Sometimes an immature blast cell has two gene mutations which prevent it from maturing into a

specialized blood cell and cause it to multiply out of control. ... This leads to a decrease in platelets, red
blood cells (RBCs) and white blood cells (WBCs).

Therapies using medication

Systemic therapy is the use of medication to destroy cancer cells. This type of medication is given
through the bloodstream to reach cancer cells throughout the body. Systemic therapies are generally
prescribed by a medical oncologist or a hematologist.

Common ways to give systemic therapies include an intravenous (IV) tube placed into a vein using a
needle or in a pill or capsule that is swallowed (orally).

The types of systemic therapies used for CML include:

 Targeted therapy
 Chemotherapy

 Immunotherapy

Each of these types of therapies are discussed below in more detail. A person may receive only 1 type of
systemic therapy at a time or a combination of systemic therapies given at the same time.

The medications used to treat cancer are continually being evaluated. Talking with your doctor is often
the best way to learn about the medications prescribed for you, their purpose, and their potential side
effects or interactions with other medications. Learn more about your prescriptions by using searchable
drug databases.
Targeted therapy
Targeted therapy is a treatment that targets the cancer’s specific genes, proteins, or the tissue
environment that contributes to cancer growth and survival. This type of treatment blocks the growth
and spread of cancer cells while limiting damage to healthy cells.

Not all cancers have the same targets. To find the most effective treatment, your doctor may run tests
to identify the genes, proteins, and other factors involved in your leukemia. This helps doctors better
match each patient with the most effective treatment whenever possible. In addition, research studies
continue to find out more about specific molecular targets and new treatments directed at them. Learn
more about the basics of targeted treatments.
For CML, the target is the unique protein called the BCR-ABL tyrosine kinase enzyme. Drugs that target
the BCR-ABL tyrosine kinase enzyme are called tyrosine kinase inhibitors or TKIs. These types of drugs
can stop the BCR-ABL enzyme from working, which causes the CML cells to die quickly.

It is important to note that men and women taking TKIs should avoid fathering a child or becoming
pregnant while taking the drugs because of a risk to the developing child. To find the best treatment,
patients should talk with their doctors about the risks and benefits of these drugs, including the possible
side effects and how they can be managed. For example, these drugs can cause inflammation of the
liver, which is a problem for people with hepatitis. So, patients should be tested for hepatitis before
starting treatment with any of these drugs. In addition, some TKIs may interact with certain foods,
vitamins, or supplements. Talk with your health care team about what foods, vitamins, or supplements
you may need to avoid. If a patient experiences too many side effects, another TKI can be used instead.
There currently 5 TKIs available for CML:

 Imatinib (Gleevec). Imatinib was the first targeted therapy approved by the U.S Food and Drug
Administration (FDA) for CML in 2001. It is taken as a pill once or twice a day. It works better
than chemotherapy to treat CML and causes fewer side effects (see below). Nearly all patients
with chronic phase CML have their blood counts return to healthy levels and their spleen shrink
after receiving this drug. Most importantly, 80% to 90% of patients newly diagnosed with
chronic phase CML who receive imatinib no longer have detectable levels of cells with the
Philadelphia chromosome. Imatinib may also be used to treat other types of cancer, such
as acute lymphoblastic leukemia (ALL) with the presence of the Philadelphia chromosome.
 The risk of developing resistant CML once it completely responds to imatinib is very low.
Patients with few numbers of cells with the Philadelphia chromosome remaining will stay in
chronic phase longer by taking imatinib than they might have with previous treatments. It is too
soon to know how long these responses will last or if patients will be cured with this medication
alone. However, there are many patients who have been treated with imatinib since the first
clinical trials in 1999 who still have no detectable cells with the Philadelphia chromosome.

The side effects of imatinib are mild but can include stomach pain, which is very uncommon
when imatinib is taken with food, changes in blood counts, fluid retention, swelling around the
eyes, fatigue, diarrhea, and muscle cramps.

 Dasatinib (Sprycel). Dasatinib is approved by the FDA as an initial treatment for patients with
newly-diagnosed chronic phase CML and when other drugs are not working. It is a pill that is
usually taken once a day, or sometimes twice a day depending on the dose. The side effects
include anemia, a low level of white blood cells called neutropenia, a low level of platelets called
thrombocytopenia, and lung problems that include fluid around the lung and/or pulmonary
hypertension. The doctor will monitor a patient’s blood counts frequently after starting
dasatinib and may adjust the dose or stop giving the drug temporarily if the patient’s blood
counts drop too low. Dasatinib may also cause bleeding, fluid retention, diarrhea, rash,
headache, fatigue, and nausea. Dasatinib requires stomach acid in order to be absorbed so
patients should not take any anti-acid medications.

 Nilotinib (Tasigna). Nilotinib is also approved by the FDA as an initial treatment for patients with
newly-diagnosed chronic phase CML and when other drugs are not working. It is a capsule that
patients take by mouth twice a day on an empty stomach. Common side effects include low
blood counts, rash, headache, nausea, diarrhea, and itching. Other possible but uncommon
serious side effects include high blood sugar levels, fluid build-up, and inflammation of the
pancreas or liver. The most serious side effect of nilotinib includes possibly life-threatening
heart and blood vessel problems that can lead to an irregular heartbeat, narrowing of the blood
vessels, stroke, and possible sudden death. These side effects are very rare, but patients may
need testing to check their heart health during treatment. There can be interactions with other
medications that may increase these risks, so be sure to talk with your doctor about all
medications you are taking.

 Bosutinib (Bosulif). In 2012, bosutinib was approved by the FDA to treat CML when 1 of the
other TKIs was not effective or if a patient experienced too many side effects. The most
common side effects include diarrhea, nausea and vomiting, low levels of blood cells, abdominal
pain, fatigue, fever, allergic reactions, and liver problems.

