant. This
approach increases the likelihood of successful remission after transplantation,
assuming that drug treatment side effects are minimal.
Allogeneic stem cell transplantation requires an HLA-matched donor (related or
unrelated) and is most successful in younger patients. Whether or not a patient is a
candidate for transplantation is determined by medical indications and availability
of donor. There is no specific age cut off for stem cell transplantation.
The decision to pursue allogeneic transplantation has become more difficult as
a result of the large proportion of patients who have a very good and durable
response to the TKIs. On the one hand, transplantation has a proven curative track
record for CML patients. On the other hand, the TKIs may be able to control
the disease for very long periods and preserve quality of life to a greater extent
than transplantation. Thus, several factors, including the patient’s age, the genetic
compatibility of the prospective donor and the degree of the patient’s response
to oral drug therapy, will be weighed by people with CML and their doctors to
determine if and when to use transplantation.
Donor Lymphocyte Infusion (DLI). About 70 percent or more of those who
undergo allogeneic stem cell transplantation are cured of their CML. A person who
had a transplant and has relapsed may be given an infusion of lymphocytes from
the original stem cell donor. This may induce a more intense immune reaction
against the recipient’s CML cells. DLI has been used effectively in patients with
CML who relapse after transplantation. One potential side effect from this therapy
is “graft-versus-host disease.” In this scenario, the infused (donor) immune cells also
recognize tissue-type determinants on other tissues in the patient’s body and may
attack them, a consequence that can be disabling. However, most patients derive a
net benefit from such an infusion.
Autologous Stem Cell Transplantation. Autologous stem cell transplantation
(in which a person’s own marrow or blood is the source of the stem cells) is rarely if
ever used to treat people with CML, given the effectiveness of Gleevec and secondgeneration TKIs, the availability of other therapy options and the limited benefit of
this method as concluded from long-standing studies.
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.
page 24
I 800.955.4572 I
Clinical Trials
New approaches under study in clinical trials for CML treatment, many of which
are being supported by LLS research programs, hold the promise of increasing the
rate of remission and finding a cure for CML.
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
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.
CML Drugs in Development. Several drugs are in active development, including
(AP24534). Ponatinib, which is in clinical development, is an
oral CML drug that has promising clinical activity against a large number of
mutations that cause resistance to Gleevec, Sprycel and Tasigna, most notably
the T315I mutation, which is one of the more common mutations seen when
a response to imatinib mesylate (GleevecВ®), Sprycel or Tasigna is lacking or lost.
Ponatinib appears to be generally well tolerated; common side effects include
fatigue, constipation, rash, headache, joint pain and nausea.
Bosutinib, an oral CML drug, is a TKI that is active against a
number of Gleevec-resistant mutations, but not the T315I mutation. This drug
has undergone clinical-trial evaluation in patients who have already been treated
with one or more TKIs, as well as in newly diagnosed chronic phase CML
patients. If approved, this drug may be an option for patients who are unable to
tolerate or respond adequately to Gleevec, Sprycel or Tasigna.
Disease Eradication Strategies. A number of laboratory studies have identified
potential treatments that may help eradicate the few remaining CML cells in most
patients treated with TKIs, and thus hopefully cure patients so that they may
discontinue medical therapies altogether. One such area of interest involves inhibitors
of a protein called “smoothened” (SMO) in combination with Bcr-Abl TKIs. As
Chronic Myeloid Leukemia
I page 25
with all clinical advances, the participation of patients in clinical trials is crucial
to determining whether such strategies are of clinical promise. Given that chronic
phase CML is generally a slowly progressive disease even in the absence of effective
therapy, it will likely be many years before it is known whether strategies aimed at
disease eradication truly achieve disease cure.
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.
Modified Stem Cell Transplantation. A modified form of allogeneic
transplantation called “reduced-intensity” or “nonmyeloablative” allogeneic stem
cell transplantation may be an option for CML 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 patient’s CML cells (a result called “graft-versus-tumor effect”). The
theory being tested with a reduced-intensity transplant is that by undergoing
less-toxic procedures prior to the transplant, the body is better able to withstand
the transplant. However, full donor engraftment would still take place, and the
desired graft-versus-tumor effect would still occur.
