PS31 - CML Booklet - 2019
PS31 - CML Booklet - 2019
PS31 - CML Booklet - 2019
Chronic Myeloid
Leukemia
Revised 2019
Stay strong and keep moving forward. Find the positive in every day.
Be your own best patient advocate. Changed my life for the better.
Accept, learn and focus on present. Learning to live a different life.
Sudden and life changing—be positive. Waiting, worrying, anxiousness/
happy I’m alive! Embrace a new normal each day. 5 years, 41 infusions,
constant fatigue. Patience, positive attitude, hope and faith. Test to test,
I will survive! Treatment, fatigue, treatment, fatigue and survival.
Love life, live better every day. I don’t look back only forward. So far,
so good, live life. Meditation, mindfulness, wellness, faith, nutrition
and optimism. Finding the joy while living with uncertainty. Watch, wait,
treat, regroup, rest, re-energize. Blessed to be doing so well! Eye opening
needed learning and healing. Feel great: uncertain travel plans annoying.
Renewed faith, meditation, diet, mindfulness, gratitude. Watchful waiting
can be watchful worrying. Scary, expensive, grateful, blessings, hope,
faith. Thank god for stem cell transplants! Do not know what to expect.
Extraordinarily grateful, I love my life. Diagnosed; frightened; tested;
treating; waiting; hoping. I’m more generous, impatient less often.
Embrace your treatment day after day. Live today, accept tomorrow, forget
yesterday. Strength you never realized you had. Challenging to our hearts
and minds. Life is what we make it. Live life in a beautiful way.
Acknowledgements
The Leukemia & Lymphoma Society appreciates the review of this material by
Michael E. Rytting, MD
Professor, Department of Pediatrics Patient Care,
Division of Pediatrics,
The Children’s Cancer Hospital at The University of Texas MD Anderson Cancer Center,
Leukemia/Lymphoma Section,
Houston, TX
New treatments may have been approved since this book was printed.
Check www.LLS.org/DrugUpdates or call (800) 955-4572.
This publication is designed to provide accurate and authoritative information. 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.
Introduction
Chronic myeloid leukemia (CML), also known as chronic myelogenous leukemia,
is a type of cancer that starts in the blood-forming cells of the bone marrow and
invades the blood.
Approximately 8,990 new cases of CML are expected to be diagnosed in 2019.
As of 2015, the latest year for which statistics are available, an estimated 50,948
people are either living with or in remission from CML.1 See Incidence, Causes
and Risk Factors on page 40.
Since the introduction of tyrosine kinase inhibitor (TKI) therapy in 2001, CML
has been transformed from a life-threatening disease to a manageable chronic
condition for most patients. People with CML are living longer and experiencing
fewer treatment side effects, and the possibility of discontinuing treatment is now
feasible for select patients in remission who meet specific criteria.
The more you know about your disease, the better you can take care of yourself—
your mind, your body and your health. This booklet provides information about
CML, defines complicated terms, provides information about normal blood and
bone marrow, explains tests and treatments for CML and lists new research
options and clinical trials.
We trust that the information in this booklet will provide you with a good working
knowledge of CML, or that it will reinforce what you already know. We hope you
keep this booklet handy. Should you ever feel alone in confronting problems, we
hope you will turn to it for information, guidance and assistance in locating the
support and resources that you need.
We are here to help.
1
Source: Facts 2018-2019. The Leukemia and Lymphoma Society. April 2019.
Leukemia
Leukemia is a cancer that starts in the blood-forming cells in the bone marrow.
Bone marrow is the sponge-like tissue in the center of most bones. It produces
red blood cells, white blood cells and platelets. In leukemia, cancerous blood cells
form and crowd out healthy blood cells in the bone marrow. The four major types
of leukemia are
{{Acute myeloid leukemia (AML)
{{Chronic myeloid leukemia (CML)
{{Acute lymphoblastic leukemia (ALL)
{{Chronic lymphocytic leukemia (CLL).
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Leukemia is classified as either “acute” or “chronic.” These two terms describe
how quickly the disease progresses in the absence of treatment. Acute forms of
leukemia progress rapidly and produce cells that are not fully developed. These
immature cells cannot perform their normal functions. Chronic forms of leukemia
usually progress slowly, and patients have greater numbers of mature cells. In
general, these more mature cells can carry out some or all of their normal functions.
See Normal Blood and Bone Marrow on page 41.
Leukemia is further classified by the type of white blood cell, either “myeloid”
or “lymphoid,” that becomes cancerous. The name of each of the four types of
leukemia describes whether the disease progresses quickly (acute) or slowly
(chronic) and identifies the type of white blood cell that is involved (myeloid
or lymphoid).
What Is CML?
Chronic myeloid leukemia (CML) is a type of leukemia that progresses slowly
(is chronic) and involves the myeloid white blood cells in the bone marrow. It is
known by several other names, including
{{Chronic myelogenous leukemia
{{Chronic granulocytic leukemia
{{Chronic myelocytic leukemia
CML is classified by the World Health Organization (WHO) as a “myeloproliferative
neoplasm.” This is a type of disease in which the bone marrow makes too many
white blood cells. As the number of extra cells build up in the blood and/or
bone marrow, this disease usually gets worse slowly over time. This increased
accumulation of cells may eventually cause anemia, fatigue, bleeding and other
problems.
Visit www.LLS.org/booklets to reach the free LLS booklet The CML Guide:
Information for Patients and Caregivers.
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More than 95 percent of CML patients have the Philadelphia chromosome.
This is called Ph+ CML. However, a very small number of CML patients have the
BCR-ABL1 gene but no detectable Philadelphia chromosome. This is called
Ph negative (Ph–) CML. Patients with CML who have the BCR-ABL1 gene
rearrangement but are Ph- have the same prognosis (likely outcome) as
Ph+ patients.
Some patients have a type of leukemia in which too many granulocytes are made
in the bone marrow. However, these patients are Ph— and do not have the
BCR-ABL1 gene. They may be diagnosed as having “atypical CML.” This means
there may be other, unknown oncogenes that caused the disease in these
patients. These patients generally have poorer responses to treatment and
shorter survival times.