 Ponatinib (Iclusig). Ponatinib was also approved by the FDA in 2012 for patients when 1 of the
other TKIs was not effective or if a patient experienced too many side effects. Ponatinib also
targets CML cells that have a particular mutation, known as T315I, which makes these cells
resistant to other currently approved TKIs. The most common side effects include high blood
pressure, rash, abdominal pain, fatigue, headache, dry skin, constipation, fever, joint pain, and
 nausea. Ponatinib may also cause heart problems, severe narrowing of blood vessels, blood
clots, stroke, or liver problems.
Measuring treatment effectiveness of TKIs
Patients receiving a TKI should receive regular check-ups with the health care team to see how well the
treatment is working. To start, these tests are generally done every 3 months during the first year of
treatment. The response of CML includes:

 Complete hematologic response:

o Healthy levels of white blood cells and platelets

o No signs of abnormal blood cells, such as blasts, in the blood

o The spleen is a normal size and cannot be felt on a physical exam

o There are no CML symptoms

 Partial response:

o Blood counts are still abnormal

o There may still be some blasts in the blood

o The spleen may still be enlarged

o Symptoms and blood test results have improved since treatment began.

These responses can change over time, and there is a risk that the CML will worsen without more
effective treatment. Sometimes this means continuing on the current TKI to see if the treatment helps
further or it may mean changing to another TKI.

Other specific tests are used to find the number of cells that have the Philadelphia chromosome or
contain the BCR-ABL fusion gene. When CML is diagnosed, the Philadelphia chromosome is found in
almost all of a person’s bone marrow and blood cells. Once a person’s CML shows a complete
hematologic response, the doctor then looks for a cytogenetic response with tests such as FISH
(see Diagnosis).
 A complete cytogenetic response means that there are no cells with the Philadelphia
chromosome found on the routine cytogenetic tests.
 A partial cytogenetic response means that between 1% and 35% of the cells still have the
Philadelphia chromosome.
 A minor cytogenetic response means that more than 35% of the cells still have the Philadelphia
chromosome.

A molecular response can be determined when the PCR test is used to find the BCR-ABL fusion gene.
 A major molecular response means that a very small number of cells (more than 1,000 times
fewer than when diagnosed) with the BCR-ABL fusion gene are found in the bone marrow or
peripheral blood.
 A complete molecular response is when no cells with the BCR-ABL fusion gene are found in the
bone marrow or peripheral blood.
An important initial goal of treatment is to achieve a complete cytogenetic response. This may require
doing another bone marrow biopsy if it is unclear whether the drug is working. Or, another bone
marrow biopsy may be needed after 6 to 12 months of treatment to confirm a cytogenetic response. It
is not clear whether any of these drugs can cure CML. The disease may come back if treatment is
stopped. If treatment with 1 of these drugs is working, a patient no longer has evidence of cells with the
Philadelphia chromosome in the bone marrow and has normal levels of blood cells. This is called a
complete cytogenetic remission. It is currently recommended that patients take these drugs
throughout their lives prevent the CML from coming back. Recent research suggests that some patients
may be able to safely stop treatment after a deep and stable response.
Monitoring
More sensitive blood tests, such as PCR and occasionally FISH (see Diagnosis), are usually done every 3
months on a blood sample after a person has a cytogenetic response in the bone marrow cells. Patients
who have no cells with the Philadelphia chromosome on regular cytogenetic tests often need to have
PCR testing to find a molecular response. Patients who have a rapid decrease in the number of cells with
the Philadelphia chromosome by 3 months after starting treatment may have the best long-term
outcomes.
The most sensitive test to look for remaining CML is called a quantitative reverse transcriptase PCR (Q-
RT-PCR) test. This test is recommended every 3 months on a blood sample. Generally, this test can find 1
CML cell remaining among 1 million healthy blood cells. When this test is negative, it is very likely that
the CML is nearly gone. On the other hand, if a person continues taking the medication as directed and
the results of this test begin to rise, then the current treatment is no longer working. This means that it
may be time to switch medications before the disease worsens.

Sometimes, a TKI stops working because the CML develops resistance to it. One reason resistance can
occur is if patients do not take their medication regularly, as prescribed, so it is important for patients
to take their medication as prescribed. Even if patients do take the medication correctly, CML may still
become resistant to a TKI, which is why it is also important to receive regular monitoring with
cytogenetic testing, FISH, or PCR to see how well the drug is continuing to work.

Both dasatinib and nilotinib have been shown to bring about a complete cytogenetic response sooner
and in more people newly diagnosed with CML when compared with imatinib. However, imatinib has
been used for longer. There is no difference in overall survival when using either imatinib or another TKI
as initial treatment. Bosutinib and ponatinib are newer drugs but both have also produced complete
cytogenetic responses in people with CML. Because of possible severe side effects, caution and careful
monitoring is needed if ponatinib is recommended after other drugs have stopped working. However,
ponatinib is the only TKI that works for patients whose CML cells have the T315I mutation. If the
medication you start with stops working, the dose may be increased or a different TKI may be used
instead.

CML being treated with a TKI over the long term may be called a chronic cancer. This type of extended
treatment can bring unique challenges. Learn more about living with chronic cancer.

Chemotherapy
Chemotherapy is the use of drugs to destroy cancer cells, usually by ending the cancer cells’ ability to
grow and divide.
A chemotherapy regimen, or schedule, usually consists of a specific number of cycles given over a set
period of time. A patient may receive 1 drug at a time or a combination of different drugs given at the
same time.

A drug called hydroxyurea (Droxia, Hydrea) is often given to lower the number of white blood cells until
CML can be diagnosed with the tests described in the Diagnosis section. Given in capsule form, this drug
works well to return blood cells to normal levels within a few days or weeks and reduce the size of the
spleen, but it does not reduce the percentage of cells with the Philadelphia chromosome and does not
prevent blast phase alone. Although hydroxyurea has few side effects, most patients newly diagnosed
with chronic phase CML receive imatinib or another TKI (see above) as soon as possible. This means that
they do not need hydroxyurea, or use it for only a short time. Side effects of chemotherapy depend on
the specific drug and the dosage and usually become less severe over time.
In 2012, the drug omacetaxine mepesuccinate (Synribo) was approved by the FDA for patients with
chronic or accelerated phase CML that is not responding to the TKIs described above. Omacetaxine is
given by injection under the skin daily for 7 to 14 days. The most common side effects include
thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, weakness, skin irritation where the
drug was given, fever, and infection.