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-versushost 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-versushost 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.
page 26
I 800.955.4572 I
CML-Related Disorders
There are other types of myeloid leukemia that have a chronic course. Chronic
myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML)
and chronic neutrophilic leukemia (CNL) have some of the signs and symptoms
of CML. These diseases are less common “myeloproliferative neoplasms” that are
distinct subtypes of myeloid leukemia and, like CML, progress more slowly than
acute myeloid leukemia. People with these diseases do not have the BCR-ABL gene;
the absence of the BCR-ABL gene is one of several distinguishing features used to
make the correct diagnosis.
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.
See the free LLS publication Chronic Myelomonocytic Leukemia (CMML)
and Juvenile Myelomonocytic Leukemia (JMML) for more information about
these diseases.
Chronic Myeloid Leukemia
I page 27
Normal Blood and Marrow
Blood is composed of plasma and cells suspended in plasma. Plasma is largely made
up of water in which many chemicals are dissolved. These chemicals include
the most common protein in blood
proteins, made by the liver
a protein made by the kidneys that stimulates red cell
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)
(such as thyroid hormone and cortisol)
(such as iron and magnesium)
(such as folate and vitamin B12)
(such as calcium, potassium and sodium).
The cells suspended in plasma include red cells, platelets and white cells
(neutrophils, monocytes, eosinophils, basophils and lymphocytes).
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.
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.
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.
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.
page 28
I 800.955.4572 I
Blood Cell & Lymphocyte Development
Stem Cells
Hematopoietic Cells
Lymphoid Cells
Differentiate & mature into
six types of blood cells
Differentiate & mature into
three types of lymphocytes
Red Cells
Figure 6.
T Lymphocytes
B Lymphocytes
Natural Killer Cells
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.
Chronic Myeloid Leukemia
I page 29
Medical Terms
ABL. The human proto-oncogene located on chromosome 9 that is mutated by
the translocation of a piece of chromosome 9 to chromosome 22. The mutation of
this gene causes chronic myeloid leukemia and some cases of acute lymphoblastic
leukemia. The designation for the gene derives from the name of the scientist,
Herbert Abelson, MD, who discovered the gene while studying cancer-causing viruses
in mice.
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 blood cancer and to “turn off” the patient’s immune system so
that the donor stem cells will not be rejected. A type of allogeneic transplant called
“nonmyeloablative” or “reduced-intensity” is under study. It uses lower doses of
conditioning therapy and may be safer, especially for older patients. Allogeneic stem
cell transplantation is the only available treatment known to cure chronic myeloid
leukemia. For more information, see the free LLS publication Blood and Marrow
Stem Cell Transplantation.
Anemia. A decrease in the number of red cells and, therefore, the hemoglobin
concentration of 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 the specific foreign substances called “antigens.” Antibodies
coat, mark for destruction or inactivate foreign particles, such as bacteria, viruses
or harmful toxins. Antibodies can also be made in the laboratory in two ways. In
the first method, material from one species is injected into a different species; the
receiving species recognizes the material as foreign and makes 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 so as to become
useful in antibody-mediated immunotherapy.
Antigen. A foreign substance, usually a protein, that stimulates an immune
response when it is ingested, inhaled or comes into contact with the skin or mucous
membranes. Examples of antigens are bacteria, viruses and allergens. Antigens
stimulate plasma cells to produce antibodies.
Antioncogene. See Tumor Suppressor Gene.
Apheresis. The process of removing certain components of a donor’s blood
and returning the unneeded parts to the donor. The process, also called
page 30
I 800.955.4572 I
“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 and stored for later use in 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
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 CML. For more information about all types
of stem cell transplantation, see the free LLS publication Blood and Marrow Stem
Cell Transplantation.
Autosomes. See Karyotype.
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.