Figure 1. Shown here is the set of chromosomes from a marrow cell of a female patient with CML. The higher
the chromosome number, the smaller the chromosome. The arrow in the fourth row indicates the shortened
arm of chromosome 22 (the Ph chromosome), characteristic of the leukemic marrow cells of patients with CML.
The arrow in the second row indicates chromosome 9, which is elongated. These two changes reflect the
translocation of chromosome material between chromosomes 9 and 22.
This figure kindly provided by Nancy Wang, PhD, University of Rochester Medical Center, Rochester, NY.
9 22 9 22 BCR-ABL1
oncogene
Piece of 9
BCR
Philadelphia
chromosome
ABL1
Piece of 22
Figure 2.
{{Fatigue
{{Bone pain
{{Unexplained weight loss
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{{Pain or a feeling of fullness below the ribs on the left side, due to an
enlarged spleen
{{Night sweats
Many of the signs and symptoms occur because the CML cells crowd out the
bone marrow’s healthy red blood cells, white blood cells and platelets.
Anemia is a shortage of red blood cells that can cause weakness, fatigue and
shortness of breath. A shortage of normal white blood cells can increase the risk
of infection in CML patients and a shortage of platelets can lead to excessive
bruising or bleeding. Symptoms may also occur because CML cells collect in
organs such as the spleen.
Diagnosis
Many people with CML do not have symptoms when diagnosed. The most common
sign of CML is an abnormal white blood cell count, often found during blood tests for
an unrelated health problem or during a routine checkup.
To diagnose CML, doctors use a variety of tests to analyze blood and bone
marrow cells. A pathologist—a doctor who specializes in identifying diseases by
studying cells under a microscope—will examine the blood cells and the bone
marrow cells. The samples should also be examined by a hematopathologist, a
specialist who diagnoses diseases of the blood and marrow.
The following are some of the tests done to diagnose CML.
Complete Blood Count (CBC) with Differential. This test is used to measure the
number of red blood cells, white blood cells and platelets in a sample of blood.
It also measures the amount of hemoglobin (a protein in red blood cells that
carries oxygen) in the red blood cells and the percentage of red blood cells in the
sample. The CBC should include a differential, which measures the different types
of white blood cells in the sample. People with CML often have
{{An increased white blood cell count, often very high levels
{{A decreased red blood cell count
{{The possibility of increased or decreased platelet counts depending on the
severity of the disease
Peripheral Blood Smear. In this test, blood cell samples are stained (dyed) and
examined with an optical microscope. These samples show
{{The number, size, shape and type of blood cells
{{The specific pattern of white blood cells
Bone Marrow Aspiration and Biopsy. These tests are used to examine bone
marrow cells to find abnormalities and are generally done at the same time. In
both cases, after medicine has been given to numb the skin, a needle is inserted
into the patient’s hip bone. For a bone marrow aspiration, the needle is inserted
into the bone marrow to remove a liquid sample of cells. For a bone marrow
biopsy, the needle removes a small sample of bone that contains marrow. Both
samples are examined under a microscope to look for chromosomal and other
cell changes.
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Figure 3. Identifying the BCR-ABL1 Gene Using FISH
Normal Abnormal
Figure 3. Fluorescence in situ hybridization, or FISH, is a testing method that uses fluorescent molecules to
mark the BCR-ABL1 gene in CML. In normal cells, two red and two green signals indicate the location of the
normal ABL1 and BCR genes, respectively. In abnormal cells, the fusion of BCR and ABL1 is visualized through
the fusion of the red and green signals. It is frequently detected as a yellow fluorescence (indicated above
by arrows).
Quantitative Polymerase Chain Reaction (qPCR). The qPCR test is the most
sensitive test that detects and measures the quantity of the BCR-ABL1 gene in
blood or bone marrow samples. It can detect very small amounts of the
BCR-ABL1 gene (even when the Ph chromosome cannot be detected in blood
or bone marrow cells with cytogenetic testing), to a level of one CML cell among
100,000 to 1,000,000 normal cells.
Blood cell counts, bone marrow examinations, FISH and qPCR may also be used
to monitor a person’s response to therapy once treatment has begun. A qPCR test
is recommended every 3 months initially. Even for patients with relatively deep
remissions lasting at least 2 years, the test should continue to be done every
3 to 6 months.
Visit www.LLS.org/booklets to reach the free LLS booklet Understanding Lab
and Imaging Tests.
Chronic Phase. Most patients are diagnosed with CML in the chronic phase of the
disease. People with chronic phase CML
{{May or may not have symptoms
{{Have an increased number of white blood cells
{{Usually respond well to standard treatment
Specifically,
{{ symptoms go away, white blood cell counts return to normal
levels, hemoglobin concentration improves and the spleen reduces in size.
If untreated, chronic phase CML will eventually progress to accelerated phase
and/or blast phase CML.
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Blast Phase (Also Called “Blast Crisis Phase”). The blast phase looks and
behaves like the acute form of myeloid leukemia.
People who have blast phase CML may have
{{Anemia
Fatigue
{{
Shortness
{{ of breath
Abdominal
{{ pain
Bone
{{ pain
Enlarged
{{ spleen
Poor
{{ appetite and weight loss
Bleeding
{{
Infections
{{
Prognostic Factors. There are other factors in addition to the phase of CML that
affect treatment decisions and predict a patient’s prognosis (likely outcome).
These are known as prognostic factors. The following are prognostic factors
for patients with CML at the time of diagnosis and also indicate when the likely
outcome is less favorable:
{{Phase of CML—Patients who have accelerated or blast phase CML have a less
favorable prognosis than those who have chronic phase CML.
{{Age—Patients age 60 years and older have a less favorable prognosis.
{{Spleen size—Patients with an enlarged spleen have a less favorable prognosis.
{{Plateletcount—Patients who have very high or very low platelet counts at
diagnosis have a less favorable prognosis.
{{Blasts in the blood—Patients who have a high number of blasts in the blood
have a less favorable prognosis.
{{Increased numbers of basophils and eosinophils in the blood—Patients with
increased numbers of these types of white blood cells have a less favorable
prognosis.
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A generic drug is a medication created to be the same as an already marketed
brand-name drug in terms of dosage form, safety, strength, route of administration,
quality, performance characteristics and intended use. These similarities help to
demonstrate bioequivalence, which means that a generic medicine works in the
same way and provides the same clinical benefit as its brand-name version. In
other words, you can take a generic medicine as an equal substitute for its
brand-name counterpart. The US Food and Drug Administration (FDA) employs
strict standards to ensure that generic drugs are bioequivalent to brand name
drugs in the US.