Immunotherapy
Immunotherapy, also called biologic therapy, is designed to boost the body's natural defenses to fight
the cancer. It uses materials made either by the body or in a laboratory to improve, target, or restore
immune system function. Interferon (Alferon, Infergen, Intron A, Roferon-A) is a type of
immunotherapy. It can reduce the number of white blood cells and sometimes decrease the number of
cells that have the Philadelphia chromosome.

Interferon is given daily or weekly by an injection under the skin. It sometimes causes flu-like side
effects, such as fever, chills, fatigue, and loss of appetite. When given on an ongoing basis, it can also
cause loss of energy and memory changes. Interferon was the primary treatment for chronic phase CML
before imatinib became available. However, interferon is no longer recommended as the first treatment
for CML because research has shown that TKIs work better to treat CML and cause fewer side effects.
However, unlike TKIs, interferon is safe to use during pregnancy.

Bone marrow transplantation/stem cell transplantation

A bone marrow transplant is a medical procedure in which bone marrow that contains leukemia is
replaced by highly specialized cells, called hematopoietic stem cells, that develop into healthy bone
marrow. Hematopoietic stem cells are blood-forming cells found both in the bloodstream and in the
bone marrow. Today, this procedure is more commonly called a stem cell transplant, rather than bone
marrow transplant, because it is the stem cells in the blood that are typically being transplanted, not the
actual bone marrow tissue.

Before recommending transplantation, doctors will talk with the patient about the risks of this
treatment. They will also consider several other factors, such as the phase of CML, results of any
previous treatment, and patient’s age and general health. Although a bone marrow transplant is the
only treatment that can cure CML, it is used less often now. This is because bone marrow transplants
have a lot of side effects, while TKIs are very effective for CML and have fewer side effects.
There are 2 types of stem cell transplantation depending on the source of the replacement blood stem
cells: allogeneic (ALLO) and autologous (AUTO). ALLO uses donated stem cells, while AUTO uses the
patient’s own stem cells. In both types, the goal is to destroy cancer cells in the marrow, blood, and
other parts of the body using chemotherapy and/or radiation therapy and then allow replacement blood
stem cells to create healthy bone marrow. Only ALLO transplants are used to treat CML.

Complementary and Alternative Medications for treating Leukemia

Patients with leukemia often seek additional treatments not prescribed by their oncologist in an effort
to improve their cancer treatment outcome or to manage symptoms. The term ‘complementary and
alternative medicine’ has been in common use to describe therapies that are not typically part of
mainstream medicine. Unfortunately, the term is misleading because it combines two very different
approaches. ‘Alternative treatments’ are unproven or disproved remedies promoted for use instead of
gold-standard cancer care, and they have no role in the treatment of cancer or other life-threatening
illnesses. Combining the terms ‘complementary’ and ‘alternative’ lends an unwarranted legitimacy to
the alternative treatments and taints the value of adjunctive, evidence-based complementary
modalities.
There are no viable ‘alternatives’ to mainstream cancer care. The so-called ‘alternative therapies’ are
not effective and often delay receipt of needed treatment until the tumor has advanced to a later stage,
thus impacting survival. They should be avoided. Many over-the-counter agents directly interfere with
medical treatments by chemically blocking the action of the cancer treatments, as seen with the use of
many botanical extracts or antioxidants concurrent with radiation or chemotherapy, or by stimulating
cancer cell growth, as occurs with botanical extracts such as cat’s claw and dragons blood, which have
often been used by parents in an effort to treat their child’s leukemia.
By contrast, complementary therapies are used in conjunction with mainstream medical therapies and
are evidence-based. They decrease side effects associated with cancer or its treatment. These therapies
do not directly treat the cancer. Rather, they decrease side effects and improve quality of life.
Complementary therapies are rational, evidence-based and cost effective. They are pleasant and,
importantly, provide patients with a sense of control.

Prevalence of complementary therapy use

The main complementary therapies include massage, acupuncture, mind–body interventions, including
self-hypnosis, meditation, yoga and tai chi/qi gong, botanical and other supplements plus fitness
(nutrition and physical activity).
There is minimal specific information regarding patients with leukemia and their utilization of
complementary therapies. Approximately a third of children with cancer have leukemia; however, the
studies do not separate the results into different cancer types when reporting complementary therapy
use concurrent to cancer treatment. Only two reports specifically discuss complementary therapy use in
patients with leukemia. Gupta documented that 56% of patients with leukemia in northern India used
complementary therapies, with 33% using Ayurveda. Hensel et al. surveyed 247 chronic lymphocytic
leukemia patients in Germany, with 44% using complementary therapies. Massage and mind–body
therapies were not utilized in this German cohort. In total, 26% used vitamin supplementation, 18%
mineral supplementation, 14% homeopathy, 9% mistletoe therapy and 7% used acupuncture. Patients
largely used these treatments without physician recommendations and 32% of patients received their
information through the internet. Of particular concern is the high percentage of patients who reported
using vitamin supplementation, as these products are not necessarily safe when taken concurrent to
cancer treatment. Mistletoe therapy is not legally available in the USA, but is commonly used in Europe.
In the UK, complementary therapy use in adults with all cancers is similar to that of the general
population with approximately 33% of patients using these therapies. While 33% reported that they had
used complementary therapies prior to diagnosis, 29% used them after the cancer diagnosis. Of patients
using the complementary therapies, 64% chose aromatherapy and reflexology treatments, both of
which were offered at their cancer center. Another 23% of patients used acupuncture, 22% herbal
medications and 20% yoga.
When pediatric cancer patients are questioned regarding their use of complementary therapies, 30–80%
used one or more complementary therapies in conjunction with traditional cancer care. Children have
an especially high percentage of vitamin and nutritional supplement use, with over 40% of patients
consuming these products. Parents most often state that they want to “do everything possible” as the
reason for including these therapies with the cancer treatment. The mind–body therapies were the
second most commonly used complementary therapies. In adolescents with cancer, 80% report to have
used complementary therapies in their lifetime, with 50% having used them in the previous month.
Many patients do not report their use of complementary therapies to the oncologist, with the main
reason being that the oncologist did not ask. Of particular concern is that herbal teas, plant extracts and
therapeutic vitamins comprised the highest percentage of use in most patient surveys, as these
therapies risk directly interfering with cancer treatment. The complementary therapies of guided
imagery, self-hypnosis, massage, acupuncture and physical fitness do not have the same potential for
adversely affecting the cancer treatment.