Bcr-Abl Tyrosine Kinase Inhibitor. See Tyrosine Kinase Inhibitor.
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.
Chronic Myeloid Leukemia
I page 31
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.
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.
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, GroshongВ®,
HickmanВ®, and BroviacВ®) 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.
page 32
I 800.955.4572 I
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
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.
Colony-Stimulating Factor. See Growth Factor.
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.”
Differentiation. See Hematopoiesis.
Donor Lymphocyte Infusion (DLI). A therapy that involves giving lymphocytes
from the original stem cell donor to a patient who has had an allogeneic bone
marrow transplant followed by a relapse of disease. DLI may induce an immune
reaction against the patient’s cancer cells. This therapy has been most effective in
patients with chronic myeloid leukemia who relapse after transplantation, but it is
being studied as treatment for patients with myelodysplastic syndromes and other
blood cancers.
Eosinophil. A type of white cell that participates in allergic reactions and helps
fight certain parasitic infections.
Chronic Myeloid Leukemia
I page 33
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 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.
Genome. See Chromosome.
Germ Cell Mutation. See Mutation.
Graft-Versus-Host Disease. 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 the T lymphocytes present
in the donor’s blood or marrow, the source of the stem cells. The principal sites of
injury to the patient 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 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. See HLA.
Graft-Versus-Tumor Effect (Graft-Versus-Leukemia Effect). The potential
immune reaction by which transplanted (donor) T lymphocytes recognize and
attack the malignant cells of the recipient (host). 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
(GVHD) was; and 3) the removal of donor T lymphocytes decreased the incidence
page 34
I 800.955.4572 I
of 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 T lymphocytes
against recipient tumor cells that, along with the intensive conditioning treatment,
serves 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.
See HLA.
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.
Granulocytic Sarcoma. A local tumor composed of leukemic myeloblasts and,
sometimes, related myeloid cells. These tumors are found outside the marrow and
may occur beneath the skin or in many other sites. They may be the first evidence
of leukemia or may occur after the disease has been diagnosed.
Granulocytosis. An increase above normal of the concentration of blood
leukocytes (white cells)—specifically, granulocytes (neutrophils, eosinophils and
basophils). This designation excludes lymphocytes and monocytes.
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.
GVHD. See Graft-Versus-Host Disease.
Hasford Scoring System. A prognostic scoring system that estimates survival of
patients with chronic myeloid leukemia who are treated with interferon alfa. This
system designates a patient as low-risk, intermediate-risk or high-risk and is based
on diagnosis markers of spleen size, platelet count, age and blast count as well as
eosinophils and basophils in the peripheral blood. The Hasford scoring system may
be less predictive in the imatinib mesylate (GleevecВ®) era; however, it does predict
the probability of achieving a response to tyrosine kinase inhibitors.
Hemapheresis. See Apheresis.
Hematocrit. The volume percentage of red cells in whole blood.
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
Hematopathologist. See Pathologist.
Hematopoiesis. The process of blood cell development in the bone marrow.
The most undeveloped cells in the marrow are stem cells. They start the process of
Chronic Myeloid Leukemia
I page 35
blood cell development. The stem cells begin to develop into young or immature
blood cells such as red cells or white cells of various types. 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 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.
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”).
Hyperleukocytosis. An extremely elevated white cell count found in some
patients at the time they are diagnosed with leukemia. This circumstance occurs
most frequently in patients with chronic myeloid leukemia. If the condition
is severe enough, blood flow may be impaired by the very high concentration
of leukocytes. Urgent treatment with apheresis and chemotherapy is usually
administered if symptoms are severe.
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.
Immunotherapy. Any of several treatment approaches that harness the body’s
immune system to treat diseases. These therapies include monoclonal antibody
therapy, radioimmunotherapy and vaccine therapy. Monoclonal antibodies are
proteins made in the laboratory that either react with or attach to antigens on
the target cells. The antibodies are used therapeutically in three ways: as “naked”
page 36
I 800.955.4572 I
antibodies (monoclonal antibodies), as antibodies to which radioactive isotopes are
attached (radioimmunotherapy), and as antibodies to which toxins are attached
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.