The approach for treating each patient and the choice of treatment is based on
the phase of CML at diagnosis, risk scores, age and the patient’s other health
issues. For a list of drugs used to treat CML, see Table 1 on page 22.
Lowering High White Blood Cell Counts. Some patients have very high white
blood cell (WBC) counts at the time of diagnosis. These elevated WBC counts can
sometimes impair blood flow to the brain, lungs, eyes and other sites, and also
cause damage in small blood vessels.
Hydroxyurea (Hydrea®) is sometimes given to lower very high WBC counts
rapidly, until a suspected CML diagnosis can be confirmed through blood and
bone marrow tests. Hydroxyurea is taken as a capsule by mouth. Hydroxyurea
can help reduce the size of the spleen. Once a diagnosis of CML is confirmed,
doctors usually start TKI therapy and discontinue hydroxyurea.
Leukapheresis is a procedure that uses a machine similar to a dialysis machine
to remove white blood cells from the circulating blood. Leukapheresis is used to
lower WBC counts in female patients diagnosed with chronic phase CML during
the first months of pregnancy, when other treatments may be harmful to fetal
development, or to immediately reduce a dangerously high WBC count. For more
information about fertility and pregnancy, see page 35.
Tyrosine Kinase Inhibitor Therapy. Tyrosine kinase inhibitors (TKIs) are a type
of targeted therapy taken orally as pills. Targeted therapies identify and attack
specific types of cancer cells while causing less damage to normal cells than
conventional treatments. In CML, TKIs target the abnormal BCR-ABL1 protein that
causes uncontrolled CML cell growth and block this abnormal protein’s ability to
function, causing the CML cells to die.
The first therapy given for a disease is called “initial” treatment. Four TKI drugs are
approved as initial therapy (first-line treatment) for chronic phase CML:
{{Imatinib mesylate (Gleevec®)
{{Dasatinib (Sprycel®)
{{Nilotinib (Tasigna®)
{{Bosutinib (Bosulif®)
Rashes
{{
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Edema
{{ (fluid retention—swelling around the eyes, feet, lungs or heart)
Congestive
{{ heart failure (impaired ability of the heart to pump blood) and
left ventricular dysfunction (impaired functioning of the left side of the heart),
particularly in patients with other health issues and risk factors. Patients with
heart disease or risk factors for heart disease should be monitored and
treated for this condition.
Severe
{{ liver problems
{{Some CML patients are not able to tolerate the side effects of imatinib. For other
patients imatinib stops working, which is known as “imatinib resistance.” In some
cases, patients can overcome imatinib resistance by increasing the dose of
imatinib. Other patients, however, may need to take a different TKI. Fortunately,
there are other approved therapies for people with imatinib intolerance or
resistance. When imatinib is not a treatment option, doctors decide, along with
their patients, which of the other treatment options is the best alternative.
Dasatinib (Sprycel)
{{Dasatinibwas initially approved by the FDA in 2006. Because dasatinib was
developed after imatinib, it is called a “second-generation” TKI.
{{The FDA has approved dasatinib to treat adults with
Newly
{{ diagnosed Ph+ CML in chronic phase
Chronic,
{{ accelerated or blast phase Ph+ CML with either resistance to or
intolerance of other treatments (including imatinib)
{{In 2017, dasatinib was approved by the FDA to include treatment for pediatric
patients with CML in chronic phase.
{{Dasatinib is taken once daily, either in the morning or evening, with or without
food. Patients taking an antacid medicine should take it either 2 hours before
or 2 hours after taking dasatinib.
{{Grapefruit products may increase the amount of dasatinib in the blood. Patients
should avoid grapefruit, grapefruit juice and any supplement containing
grapefruit extract while taking dasatinib.
{{Studies of dasatinib have shown that it is more potent than imatinib and it
induces faster and deeper molecular responses. To date, dasatinib has not
been shown to increase survival compared to imatinib.
{{Common side effects of dasatinib include
Nausea
{{
Diarrhea
{{
Headache
{{
Fatigue
{{
Shortness
{{ of breath
Chronic Myeloid Leukemia I 15
Rash
{{
Fever
{{
Nilotinib (Tasigna)
{{Nilotinib is a second-generation TKI approved by the FDA in 2007 to treat
CML, and is approved for
Newly
{{ diagnosed adults with Ph+ CML in chronic phase
Adults
{{ with Ph+ CML in chronic phase and accelerated phase who are
resistant to or intolerant of prior therapy (including imatinib)
{{In 2018, nilotinib was also approved for pediatric patients age 1 and older who
Are
{{ newly diagnosed and in chronic phase
Have
{{ resistance to or intolerance of prior TKI therapy
{{Grapefruit products increase the amount of nilotinib in the blood. This may
increase a patient’s chance for serious and life-threatening side effects.
Patients should avoid grapefruit, grapefruit juice and any supplement
containing grapefruit extract while taking nilotinib.
{{Nilotinib is usually taken twice a day. It should be taken on an empty stomach.
Patients should avoid eating food for at least 2 hours before and also at least
1 hour after the dose is taken.
{{Studies have shown that nilotinib is more potent than imatinib and that it
induces faster and deeper molecular responses. To date, nilotinib has not
been shown to increase survival compared to imatinib.
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{{One serious side effect of nilotinib is that it may cause heart rhythm problems
in some patients. This is sometimes caused by nilotinib interacting with other
drugs or supplements, so it is very important for patients to tell their doctors
about any supplements or medicines, including over-the-counter medicines
they are taking.
{{Patients who take histamine type 2 receptor antagonists/blockers (called H2
blockers) should take these medicines about 10 hours before or about 2 hours
after taking nilotinib. Patients taking antacids containing aluminum hydroxide,
magnesium hydroxide or simethicone should take these medicines about 2
hours before or about 2 hours after taking nilotinib.
{{Common side effects include
Nausea,
{{ vomiting, diarrhea
Rash
{{
Headache
{{
Fatigue
{{
Itching
{{
Cough
{{
Constipation
{{
Runny
{{ or stuffy nose, sneezing, sore throat
Fever
{{
Night
{{ sweats
{{Serious side effects of nilotinib include
Low
{{ blood cell counts. Having low numbers of red blood cells, white blood
cells and platelets can increase a patient’s risk of anemia, infection and/or
bleeding.