Complementary therapies for leukemia symptom relief

Many of the symptoms associated with both the acute and chronic leukemias are decreased by the
complementary therapies, including the symptoms of fatigue, nausea, stress, decreased appetite, bone
and joint pain, fevers and sweats. In addition, symptoms associated with chemotherapy and radiation
therapy to treat leukemia are very responsive to the complementary therapies of massage,
acupuncture, mind–body interventions, physical fitness and good nutrition. While many of the clinical
trials evaluating specific complementary therapies did not include leukemia patients, the symptoms
addressed by the treatments are common to patients with leukemia, and the study results can be
extrapolated into the leukemia patient population.

Massage
Massage has been demonstrated to be very beneficial for decreasing symptoms of pain, nausea, fatigue,
anxiety and insomnia in clinical trials. Massage techniques range from light touch to deeper tissue
pressure and include reflexology treatments involving only foot massage. The choice of technique is
dependent on the patient’s clinical condition. Although there are no studies evaluating the platelet level
required for deep tissue massage, thrombocytopenia is a relative contraindication to deep tissue
massage and, in this setting, light-touch massage or reflexology may be a better treatment option.
Those who are frailer and who are near the end of life may tolerate the reflexology treatment rather
than full body massage. Symptom management is achieved equally through the reflexology and the full
body massage, with an average decrease in symptom intensity by 50% for all presenting complaints, and
the relief lasted at least 48 h post massage/reflexology treatment. The massage treatments have a very
favorable risk–benefit ratio and very low risk of adverse side effects.

Acupuncture
Acupuncture is part of the ancient Chinese traditional system of medicine and has been used for
millennia. The acupuncture points used are based on the theory that energy or ‘qi’ is thought to flow
along multiple channels or ‘meridians’, which approximately correspond to tissue planes. Disease occurs
when these energy channels become blocked. Insertion of the thin, sterile, filiform needles superficially
into these acupuncture points is thought to release the blocked energy, thereby restoring health.
There is minimal risk of injury from acupuncture treatments, with reports of less than one adverse event
in over 10,000 acupuncture treatments. Acupuncture needles are 38–40 gauge and filiform, as opposed
to the 21–25 gauge hollow needles used for phlebotomy. The acupuncture needles are only inserted
approximately a quarter inch or less depending on the exact insertion site, and, therefore, acupuncture
is considered safe during acute anticoagulation with Coumadin® or heparin. Thrombocytopenia is not a
contraindication unless the platelet count is below 50,000. There is one report of acupuncture ear studs
causing auricular hematomas during acute dilutional thrombocytopenia; however, acupuncture has also
been safely administered repeatedly during acute pregnancy-induced thrombocytopenia for analgesia.
Electroacupuncture should be avoided during anticoagulation or acute thrombocytopenia, although
there are no reports demonstrating acute toxicity.
Research has demonstrated acupuncture to be beneficial for many cancer-related symptoms. Certain
chemotherapy agents, such as paclitaxel, can cause neuropathy. This chemotherapy-associated
peripheral neuropathy has favorably responded to acupuncture treatments. Chemotherapy dose
reduction is at times necessary to prevent further neuropathy progression. Decreasing the neuropathy
symptoms through acupuncture can maximize the chemotherapy delivered to a patient, thereby
increasing the chance for successful cancer outcome.
Nausea prevention and treatment is also very successful with weekly acupuncture. Optimal timing of the
acupuncture treatments is 1–2 days prior to the chemotherapy infusion, and continues weekly
throughout the chemotherapy. Xerostomia, or extreme dry mouth. following head and neck radiation
therapy is also very responsive to acupuncture treatments with increased salivation compared with
control. Acupuncture also decreases the vasomotor symptoms of hot flashes and decreases pain.

Mind–body
The mind–body practices, such as meditation, self-hypnosis, guided imagery and music therapy, have
been demonstrated to decrease cancer-related symptoms. A recent trial examined a 15-min presurgical
self-hypnosis session compared with empathetic listening in women who were undergoing excisional
breast biopsy or lumpectomy. The self-hypnosis group experienced decreased nausea, pain, fatigue and
discomfort when compared with the control group. In addition, the self-hypnosis group required less
time in the operating room and the recovery room, less anesthesia and was more cost effective, saving
the hospital nearly US$800 per patient through decreased resource utilization.
Music therapy has been demonstrated to be effective in decreasing mood disturbance in patients
undergoing stem cell transplantation, with significantly decreased anxiety and depression in those who
received music therapy compared with usual care. Music therapy involves more than simply listening to
music. Music therapy is delivered by professional musicians who have received advanced training in
music therapy. Rather than using words as in psychotherapy, music is utilized. Music bypasses many
higher cortical centers, and allows people who are frailer or who do not have access to words to derive
benefit from the music therapy.
Sahler et al. examined music therapy in conjunction with guided imagery for persons receiving stem cell
transplantation. In contrast to the results seen by Cassileth et al., the combined music therapy with
guided imagery participants encountered difficulty in adhering to the imagery. The researchers
concluded that the patients were often too ill to actively focus on the imagery. A more passive and
receptive intervention may be more appropriate for those patients who are very ill and who are frail.

Botanical & nutritional supplements

A large percentage of cancer patients, as well as the German Chronic Lymphocytic Leukemia (CLL)
patients, surveyed used botanical and nutritional supplements in conjunction with their cancer
treatments. In contrast to the aforementioned complementary therapies, which are appropriate for all
patients with leukemia, botanical and nutritional supplements may be contraindicated depending on the
therapy used and the cancer treatments received.