Leukocyte Alkaline Phosphate (LAP). A neutrophil enzyme that is markedly
decreased in its activity in patients with chronic myeloid leukemia (CML). It was
formerly used to distinguish the increase in the white cell count in CML from other
causes of increased white cell counts. The test has been replaced by measurement of
the BCR gene rearrangement, a more specific alteration present in virtually all patients
with CML.
Leukocytes. See White Cells.
Leukocytosis. An increase above the upper limit of normal in the concentration
of blood leukocytes (white cells).
Leukopenia. A decrease below normal in the concentration of blood leukocytes
(white cells).
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
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.
Macrophage. See Monocyte/Macrophage.
Magnetic Resonance Imaging (MRI). A testing procedure that provides detailed
images of body structures. It differs from a CT scan in that the patient is not
exposed to x-rays. Signals generated in the tissues in response to a magnetic field
Chronic Myeloid Leukemia
I page 37
produced by a specialized instrument are converted by a computer into images of
body structures. Thus, the size, or a change in size, of organs such as the lymph
nodes, liver and spleen or of tumor masses can be measured.
Maturation. See Hematopoiesis.
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.
Molecular Targeted Therapy. See Tyrosine Kinase Inhibitor.
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. A characteristic of cells that makes them resistant to
the effects of several different classes of drugs. This resistance can be traced to the
expression of genes that direct the formation of high amounts of the 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 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.
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
page 38
I 800.955.4572 I
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 Stem Cell Transplantation. See Allogeneic Stem Cell
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.
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 CML. 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.
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.
Chronic Myeloid Leukemia
I page 39
Philadelphia Chromosome (Ph Chromosome). An abnormality of
chromosome 22 found in the marrow and blood cells of patients with chronic
myeloid leukemia and of some patients with acute lymphoblastic leukemia. The
abnormality, a shortening of the long arm of this chromosome, was first observed
and reported by doctors at the University of Pennsylvania in Philadelphia; thus
the name “Philadelphia chromosome.” Since this discovery, the lost piece of
chromosome 22 has been shown to stick (translocate) to chromosome 9 in most
cases. Indeed, some of chromosome 9 also sticks (translocates) to chromosome
22. This circumstance is referred to as a “balanced translocation,” because virtually
equal lengths of partial chromosome arms exchange position. Because chromosome
22 is a very short chromosome and chromosome 9 a very long one, the lengthening
of chromosome 9 was less apparent than the shortening of 22 until more sensitive
detection techniques became available. The abnormality of chromosome 22 is now
usually abbreviated as “Ph chromosome.”
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. For more information, see the free LLS
publication Blood Transfusion.
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, such as 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
page 40
I 800.955.4572 I
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.
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. See Allogeneic Stem Cell
Refractory Disease. See Resistance to Treatment.
Relapse/Recurrence. A return of the disease after it has been in remission
following therapy.
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.
Salvage Therapy. Treatment for a person who has cancer that has not responded
to other primary treatments.
Scavenger Cell. See Monocyte/Macrophage.
Sokal Scoring System. A frequently used prognostic scoring system, done at
diagnosis, that estimates survival of patients with chronic myeloid leukemia. The
system was originally developed when patients were treated with chemotherapy.
This system identifies a patient as low-risk, intermediate-risk or high-risk based on
diagnosis markers of the spleen size, platelet count, age and blast count. The Sokal
system predicts the probability of achieving a response to tyrosine kinase inhibitors.
In studies, a patient with a low-risk Sokal score had a higher incidence of complete
cytogenetic remission compared to a high-risk patient. See Measuring Treatment
Response on page 21.
Somatic Mutation. See Mutation.
Chronic Myeloid Leukemia
I page 41
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. 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.
Thrombocyte. A synonym for “platelet.”
Thrombocythemia. An increase above normal in the concentration of platelets in
the blood.
Thrombocytopenia. A decrease below normal in the concentration of platelets in
the blood.