QT
{{ interval prolongation, a serious heart problem that causes a change in
heartbeat rhythm that can be fatal. The patient should contact the doctor
immediately if he or she feels lightheaded, faint or has an irregular heartbeat
while taking nilotinib. Before starting nilotinib and during treatment with
nilotinib, the doctor should check the patient’s heart with a test called an
electrocardiogram (ECG).
Blood
{{ clots or blockages in blood vessels (arteries), which can cause
decreased blood flow to the leg, heart or brain
Liver
{{ damage symptoms, including yellow skin and eyes (“jaundice”)
Inflammation
{{ of the pancreas. Symptoms include stomach pain with nausea
and vomiting.
Bosutinib (Bosulif)
{{Bosutinib is a second-generation TKI that was approved by the FDA in 2012 to
treat adults with chronic, accelerated or blast phase Ph+ CML with resistance to
or intolerance of prior therapy.
{{In 2017, bosutinib’s FDA approval was expanded to include treatment of adult
patients with newly-diagnosed chronic phase Ph+ CML.
{{Side effects include
Stomach
{{ pain, diarrhea, nausea and/or vomiting
Fluid
{{ retention
Rash
{{
Fatigue
{{
Ponatinib (Iclusig)
{{The FDA approved ponatinib to treat CML in 2012. Ponatinib is a
third-generation TKI approved for
Adult
{{ patients in chronic, accelerated or blast phase CML for whom no other
TKI is indicated
Adult
{{ patients with the T315I mutation in chronic, accelerated or blast phase
CML
{{Ponatinib may be taken either with or without food.
{{Ponatinib targets all the changes (mutations) on the BCR-ABL1 protein that are
resistant to imatinib and other TKIs. However, this drug can cause severe side
effects and is not a good option for all patients.
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{{The most common side effects include
Skin
{{ rash
Stomach-area
{{ (abdominal) pain
Fatigue
{{
Headache
{{
Dry
{{ skin
Fever
{{
Constipation
{{
High
{{ blood pressure
{{Serious or life-threatening risks include
Blood
{{ clots or blockages in blood vessels (arteries and veins). Patients
should get medical help right away if they have any of the following
symptoms: chest pain or pressure; pain in the arms, legs, back, neck or jaw;
shortness of breath; numbness or weakness on one side of the body; leg
swelling; headache; severe stomach pain; dizziness; decreased vision or
loss of vision; and/or trouble talking.
Heart
{{ problems, including heart failure, irregular, slow or fast heartbeats and
heart attack. Doctors will check patients’ heart function, both before and
during treatment with ponatinib. Patients with cardiovascular risk factors
should be referred to a cardiologist. Get medical help right away if you
have any of the following symptoms: shortness of breath, chest pain, fast or
irregular heartbeats, dizziness or feeling faint.
Liver
{{ problems, including liver failure. Symptoms may include yellowing of
the skin or white part of the eyes (jaundice), dark-colored urine, bleeding or
bruising, loss of appetite and sleepiness.
{{Other serious side effects include
High
{{ blood pressure
Pancreatitis
{{ (inflammation of the pancreas)
Neuropathy
{{ (damage to the nerves in the arms, brain, hands, legs or feet)
Serious
{{ eye problems that can lead to blindness or blurred vision
Severe
{{ bleeding
Fluid
{{ retention
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In most patients, TKIs can control CML. Patients should not skip doses to try to
reduce the side effects of the medication. Patients should tell their doctors about
any side effects that they are experiencing. Doctors can provide supportive
treatment (palliative care) to help patients manage these side effects.
Patients must take their medication as prescribed to achieve the best response.
Poor adherence to the medication regimen is a primary reason for inadequate
response to the prescribed treatment. Patients should not stop taking their
medication, nor should they take less than the amount prescribed, unless they are
instructed to do so by their doctors. Taking less than the amount prescribed can
affect how well the medication works and may result in less than optimal treatment
outcomes.
The following drugs were used as initial therapy before TKIs were introduced.
They may continue to be used in select patients.
Interferon alfa (Roferon-A®, Intron A®)
Pegylated interferon alfa
Hydroxyurea (Hydrea®)
Cytarabine (Cytosar-U®)
Busulfan (Myleran®)
New treatments may have been approved since this book was printed.
Check www.LLS.org/DrugUpdates or call (800) 955-4572.
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Chemotherapy. Chemotherapy is generally used only in patients with blast phase
CML to return the disease to the chronic phase. Very high-dose chemotherapy is
sometimes used to prepare patients for an allogeneic stem cell transplant.
Omacetaxine mepesuccinate (Synribo®), a protein synthesis inhibitor, is a
treatment option for adults with chronic or accelerated phase CML with resistance
to and/or intolerance of two or more TKIs. Omacetaxine can be used to treat
patients with all mutations (including the T315I mutation) that are resistant to TKIs.
In general, its use is limited to patients who have exhausted all other TKI options
and who are not candidates for an allogeneic transplant. Omacetaxine is given as
a liquid injected under the skin. The most common side effects include
{{Low red blood cell, white blood cell and platelet counts
{{Diarrhea
{{Nausea
{{Fatigue
{{Fever
{{Infection
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Treating CML by Phase
Each phase of CML requires different treatment.
Treatment for Chronic Phase CML. TKI therapy is standard treatment for chronic
phase CML. TKIs are often successful at managing CML for long periods of time.
Four TKIs are approved as primary treatment for chronic phase CML:
{{Imatinib
{{Dasatinib
{{Nilotinib
{{Bosutinib
When choosing a first-line TKI, doctors may consider factors such as a patient’s
pre-existing health conditions, age and risk score, as well as the plus dose
schedule and drug cost. After the start of therapy, doctors will monitor patients to
evaluate treatment response. A patient who is responding well will stay on his or
her current drug therapy. If the patient is not meeting treatment milestones, the
doctor will need to find out why.