Potential risks of using botanical supplements

The consumption of large quantities of supplements may interfere with obtaining adequate nutrition
through decreased food intake, especially for children. In addition, the metabolism of these
supplements may not be similar in children compared with adults, leading to increased toxicity. The
botanical extracts are a complex mixture of chemical structures, which can have unpredictable effects
on the immune system. There is ongoing research through the National Institute of Health funding
regarding botanical use as immunomodulators. Outside of a well-designed clinical trial, using botanical
extracts in patients with leukemia for affecting the immune system is not advised.
Patients can interpret in vivo or animal studies as definitive evidence and begin using the product before
any safety and efficacy data are available from human studies. The aggressive marketing of botanical
products and nutritional supplements to cancer patients can add to the confusion and convince patients
that these products are safe to use when there may not be scientific evidence of safety. Unfortunately,
some of the popular botanical therapies that parents are giving to children with leukemia can actually
increase growth of the cancer cells. A study evaluating cat’s claw, dragon’s blood and mistletoe in
childhood leukemia cells showed high resistance to these products. There was increased leukemic cell
survival by 45% for mistletoe, 96% by cat’s claw and 83% for dragon’s blood.
Another risk of using botanical extracts in cancer treatment is that many of these products are
advertised to “boost the immune system”. While this may sound positive, boosting the immune system
may be detrimental for persons who are receiving immunosuppression through corticosteroids,
methotrexate or other medications. Corticosteroids are commonly used with chemotherapy for
leukemia. Patients taking unregulated botanicals to boost their immune system may directly interfere
with their chemotherapy. There is also at least a theoretical risk for leukemia patients of inducing cancer
recurrence through stimulating the immune system.
In addition, these agents are not regulated by the US FDA and, as such, there are issues of quality
control, possible heavy metal contamination, endotoxin presence and stability issues that can make
using these products problematic. The United States Pharmacopeia (USP) is an independent agency with
offices in Rockville, (MD, USA), Hyderabad (India), and Shanghai (China). The USP verifies the identity,
strength, purity and quality of dietary supplement finished products, dietary supplement ingredients
and pharmaceutical ingredients. Products that bear the USP seal have been verified to contain what is
stated on the label. This verification, however, does not address issues of safety and efficacy. A minority
of manufacturers have the USP verification, as this process is not required by any federal agency.

Potential benefits of botanicals

Shanafelt et al. from the Mayo Clinic reported that, after their initial in vitro report of epigallocatechin
gallate (EGCG) extract inducing apoptosis in leukemic B cells from CLL patients, a large number of their
patients began using EGCG despite no evidence regarding clinical efficacy and no available data
regarding possible toxicity, or optimal dosing or schedule. This increased patient use resulted in a case
series using EGCG in early CLL patients and a newly released dose-escalation trial examining EGCG
extracts in asymptomatic stage (e.g., stage II patients with CLL). The Phase I study used decaffeinated
green tea extract administered in increasing doses up to 2000 mg twice daily. There were few dose-
limiting toxicities, with two out of 33 patients experiencing a grade 3 toxicity. More than 75% of the
patients who were receiving between 1200 and 2000 mg twice daily experienced at least a partial
response, defined as reduction in the absolute lymphocyte count of greater than 20% from the
pretreatment level for at least 2 months. Less than 20% of those receiving 400–1000 mg twice daily
achieved a biologic response. The mechanism of action is unknown and there are multiple possible
theories under investigation.
While these EGCG extract results are encouraging for early-stage CLL patients, it is important to note
that these patients were not receiving any concurrent cancer treatment aside from the EGCG extract.
Another recent study demonstrated that EGCG extract completely blocks bortezomib activity, rendering
the agent useless in its anti-tumor activity.
The medicinal mushrooms show promise from in vitro, ex vivo and animal models for increasing cancer
cell death and decreasing tumor growth. The Agaricus mushroom has shown promising results in in
vitro studies using human myeloid leukemia cell lines regarding decreasing leukemic cell growth.
Additional research evaluating various medicinal mushrooms and their immunomodulatory properties
are ongoing, but until clinical trial results are available and more data is present regarding safety and
potential toxicity, it is prudent for leukemia patients to avoid using these supplements.
Go to:

Multivitamin use & potential risks

Currently US$20 billion are spent annually on nutritional and botanical supplements in the USA. Much of
this is in the hope of preventing or curing disease. The most common complementary therapy for many
cancer patients is multivitamin and multimineral use. Unfortunately, clinical trials that have examined
the use of high dose single vitamin and nutrient supplement for cancer prevention and cancer treatment
have not shown benefit. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was stopped early
owing to adverse outcomes with increased risk of prostate cancer in the vitamin E group and increased
incidence of diabetes in the selenium group. The Physicians Health study examining vitamin C and E for
cancer prevention also did not show any benefit. A recent publication demonstrated reduced activity of
bortezomib in healthy volunteers taking 1000 mg of vitamin C orally. The results were confirmed in a
xenograft model of human multiple myeloma in severe combined immune-deficient (SCID) mice. This
suggests that oral doses of vitamin C that are routinely consumed in over-the-counter supplements
clinically block the effects of boronate class proteasome inhibitors. Similar effects of ECGC blocking
bortezomib activity was mentioned previously.
The 2008 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) formal
recommendations are to meet our nutritional needs through food products alone rather than through
vitamin and mineral supplements; supplements are also not advised for cancer prevention. The
marketing for these nutritional supplements is very strong and the public can easily be convinced to
purchase and consume these products.

Antioxidant controversy

Many of the multivitamin supplements available today through health food stores, pharmacies and
nutritional supplement retailers contain doses of individual vitamins well above the current
recommended daily intake or recommended daily allowance set by the Food and Nutrition Board of the
National Academy of Sciences. Certain cancer treatment regimens that work through generating
reactive oxygen species (ROS) can have decreased efficacy when combined with a high dose of vitamin
supplementation. Specifically, the high antioxidant-containing vitamins A, C and E can interfere by
blocking ROS.
A randomized clinical trial among 540 head and neck cancer patients examining the effects of α-
tocopherol (400 IU/day) and β-carotene (30 mg/day) supplements concurrent to radiation therapy
demonstrated decreased effectiveness of the radiation therapy and more aggressive tumors in those
who were receiving the antioxidants. Similar results were found from the β-carotene studies in male
smokers, demonstrating an 18–28% increased incidence in lung cancers in the group who received β-
carotene compared with placebo. Additional analysis of the β-Carotene and Retinol Efficacy Trial
(CARET) showed a benefit for increased fruit and vegetable intake only in the placebo arm. The placebo
participants in the top quintile of fruit intake had a risk ratio of 0.63 for lung cancer and the risk ratio
was 0.68 for cruciferous vegetable intake. Those who had increased intake of β-carotene through
supplements did not benefit from higher fruit and cruciferous vegetable intake.
Concerns have been demonstrated by vitamin C adversely affecting chemotherapy agents by decreasing
the production of ROS. A prominent meta-analysis of antioxidant use concurrent to chemotherapy and
radiation therapy consensus is that outside of a well-designed clinical research trial, the use of
antioxidants in conjunction with chemotherapy and radiation therapy is not advised.