Translocation. An abnormality of chromosomes in 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 takes place, 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.
Tumor Suppressor Gene. A gene that acts to prevent cell growth. If a mutation
occurs in this gene that “turns off” the gene and causes loss of function, it may
make the individual more susceptible to the development of cancer in the tissue
in which the mutation occurred. Another term for tumor suppressor gene is
Tyrosine Kinase. A type of enzyme that plays a key role in cell function. It is
normally present in cells, and a normal gene, ABL on chromosome 9, directs
its production. In chronic myeloid leukemia, an alteration in the DNA results
in a mutant fusion gene, BCR-ABL, which produces an abnormal or mutant
tyrosine kinase. This abnormal enzyme leads to a cascade of effects in the cell that
transforms it into a leukemic cell.
page 42
I 800.955.4572 I
Tyrosine Kinase Inhibitor (TKI). A type of drug, the most noteworthy of which is
imatinib mesylate (GleevecВ®), that blocks the effects of the mutant Bcr-Abl tyrosine
kinase found in chronic myeloid leukemia. This specific approach to cancer therapy
is referred to as “molecular-targeted therapy” since the drug is designed to block the
effect of a specific protein that is the essential cause of the leukemic transformation.
Dasatinib (SprycelВ®) and nilotinib (TasignaВ®) are second-generation TKIs being
used now as initial treatment or after therapy when patients prove resistant to or
cannot tolerate Gleevec.
White Cells. Any of the five major types of colorless, infection-fighting cells in the
blood: neutrophils, eosinophils, basophils, monocytes and lymphocytes. White cells
are also called “leukocytes.”
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 to see helpful books on a
wide range of topics.
Apperley J. CML in pregnancy and childhood. Best Practice and Research Clinical
Haematology. 2009;22(3):455-474.
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.
Howlader N, Noone AM, Krapcho M, et al. (eds). SEER Cancer Statistics Review,
1975-2008, National Cancer Institute. Bethesda, MD,
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.
Chronic Myeloid Leukemia
I page 43
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, RГ©a D, Guilhot J, et al. Discontinuation of imatinib in patients with
chronic myeloid leukaemia who have maintained complete molecular remission for
at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial.
Lancet Oncology. 2010;11(11):1029-1035. Epub 2010 Oct 20.
National Comprehensive Cancer Network. Practice Guidelines in
Oncology—v.2.2012. Chronic myelogenous leukemia.
professionals/physician_gls/f_guidelines.asp. Accessed January 20, 2012.
Porter DL. CML: Updates from the American Society of Hematology (ASHВ®)
Annual Meeting. Teleconference of The Leukemia & Lymphoma Society, Past
Patient Education Programs, Leukemia. January 26, 2012.
The Leukemia & Lymphoma Society’s
Light The Night Walk
Taking Steps to
Cure Cancer
page 44
I 800.955.4572 I
The Leukemia & Lymphoma
Society’s (LLS) Information
Specialists provide patients,
families and healthcare
professionals with the latest
information on leukemia,
lymphoma and myeloma.
Our team consists of master’s
level oncology professionals who
are available by phone Monday
through Friday, 9 am to 6 pm (ET).
Co-Pay Assistance
LLS’s Co-Pay Assistance Program
helps blood cancer patients cover
the costs of private and public
health insurance premiums,
including Medicare and Medicaid,
and co-pay obligations. Support
for this program is based on the
availability of funds by disease.
For more information,
call 877.557.2672 or
For a complete directory of our patient services programs, contact us at
800.955.4572 or
(Callers may request a language interpreter.)
For more information, please contact:
National Office
1311 Mamaroneck Avenue, Suite 310, White Plains, NY 10605
Contact our Information Specialists 800.955.4572 (Language interpreters available upon request)
Our Mission:
Cure leukemia, lymphoma, Hodgkin’s disease and myeloma, and improve the
quality of life of patients and their families.
LLS is a nonprofit organization that relies on the generosity of individual,
foundation and corporate contributions to advance its mission.
PS31 35M 5/12