If the patient’s current treatment is not working, a BCR-ABL1 kinase domain
mutation analysis (see page 29) should be done to check for mutations of the
BCR-ABL1 gene. The doctor will also determine whether the patient has been
adhering to the treatment plan. There are a number of options at this point,
which include:
{{Advising patients who have not been taking their TKIs as prescribed about the
importance of adhering to their medication regimen
{{Increasing the dosage of the current drug (if possible)
{{Switching to another TKI, for example, switching from imatinib to dasatinib,
nilotinib, bosutinib or ponatinib
{{Trying other therapies (such as omacetaxine, an option for patients with
resistance or intolerance to two or more TKIs or interferon)
{{Assessing whether an allogeneic stem cell transplant is an option
Treatment for Accelerated Phase CML. The goal in treating accelerated phase
CML, just as with the chronic phase, is to eliminate all cells that contain the
BCR-ABL1 gene, leading to a remission. If this is not possible, the goal is to
return the disease to the chronic phase. Treatment at a specialized center with
doctors who have expertise in treating CML is recommended for patients in the
accelerated phase of the disease.
In accelerated phase CML, the cancer cells often acquire new genetic mutations
that may make treatments less effective. Patients should undergo BCR-ABL1 gene
{{Dasatinib
{{Nilotinib
{{Bosutinib
If the CML progresses from chronic phase to accelerated phase during TKI
therapy, a doctor may increase the dosage of the current TKI (if possible) or
prescribe another TKI that the patient has not received before. Other options
include
{{The TKI ponatinib, for patients who have not responded to two or more TKIs
and for patients who have the T315I mutation
{{The drug omacetaxine (an option only for patients who have experienced
resistance to or intolerance of two or more TKIs)
{{An allogeneic stem cell transplant
Another option for patients with accelerated phase CML is to receive treatment
in a clinical trial. Clinical trials are studies done by doctors to test new drugs and
treatments, or new uses for approved drugs and treatments. Clinical trials are one
way for patients to obtain state-of-the-art cancer treatments. The goal of clinical
trials for CML is to improve treatment and quality of life and to find a cure. Patients
should talk to their doctors about the potential benefits and risks of participating in
a clinical trial. See Research and Clinical Trials on page 36.
Treatment for Blast Phase CML. Patients with blast phase CML have leukemia
cells that have become very abnormal. Blast phase disease acts more like acute
leukemia, with higher blood counts and more severe symptoms. Treatment
at a specialized center with doctors who have expertise in treating CML is
recommended for patients in the blast phase of the disease.
Two important tests are needed before starting treatment for blast phase CML:
{{The first test determines whether the blast phase involves myeloid or lymphoid
blast cells. This test is important because the type of blast cells is a factor in the
treatment decision.
{{The second test, a BCR-ABL1 kinase domain mutation analysis (see page 29),
checks for mutations in the part of the BCR-ABL1 gene that is targeted by TKIs.
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Different mutations can make the BCR-ABL1 protein either more or less resistant
to certain TKIs.
One option for patients with blast phase CML is to receive treatment within a clinical
trial. Patients should talk to their doctors about the potential benefits and risks of
participating in a clinical trials. See Research and Clinical Trials on page 36.
Another treatment option is for patients to receive TKI therapy, either with or without
chemotherapy, and then proceed to an allogeneic stem cell transplant. In general
the more potent second-generation TKIs are preferred for blast phase CML.
Patients who respond to these drugs may still want to consider allogeneic stem cell
transplantation. An allogeneic stem cell transplant is more likely to be successful if
the disease can be returned to the chronic phase before transplantation.
The International Scale (IS). This is a standardized scale for measuring qPCR
test results. The qPCR test measures the number of cells that have the BCR-ABL1
gene. It is used to determine how well treatment is working. The International Scale
defines the standard baseline as BCR-ABL1 100 percent. A log reduction indicates
the BCR-ABL1 level has decreased by a certain amount from the standard baseline.
{{1-log reduction indicates that the BCR-ABL1 levels have decreased to 10 times
below the standardized baseline. This means that 10 percent of cells (10 out
of every 100 cells) have the BCR-ABL1 gene. This is also written as “BCR-ABL1
10 percent.” This reduction is equivalent to an early molecular response when
achieved within 3 to 6 months of starting treatment.
{{2-log reduction means that BCR-ABL1 levels have decreased to 100 times
below the standardized baseline. This means that 1 percent of cells (1 out of
every 100 cells) have the BCR-ABL1 gene. This is also written as “BCR-ABL1
1 percent.”
{{3-log reduction indicates that the BCR-ABL1 levels have decreased to 1,000
times below the standardized baseline. This means that 0.1 percent of cells
(1 out of every 1,000 cells) have the BCR-ABL1 gene. This is written as
“BCR-ABL1 0.1%.” It is also known as a “major molecular response” (MMR).
{{4.5-log reduction is referred to as a “complete molecular response” (CMR) or
a “deep molecular response.” Doctors may refer to this as “MR4.5.” A 4.5-log
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reduction indicates that 0.0032% of cells (1 out of every 32,000 cells) have the BCR-
ABL1 gene. Achieving a deep molecular response is a sign of disease remission.
Patients who achieve and then sustain a deep molecular response for a significant
period of time may be considered candidates for discontinuing drug therapy under
careful medical supervision. See Treatment-Free Remission on page 32.
Mutation testing does not need to be done in patients who are switching
medication because of side effects.
Among the BCR-ABL1 mutations:
{{T315I is resistant to imatinib, dasatinib, nilotinib and bosutinib
{{F317L and V299L are resistant to dasatinib
{{Y253H, E255K/V and F359C/V are resistant to nilotinib
{{T315I, G250E and V299L are resistant to bosutinib
E255K/V, F359C/V and T315I are the mutations most commonly associated with
disease progression and relapse.
* A 3-log reduction is a 1/1,000 or 1,000-fold reduction of the level of cells with the BCR-ABL1 gene.
Table 2. Treatment responses for CML. Source: NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous
Leukemia, version 1.2019.
For people who experience a loss of response to a TKI, or those who do not
achieve the expected response within a given period of time (see Table 3 on
page 31), the most common options are switching to another approved TKI or
participating in a clinical trial.
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Table 3. Treatment Response Milestones and Follow-up Recommendation
Guidelines
TIME AFTER START OF TREATMENT
BCR-ABL1 (IS) 3 months 6 months 12 months* More than
15 months
> 10% YELLOW RED
> 1% – 10% GREEN YELLOW RED
≤ 1% GREEN
Table 3. Adapted from NCCN Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia; version 1.2019.