Fitness: nutrition & physical activity

The importance of healthy nutrition also cannot be overemphasized. The WCRF/AICR 2008 Summary of
Food, Nutrition, Physical activity and the Prevention of Cancer: a Global Perspective recommendations
regarding diet and physical fitness stress the importance of increasing plant foods and decreasing animal
foods in our diet. According to the WCRF data, approximately a third of the cancers in Western, high-
income countries are attributable to factors relating to food, nutrition and physical activity. Changing
the patterns of behavior through increasing education, as well as other means, will be of great benefit in
cancer prevention. Diets that are rich in cured meat or smoked meat and fish have been associated with
an increased risk for childhood leukemia, while consumption of increased vegetables and bean-curd
were associated with a decreased risk.
The benefits of increased adherence to a plant-based diet similar to the Mediterranean style diet have
been shown in a number of studies and in one recent meta-analysis involving 1.5 million patients. Those
people who had increased adherence to the Mediterranean diet had a 9% reduction in overall mortality,
9% reduction in cardiovascular mortality, 6% reduction in cancer mortality and 13% decreased incidence
of Parkinson’s and Alzheimer’s disease. Unfortunately, most people do not comply with the
Mediterranean diet recommendations.
Children with acute lymphoblastic leukemia (ALL) are at increased risk for cardiovascular disease and
obesity as complications of their cancer treatment. Increased adherence to dietary recommendations
regarding the Mediterranean plant-based diet may decrease the risk for these complications.
Unfortunately, many survivors do not follow these dietary recommendations. In a group of 72 adult
survivors of childhood ALL surveyed regarding their dietary patterns, no study participant reported
complete adherence to any of the guidelines set forth by the WCRF/AICR, the Dietary Approaches to
Stop Hypertension (DASH) diet, or the 2005 USA Department of Agriculture food guide. Approximately
half of the participants reported consuming at least five servings of fruits and vegetables per day,
adhering to the AICR recommendations; however, the consumption of both sugar and sodium were
above the AICR guidelines and consumption of whole grains was inadequate.
An analysis of dietary adequacy was undertaken in patients who received treatment for B-cell
lymphoma at the MD Anderson Cancer Center and 94% of participants were found to have either
excessive or inadequate intakes of nutrients, including folate, vitamin A, iron, selenium and calcium. Of
particular concern is that high dietary vitamin A intake may increase the risk of lung cancer in smokers,
while selenium may increase the risk of prostate cancer in men.
The decreased level of activity present in children who have leukemia has been studied extensively.
Implementing physical fitness programs, both during the acute hospitalization phase and following the
cancer treatment, may be beneficial for decreasing side effects, such as osteoporosis, decreased muscle
tone and slowing the weight gain often associated with post cancer treatment. These programs will also
assist in establishing healthy lifestyle habits for decreasing secondary cancer risks in this population.
A 3-week in-patient walking program intervention consisting of 12 min of daily walking significantly
improved fatigue, and decreased symptoms of distress and depression in patients undergoing bone
marrow transplantation. Another study evaluating the effects of increased fitness on decreasing
osteoporosis for children undergoing treatment for ALL did not show any benefit; however, the exercise
intervention group did regain their pretreatment weight through significantly faster weight loss
compared with the control group. The authors postulated that the lack of improvement in bone mineral
density was due to the low level of patient adherence to the fitness program and recommended that
future studies find methods to increase patient participation.

Expert commentary

The complementary therapies are of great value for decreasing leukemia-related symptoms and these
therapies are safe to use concurrent to cancer treatment. Complementary therapies have been
investigated regarding symptom control; however, we do not always have optimal dosing determined
for these therapies. For example, is it better to administer acupuncture on a weekly basis for
chemotherapy-induced peripheral neuropathy, or will twice-weekly treatments be more effective? How
many sessions are required before we determine the intervention as effective or ineffective? Is there a
difference between specific meditation techniques versus self-hypnosis in pain management? Are all
physical fitness interventions equal for decreasing cancer-related symptoms? How many minutes should
a person exercise at one setting in order to derive the maximum benefit from the intervention? Are
three 60-min sessions weekly the same regarding symptom management as six 30-min sessions? Do we
need to cycle our physical exercise with small bursts of physical activity alternating with periods of rest,
or can we exercise continuously and derive the same benefits from, for example, immune system
enhancement and increased natural killer cell activity? These areas will be addressed in future research
to further refine our recommendations to patients and the general population.
What is confused by the general public and ignored by the nutritional supplement marketers is that
there is a difference between primary cancer prevention and cancer treatment. While antioxidants are
beneficial for protecting cells from oxidative damage and for primary cancer prevention, this does not
necessarily translate into directly benefiting all cancer patients. The antioxidant fruit juice marketing for
noni, goji, açai and mangos teen, for example, imply that the antioxidants will protect only the healthy
cells and not the cancer cells, which is not necessarily what occurs. There are no adequate human
studies examining these claims for the fruit juices. The studies that have examined high doses of
antioxidants in conjunction with chemotherapy or radiation therapy have either not shown benefit or
have shown harm. In patients who are at increased risk for cancer, high dose antioxidants have also
been demonstrated benefit, such as the β-carotene lung cancer prevention studies in male smokers,
where the group receiving the β-carotene had an 18% increased incidence of lung cancer compared with
the placebo group.
Regarding botanical supplements and cancer prevention and/or treatment, additional research is
urgently needed to determine the efficacy and toxicity of these agents. The purity and consistency of
these products is not guaranteed, unless the botanical source is grown and harvested through
controlled conditions, which is not always the case. All research should incorporate stability testing and
exert quality control to ensure that the product used has batch-to-batch standardization in order to
replicate the research results in a clinical setting. Plant source verification is also important. The issue of
bioavailability is a key component for all botanical research. Simply following serum levels of a botanical
compound may also not be indicative of the mechanism of action or of the botanical’s bioavailability, as
the pharmacodynamics may depend on a mechanism other than serum transport.
The medicinal mushrooms hold great promise for immune modulation; however, their use must be
closely monitored. It may not always be in a patients’ best interest to broadly stimulate the immune
system, especially for patients with leukemia. Altering one aspect of the immune system has a cascade
effect, which can produce unexpected results. A botanical supplement may have very different
immunomodulatory effects with different doses and serum concentrations, and the maximum tolerated
dose may not necessarily provide the optimal desired effect.
Translating in vitro experimental results into animal models and human clinical results requires careful
interpretation of the experimental data. Unlike pharmaceutical drugs, which consist of one chemical
structure, the botanical extracts can contain hundreds if not thousands of chemical constituents. The
botanical agents may have unpredictable clinical results based on factors not necessarily related to their
proposed mechanism of action or chemical constituents. One such example is the EGCG and vitamin C
inactivation of bortezomib; although the mechanism of action of bortezomib does not use an
antioxidant mechanism, these two supplements do block bortezomib activity.