Abbreviations: McYR, major cytogenic response; CCyR; complete cytogenic response; TKI, tyrosine kinase inhibitor.
*BCR-ABL1 0.1% at 12 months is associated with a very low probability of disease progression and a high likelihood of
achieving a subsequent MR4.5, which may allow for discontinuation of TKI therapy.
†Discontinuation of TKI with careful monitoring is possible in selected patients.
Every patient responds differently to CML drug therapy. These general guidelines
for CML drug therapy are available online from the National Comprehensive
Cancer Network (NCCN) and the European Leukemia Net (ELN). (See the section
entitled More Information on page 56 for links to these and other resources.)
An individual’s CML drug therapy response is measured against his or her own
results at the start of therapy (the start of therapy is called “baseline”). 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 31
Treatment-Free Remission
Because of advances in the understanding of CML, as well as the very successful
treatment of patients with TKIs, treatment-free remission (TFR) is now an emerging
treatment goal. Many patients with CML have achieved a deep and stable response
to treatment. Treatment-free remission is achieved when a patient who has
discontinued TKI therapy maintains a deep molecular response (DMR, also known
as complete molecular response or CMR) and does not need to restart treatment.
The feasibility and safety of discontinuing TKI therapy has been evaluated in
several studies. Patients in the chronic phase of CML who have maintained a stable
and deep molecular response (DMR) for at least two years are considered good
candidates for TKI therapy discontinuation under careful medical supervision.
In 2017, the FDA expanded the nilotinib product label to include the safe
discontinuation of this medication for two patient groups:
{{Adult patients with newly diagnosed CML in chronic phase who were treated
with nilotinib for 3 or more years and who have achieved DMR for at least
2 years
{{Adult chronic-phase CML patients who received frontline treatment with
imatinib and who switched to nilotinib due to resistance to or intolerance of
imatinib, and who received nilotinib for 3 or more years and have achieved
DMR for at least 1 year
Table 4, below, lists the main clinical criteria for patients who want to attempt to
discontinue TKI therapy and achieve treatment-free remission.
Parameter Criteria
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CML patients have many reasons to attempt treatment-free remission. Motivations
may include convenience, economic savings and quality-of-life factors. After
discontinuing TKI therapy, some patients might experience musculoskeletal pain.
This is known as TKI withdrawal syndrome. Generally, the pain can be managed
with over-the-counter pain medication. Although this syndrome can last for months,
it can often be controlled with nonprescription drugs or nonsteroidal
anti-inflammatory drugs (NSAIDs), and in more severe cases, with corticosteroids.
CML patients may be reluctant to try treatment-free remission due to fear of
relapse or disease progression. In the case of relapse, nearly all patients who
need to restart therapy are able to obtain and maintain a major molecular
response again. Treatment-free remission periods may last from a few months to
many years.
Patients should discuss with their treatment team whether attempting treatment-
free remission may be a potential option in their case. Consultation with an
experienced CML doctor is essential.
For more information on this topic, please see the free LLS publication
Treatment-Free Remission for Chronic Myeloid Leukemia Patients.
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Talk to your child’s doctor about the best treatment option for your child and any
concerns regarding the risks associated with your child’s therapy. It is important for
your child to be seen by a doctor who specializes in pediatric leukemia.
Visit www.LLS.org/booklets to reach the free LLS booklets Choosing a Blood
Cancer Specialist or Treatment Center Facts and Coping with Childhood
Leukemia and Lymphoma.
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Research Approaches. The following approaches are under study in clinical trials
for the treatment of patients with CML.
Improving Current Treatments. Based on the positive results of tyrosine kinase
inhibitor (TKI) therapy in chronic phase CML, many trials are looking at ways to
further optimize the use of these drugs. This research includes
{{Determining which TKI should be used as initial therapy for different patients
with chronic phase CML
{{Establishing the best time to switch patients to second-line therapy
{{Finding out whether deeper responses are achieved when other agents are
added to TKIs
{{Preventing and/or predicting long-term side effects of TKIs
{{Determining which patients can successfully discontinue TKI therapy
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Follow-up Care
CML follow-up care varies from patient to patient. CML patients
{{Will need to see their doctor on a regular basis. The doctor will evaluate their
health, check blood cell counts and their molecular responses to treatment
using qPCR tests, and possibly perform bone marrow tests.
{{Are advised to receive certain vaccinations, including vaccinations for influenza
and pneumococcal pneumonia. There are two types of pneumococcal vaccines
available for adults: a pneumococcal polysaccharide vaccine (PPSV23) and a
pneumococcal conjugate vaccine (PCV13). Immunizations using live organisms
or with high viral loads, such as the herpes zoster or the Zostavax® vaccine (the
live shingles vaccine), should not be administered. CML patients can receive
the shingles vaccine Shingrix®, because it is an “inactivated” rather than a “live”
vaccine. Your doctor can give you more information.
{{Always need to keep good records and treatment notes. This information
should include
Doctors’
{{ names and contact information
Medical
{{ history
CML
{{ diagnosis
Copies
{{ of all pathology reports
A
{{ list of all treatments
Names
{{ of drugs
Transplant
{{ information
Any
{{ other important information
8.7
Incidence Rate per 100,000 People
6.3
4.9
4
3.3
2.4
2.0
2 1.7
1.4
0.9 1.1
0.7
0.4 0.2 0.4
0.1 0.1 0.1
0
<1 1-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+
Age in Years
Figure 4. The horizontal axis shows five-year age intervals. The vertical axis shows the frequency of new
cases of CML per 100,000 people, by age-group.
Source: Surveillance, Epidemiology and End Results (SEER) Program; National Cancer Institute; 2018.
Causes. No one is born with CML. It is not passed from parent to child. It occurs
when there is an injury to the DNA of a single bone marrow cell. The mutated
cell multiplies uncontrollably and crowds out the healthy red blood cells, white
blood cells and platelets in the bone marrow. The CML cells then overflow into
the bloodstream. Because CML is a slow growing form of leukemia, it does not
completely interfere with the development of mature red blood cells, white blood
cells and platelets. As a result, CML is generally less severe than acute forms of
leukemia and often patients do not have any symptoms when they are diagnosed
with CML.