Case Study: 47-Year-Old Woman with New-Onset AML and Leukocytosis

A 47-year-old woman presents to the emergency department complaining of fatigue and shortness of
breath. She reports a two-week history of worsening exercise tolerance and a rather abrupt onset of
shortness of breath over the past several hours. The patient has no major past medical history and
works as an architect. Prior to this illness, she exercised three to four times weekly. Her breathing
appears somewhat labored. Physical examination is notable for tachycardia, tachypnea, an
erythematous rash on her chest and back, and scattered ecchymosis on the extremities. Her laboratory
results reveal the following:
 Count Value Reference Range

White blood cells 174.1 × 109/L 4 x 109/L – 10 × 109/L

Hemoglobin 7.3 g/dL 14 – 18 g/dL

Platelet count 24 × 109/L 150 × 109/L – 450 × 109/L

White blood cell (WBC) differential is notable for 89 percent blasts. Peripheral blood smear shows a vast
majority of cells are large blasts with occasional cytoplasmic granules and pseudopodia. Bone marrow
aspiration and biopsy is performed, revealing a hypercellular marrow involved with monocytic-
appearing blasts comprising 80 percent of bone marrow cellularity. Cytogenetics reveal t(6;11)(q27;q23)
present in 19 out of 20 metaphase cells. Molecular studies show wild-type CEPBA and NPM1 genes and
a FLT3-ITD mutation (FMS-like tyrosine kinase 3, internal tandem duplication) is present. She is admitted
to the hospital to initiate induction chemotherapy for acute myeloid leukemia (AML).

Following acute cytoreductive strategies to treat pulmonary complications of leukostasis, which of the
following FDA-approved induction regimens is most likely to result in long-term overall survival?

A. 7+3 chemotherapy with infusional cytarabine and an anthracycline (daunorubicin or idarubicin)

plus gemtuzumab ozogamicin
B. 7+3 chemotherapy with infusional cytarabine and an anthracycline (daunorubicin or idarubicin),
plus etoposide
C. 7+3 chemotherapy with infusional cytarabine and an anthracycline (daunorubicin or idarubicin),
plus midostaurin
D. 7+3 chemotherapy with infusional cytarabine and an anthracycline (daunorubicin or idarubicin),
plus sorafenib

Answer

C. 7+3 chemotherapy with infusional cytarabine and an anthracycline (daunorubicin or idarubicin),

plus midostaurin

The correct answer is (C), 7+3 chemotherapy with infusional cytarabine and an anthracycline
(daunorubicin or idarubicin), plus midostaurin. The patient is a younger adult woman with no prior
medical history who presents with de novo AML with t(6;11) as well as a FLT3-ITD mutation. Her clinical
presentation is explained by her anemia (fatigue), thrombocytopenia (ecchymoses), and extreme
leukocytosis (pulmonary leukostasis). Her cytogenetics reveal an 11q23 translocation, associated with
therapy-related AML secondary to topoisomerase II inhibitors (such as etoposide and anthracyclines),
which she does not have given her lack of prior history of such exposures, and monocytic differentiation
of the leukemia, which she does have on the basis of her morphology. Monocytic differentiation may
increase the chance of leukemic blasts infiltrating into tissues, which may result in leukemia cutis (likely
based on her exam), gingival hyperplasia, and a higher likelihood of central nervous system involvement.
Her very high WBC count is likely a result of her FLT3-ITD mutation, which is associated with extreme
elevations in the WBC count at presentation, a shorter WBC doubling time, and an increased likelihood
of relapse following consolidation therapy. Midostaurin is a newly developed inhibitor of FLT3 that is
FDA-approved, along with standard 7+3 combination chemotherapy, for the induction therapy
of FLT3 mutation-positive AML. This is based on a multicenter phase III trial of 717 adult patients with
newly-diagnosed FLT3 mutation-positive AML who were randomized to either standard 7+3 induction
chemotherapy plus placebo or 7+3 induction chemotherapy plus midostaurin (on days 8 through 21,
following chemotherapy). After a median of 59 months of follow-up, median overall survival was
superior in the midostaurin group (75 months vs. 26 months), with a hazard ratio for death of 0.78.