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{{Radiation exposure—In a small number of patients, CML is caused by exposure
to very high doses of radiation (such as being a survivor of an atomic bomb
blast or a nuclear reactor accident).
A
{{ slight increase in risk also occurs in some individuals treated with high-
dose radiation therapy for other cancers, such as lymphoma. But most
people treated for cancer with radiation do not develop CML, and most
people who have CML have not been exposed to high doses of radiation.
Exposures
{{ to diagnostic dental or medical x-rays have not been associated
with an increased risk of CML.
Plasma. The plasma inside the blood is mostly made up of water in which the
blood cells are suspended. Plasma contains many dissolved chemicals, each of
which has a special role. They include
{{Proteins
Albumin,
{{ the most common blood protein
Blood-clotting
{{ proteins made by the liver
Erythropoietin,
{{ a protein made by the kidneys that stimulates red blood cell
production
Immunoglobulins,
{{ proteins that help the body fight infection
{{Hormones, such as thyroid hormone and cortisol
{{Minerals, such as iron and magnesium
{{Vitamins, such as folate and vitamin B12
{{Electrolytes, such as calcium, potassium and sodium
These
{{ are small cells (one-tenth the size of red blood cells).
They help stop bleeding from an injury. For example, when a person has a cut,
{{
the vessels that carry blood are torn open. Platelets stick to the torn surface of
the blood vessel, clump together and plug up the bleeding site with the help of
blood-clotting proteins (such as fibrin) and electrolytes (such as calcium).
{{White blood cells (WBCs) that fight infections. There are several types of WBCs,
including
Neutrophils
{{ and monocytes. These are cells called “phagocytes” that eat and
kill bacteria and fungi. Unlike the red blood cells and platelets, monocytes
can leave the bloodstream and enter the tissue, where they can attack
invading organisms and fight off infection.
Eosinophils and basophils. These white blood cells respond to allergens and
{{
parasites.
Lymphocytes. This type of white blood cell is mostly found in the lymph
{{
nodes, spleen and lymphatic channels. Lymphocytes are a key part of the
immune system. There are three major types of lymphocytes:
• T lymphocytes (T cells)
• B lymphocytes (B cells)
• Natural killer (NK) cells
Stem Cells
Multipotential Multipotential
Hematopoietic Cells Lymphoid Cells
Figure 5. Stem cells develop into blood cells and lymphoid cells.
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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. In adults, the spine (vertebrae), hip and
shoulder bones, ribs, sternum, pelvis and skull contain the marrow that continues
to make blood cells. The process of blood cell formation is called “hematopoiesis.”
A small group of cells, the stem cells, develop into all the blood cells in the marrow
by the process of differentiation (see Figure 5 on page 42).
In healthy individuals, there are enough stem cells to keep producing new blood
cells continuously. Blood passes through the marrow, where it picks up the fully
developed and functional red and white cells and platelets that will circulate in the
bloodstream.
Some stem cells also enter the blood and circulate. They are present in such
small numbers that they cannot be counted or identified by standard blood count
tests. Their presence in the blood is important because they can be collected
by a special technique for stem cell donation. There are also methods to induce
more stem cells to leave the marrow and circulate in the blood, allowing a greater
number of stem cells to be collected for donation. 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.
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One-on-One Nutrition Consultations. Access free one-on-one nutrition
consultations provided by a registered dietitian who has experience in oncology
nutrition. Dietitians assist callers with information about healthy eating strategies,
side effect management and survivorship nutrition. They also provide additional
nutrition resources. Please visit www.LLS.org/nutrition to schedule a consult or for
more information.
Podcast. The Bloodline with LLS is here to remind you that after a diagnosis comes
hope. Listen in as patients, caregivers, advocates, doctors and other healthcare
professionals discuss diagnosis, treatment options, quality-of-life concerns, treatment
side effects, doctor-patient communication and other important survivorship topics.
Visit www.LLS.org/TheBloodline for more information and to subscribe.
Suggested Reading. LLS provides a list of selected books recommended
for patients, caregivers, children and teens. Please visit
www.LLS.org/SuggestedReading to find out more.
{{Workers and volunteers who helped with rescue, recovery and cleanup
at the WTC-related sites in New York City (NYC)
{{Survivors who were in the NYC disaster area, lived, worked or were
in school in the area
{{Responders to the Pentagon and the Shanksville, PA crashes
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For more information, please
{{Call: WTC Health Program at (888) 982-4748
{{Visit: www.cdc.gov/wtc/faq.html
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Bone Marrow Biopsy. A test to examine bone marrow cells to detect cell
abnormalities. After medication is given to numb the skin, a special hollow
biopsy needle is used to remove a sample of bone containing marrow,
usually from the hip (pelvic) bone. Bone marrow aspiration and bone
marrow biopsy may be done in either the doctor’s office or in a hospital.
The two tests are almost always done together.
Bone Marrow Transplantation. See Allogeneic Stem Cell Transplantation.
Chemotherapy. Treatment that stops the growth of cancer cells, either by
killing the cancer cells or by preventing them from dividing.
Chromosomes. Threadlike structures within cells that carry genes in a
linear order. Human cells have 23 pairs of chromosomes.
Cord Blood Stem Cells. Stem cells collected from the placenta and
umbilical cord after a baby is born. These stem cells can repopulate the
bone marrow and produce blood cells in patients undergoing stem cell
transplantations.
Cytogenetic Analysis. The process of analyzing the number and size
of the chromosomes in cells. It detects chromosome alterations and,
in some cases, may identify the actual genes that have been affected.
These findings help healthcare professionals diagnose specific types of
blood cancers, determine treatment approaches and monitor a patient’s
response to treatment. The individual who prepares and examines the
chromosomes and interprets the results is called a cytogeneticist.
Differentiation. The process that occurs when stem cells develop and
mature and take on a new function. Stem cells mature into red blood cells,
platelets or white blood cells. See Hematopoiesis.
Donor Lymphocyte Infusion (DLI). A therapy often used for patients after
an allogeneic bone marrow transplant. In this infusion procedure, patients
are given lymphocytes (white blood cells) that come from the original
transplant donor to help attack remaining cancer cells.
Drug Intolerance. Inability to tolerate the side effects of a drug.
Drug Resistance. The failure of cancer cells, viruses or bacteria to respond
to a drug used to kill or weaken them.
Eosinophil. A type of white blood cell that promotes inflammation during
allergic reactions and helps fight certain parasitic infections.
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Hematopoiesis. The formation and development of blood cells in the bone
marrow. For the blood cell development process, see Normal Blood and
Bone Marrow on page 41.
Hyperleukocytosis. A very high white blood cell count, often found in
people when they are diagnosed with leukemia and most often in patients
with chronic myeloid leukemia.
Immunotherapy. A treatment that uses the body’s immune system to treat
cancer and other diseases.
Leukocyte. Also known as “white blood cell.” A type of blood cell that is
part of the body’s immune system. It defends the body against infections
and other diseases. Types of leukocytes include granulocytes (neutrophils,
eosinophils and basophils), monocytes and lymphocytes (T cells and
B cells). See White Blood Cell.
Lymph Node. A bean-sized structure that is part of the body’s immune
system. Throughout the body, there are hundreds of lymph nodes that
contain lymphocytes (white blood cells) that help fight infection and disease.
Lymphocyte. A type of white blood cell that performs an essential role in
the body’s immune system. There are three major types of lymphocytes.
They are
{{B lymphocytes that produce antibodies to fight infections
{{T lymphocytes that help protect the body from infections and may help
the body fight cancer
{{Natural killer (NK) cells that attack virus-infected cells or tumor cells
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break off and trade places. The result is a chromosome 22 that is shorter
than normal. The exchange of DNA between chromosomes 9 and 22
results in the creation of a new gene (an oncogene) called BCR-ABL1 on
chromosome 22.
Platelet. A small, colorless blood cell that helps control bleeding.
Platelets travel to and then collect at the site of a wound. The platelets’
sticky surface helps them to form clots at the site of the wound and stop
bleeding. Platelets make up about one tenth of the volume of red blood
cells. Also called “thrombocyte.”
Prognosis. The probable outcome or expected course of a disease. The
likelihood of recovery or recurrence of disease.
Quantitative Polymerase Chain Reaction (qPCR). A technique to
expand trace amounts of DNA so that the specific type of the DNA can
be examined. This technique has become useful in detecting a very low
concentration of residual blood cancer cells that cannot be seen using a
microscope. A qPCR test can detect the presence of one blood cancer cell
among 500,000 to 1,000,000 healthy blood cells.
Red Blood Cell. A type of blood cell that contains hemoglobin, which
carries oxygen to the tissues of the body. Red blood cells make up
about 40 to 45 percent of blood volume in healthy people. Also called
“erythrocyte.”
Reduced-Intensity Stem Cell Transplantation. A type of allogeneic
transplantation. In reduced-intensity stem cell transplantation (also called
“nonmyeloablative” stem cell transplantation), patients receive lower doses
of chemotherapy drugs and/or radiation to prepare for the transplant. The
chemotherapy and radiation do not completely kill all of the leukemia cells.
Instead, the new immune cells that the patient receives in the transplant
may attack the leukemia cells. This type of transplant may be safer than a
regular allogeneic stem cell transplant, especially for older patients. See
the free LLS publication, Blood and Marrow Stem Cell Transplantation.
Refractory. This term is used to refer to a disease that has not responded
to the initial treatment. A disease that is refractory may get worse or remain
stable.
Relapse. A return of the disease after a period of improvement.
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Tyrosine Kinase Inhibitor (TKI). A type of drug that blocks the action of
enzymes called “tyrosine kinases” that are made by the BCR-ABL1 gene
so that the enzymes cannot signal the leukemia cells to grow. This specific
approach to cancer therapy is referred to as “molecular-targeted therapy”
because the drug is designed to block the effect of a specific protein that is
the essential cause of the leukemic transformation.
White Blood Cell. A blood cell that is part of the body’s immune system.
The five types of these infection-fighting cells in the blood are neutrophils,
eosinophils, basophils, monocytes and lymphocytes. White blood cells are
also called “leukocytes.”
References
Cayssials E, Guilhot F. Chronic myeloid leukemia: immunobiology and novel
immunotherapeutic approaches. BioDrugs. 2017;31(3):143-149. doi:10.1007/
s40259-017-0225-6.
Chopade P, Akard LP. Improving outcomes in chronic myeloid leukemia over time
in the era of tyrosine kinase inhibitors. Clinical Lymphoma, Myeloma & Leukemia.
2018;18(11):710-723. doi:10.1016/j.clml.2018.06.029.
Eskazan AE. Evolving treatment strategies in CML – moving from early and deep
molecular responses to TKI discontinuation and treatment-free remission: is there
a need for longer-term trial outcomes? British Journal of Clinical Pharmacology.
2018;84(8):1635-1638. doi:10.1111/ bcp.13637.
Fanelli J. Conception and pregnancy in patients treated with TKIs for CML. Journal
of the National Comprehensive Cancer Network (JNCCN-360). Posted January
21, 2019. https://jnccn360.org/cml/medical-literature/conception-and-pregnancy-in-
patients-treated-with-tkis/. Accessed February 12, 2019.
56 I 800.955.4572 I www.LLS.org
Flynn KE, Atallah E. Quality of life and long-term therapy in patients with chronic
myeloid leukemia. Current Hematologic Malignancy Reports. 2016;11(2):80-85.
doi:10.1007/s11899-016-0306-5.
Marcucci G. New drug may be a game changer for chronic myeloid leukemia.
Oncology Times. June 2018;40(12)1,7-7. https://journals.lww.com/oncology-times/
Fulltext/2018/06200/New_Drug_May_Be_a_Game_Changer_for_Chronic_
Myeloid.2.aspx. Accessed March 4, 2019.
Naveen P. Adolescents & young adults with chronic myeloid leukemia. Oncology
Times. 2017;39(10):25-26. doi:10.1097/01.COT.0000520172.33444.4e.
Noone AM, Howlader N, Krapcho M, et al, eds. SEER Cancer Statistics Review,
1975-2015. Based on November 2017 SEER data submission, posted to the
SEER web site, April 2018. National Institutes of Health; National Cancer Institute.
Bethesda, MD; National Institutes of Health; National Cancer Institute; 2018. https://
seer.cancer.gov/csr/1975_2015/. Accessed February 1, 2019.
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