While induction therapy with midostaurin has not been directly compared to such therapy with
gemtuzumab ozogamicin (answer choice A), etoposide (answer choice B), or sorafenib (answer choice
D), studies have examined the impact of adding etoposide to 7+3 and no benefit over 7+3 alone has
been found. Sorafenib is a multi-tyrosine kinase inhibitor with activity against FLT3, and small studies
have suggested a possible role for this drug in the management of patients with FLT3 mutation-positive
AML, but more investigation is necessary, and the agent is not currently FDA-approved for this purpose.
Gemtuzumab ozogamicin is a recombinant anti-CD33 monoclonal antibody linked to a cytotoxic agent. It
had initially been approved by the FDA for use in older adults (age >60) with AML in first relapse, but it
has since been pulled from the U.S. market following a more recent randomized trial showing no benefit
from adding gemtuzumab ozogamicin to standard induction in younger adults with newly diagnosed
AML. Trials are ongoing investigating other possible uses of this agent.
Valerie Julene M. Davido
Reflection
My older brother had a classmate back in 2nd-year high school who got diagnosed with AML. At first,
nobody had any news on why he stopped showing up in school all of a sudden. Weeks later, word got to
us that he had acquired this disease. At first, he and his classmates didn’t get it much thought, since based
on their ignorant minds that leukemia is just a health condition in which there were too many white blood
cells in the blood, and that it usually goes way with just a few blood transfusions.

Two months have passed since then, and he and his classmates didn’t get any word from him. Only
when the teacher got a call from the child’s mother did they learn that he was been hospitalized for a
month already, and is in seek of additional funds to pay for the hospital’s bills. Being in a third-world
country, medical fees tend to be a bit more expensive. So, the teacher, as well as the parents of a few of
his classmates donated some money to help with his AML treatment, which amounted to somewhere
around 70,000 pesos. In the meantime, the school, being a private Catholic school at that, held a mass in
prayer for their classmate’s recovery.

He somewhat recovered two weeks later to the point that he was discharged from the hospital. My
brother and his classmates got invited to dine at his house as a thank-you for his recovery. All seemed
well at first; he was able to get back to class for two months. However, he was taken back to the hospital
again after complaining of leg pains, as well as some nasty-looking black spots all over his body.

This time, he, his teacher and his classmates had learned that their classmate’s condition had
elevated to the point where no available treatment could lead to a recovery. At that point, that was the
last time they saw of him. He got transferred to a better hospital weeks later.

Again, they held another mass in prayer to God for his recovery, as well as some of his classmates’
parents sending in more money for his cure. However, despite all the efforts, they learned that his
condition is getting worse, and so, he finally succumbed to acute myeloid leukemia, inside the ICU whilst
holding a few “get well!” cards that some of my brother’s classmates have sent him.

He was a really kind-hearted person, and he was friends with most of his classmates in his section,
including my brother. All of them stayed in his house during the one whole week for his funeral; The
teacher also held off class for the whole week and also paid visit. It was heartbreaking, losing a fellow
classmate/friend, and a very young one, at that, to a disease that they knew about, but understood very
little of. However, they had shown support to the whole ordeal, and was able to make it clear to him that
he wasn’t going to die alone, and had died a rather peaceful death.

To those who are reading this, in behalf of my brother’s experience, please do not take leukemia
lightly. It is just as deadly as any other. Make sure to be able to prove the victim emotional and moral
support, especially during the times when he/she has zero chances on getting a guaranteed recovery.
Adriel Saycon
Reflections
After all the research that I’ve done about leukemia, I can say that leukemia is no joke of a disease.
It is actually a form of cancer that is just as deadly as any other cancers that is hidden underneath a less
intimidating name. Acquiring this disease is not to be taken with light consideration.

For the people who acquire this form of cancer this would definitely affect their lives and the people
around them, especially friends and family. This would definitely ruin their lives and their dreams of being
able to live a normal life. However, that doesn’t mean that people aren’t able to achieve a happy life while
under the mercy of this disease. With proper treatment, as well as proper moral and mental support from
everyone around him, being able to win over this kind of disease is not an impossible thing to do.

Leukemia has been a very deadly disease throughout history. Before, having acquired this disease is
basically a death sentence to its unfortunate victims. But, fortunately, with the progress we’ve had in the
field of medicine for the past 300 years has proved that leukemia is actually treatable, shedding some
hope for the patients having this disease.

With all the modern advancements to medicine in the 21st century, leukemia is less of a threat than
ever, with some of the most fatal forms of leukemia being now reduced in lethality, and therefore, being
easier to achieve a full recovery.

I believe that within a few decades, researchers will be able to discover a full cure not to just
leukemia, but in all other forms of cancer overall. I truly believe that the day will come where leukemia,
as well as other forms of cancer will be an unquestionably curable disease. I hope that the day in which
leukemia will be curable will be closer to us than we would first imagine.
 Adrian Alain Vargas
Reflection
I’ve read some case studies about leukemia, and the experiences that these leukemia patients have
to go through are no less startling than any other cancer patients. Imagine waking up on a normal day and
suddenly feeling tired and weak, as well as complaining about leg pains and dark black-and-blue spots
appearing all over your body, only to find out after the visit to the doctor that you have acquired leukemia.
So yeah, acquiring leukemia isn’t going to be very fun, as far as I know.

After that, you will be facing one of the hardest challenges in your life, and that is to fight with your
life against this disease. Not only will this test you mentally, emotionally, morally, and even spiritually, but
even financially. Most of your family’s savings will be mostly spent for the expensive treatments that need
to be taken if you were to survive. After all, health is wealth, and an ill person with a life-threatening
disease will significantly put a financial strain on your wallet.

Most of the people who actually survived the fight against leukemia came from well-developed
countries that offer the best medical care that is readily available. Patients from less well-developed
countries don’t get to be as lucky, due to the treatments being not only expensive, but also not readily
available due to how uncommon this disease actually is. This meant that if you are to live from a less
economically-stable country, your chances of recovery would be quite lower than those over America or
Europe. Your best bet for be able to have a full recovery from leukemia is to move to another country to
be able to receive the best treatments possible. And to be honest, most of us can’t even afford that, and
this, in itself, is a big problem.

I hope that everyone gets to have the same quality of treatment available to them at a fairly doable
price, because it would technically be unfair for those leukemia patients living in poor countries to be
having lower chances of survival from leukemia due to economic status of the country that they happen
to live in. I wish that in a few years, treatment for cancer patients would be readily available and
affordable, so that everyone gets to have equal opportunities to be able to win over the battle against
leukemia.