Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. CML originates in the bone marrow, where blood cells are made. This cancer is caused by a mutation (change) in the genes of progenitor (early) cells.

Human cells contain 46 chromosomes. These coiled structures contain our genes, the blueprints for the body and its functions. In CML, the ABL gene on chromosome 9 joins to the BCR gene on chromosome 22. They form a new BCRABL “fusion gene” that changes chromosome 22. This altered chromosome is called the Philadelphia (Ph) chromosome.

There are three phases of CML: chronic (the leukemia is slow growing and responds more easily to treatment), accelerated (cancer cells start to grow more quickly) and blast crisis (leukemia is fast growing and treatment is needed right away). Nearly every case of CML has the Ph chromosome, although, on rare occasions, an illness which appears like CML can be present without evidence of the Ph chromosome. The BCRABL fusion gene mutation happens sporadically and without clearly identified risk factors. It cannot be passed on from parents to children.

Often, the symptoms of CML are not very specific: feeling run down or tired, night sweats, loss of appetite or bleeding easily. Doctors may discover an enlarged spleen (located below the ribs on the left side) when examining a person with CML. The spleen can enlarge because it is overactive in removing and destroying abnormal blood cells.

CML is most often suspected when blood counts are performed and characteristic changes are seen in the white blood count. The best way to diagnose and confirm CML is to look for the presence of the Ph chromosome through a blood or bone marrow test.

In the last 15 years, treatments for CML have dramatically improved. Due to these advances, there are an increasing number of people with CML who are in remission (no signs or symptoms of cancer).

Tyrosine-Kinase Inhibitors (TKIs)

TKIs are oral medications designed to block the signals that tell cancer cells to grow and divide. TKIs are targeted treatments, which means that they focus on specific cell mechanisms thought to be important for cancer growth. Because of this focus, targeted treatments tend to spare healthy cells and cause less severe side effects than chemotherapy.

Imatinib (Gleevec). This drug was the first TKI approved by the FDA for CML and dramatically changed the outlook for people with CML. Imatinib, taken as a pill every day, makes the cancer go into long term remission in most patients. It works by shutting down the function of BCR-ABL, the abnormal protein produced by the Ph chromosome. This altered protein permits CML cells to grow and divide in excess and prematurely leave the bone marrow. In eight out of ten people treated with imatinib, the Ph chromosome disappears completely (deep molecular remission).

Many of the earliest patients treated with imatinib have now been in remission for more than ten years, and research is ongoing to explore the possibility of a “treatment free remission”; however, indefinite treatment continues to be the standard. Despite its long safety and successful response record, imatinib is not effective for all patients, either due to resistance or intolerance, so doctors sometimes must turn to other treatments.

Nilotinib (Tasigna) and dasatinib (Sprycel). Like imatinib, nilotinib and dasatinib are taken in pill form and treat CML by blocking the growth and division of cells. They target the same BCR-ABL protein, but with increased potency. When used as a first-time treatment, both drugs have been shown to be more effective than imatinib as measured by an increase in deep molecular remissions and protection against the progression to advanced phases of CML. These medications can also benefit people whose CML stops responding to imatinib and those who cannot continue on imatinib because of its side effects.

Both of these drugs have their own distinct side effects. Nilotinib is associated with liver enzyme elevation, changes in blood sugar, and increased risk of vascular problems. Dasatinib is associated with fluid retention in the lungs (pleural effusion) and elsewhere in the body (pericardial effusion). Rarely, there can be an increase in pressure in the blood flow between the heart and lungs (pulmonary hypertension). These side effects need to be weighed against the benefits for people considering treatment with nilotinib or dasatinib.

Bosutinib (Bosulif). Similar to nilotinib and dasatinib, bosutinib was developed for people with CML who cannot benefit from taking imatinib. Like all targeted treatments, bosutinib causes side effects that must be carefully monitored by patients and their doctors; side effects can include liver function problems and GI symptoms, such as diarrhea. Despite these issues, bosutinib provides an alternative for patients with resistance to or intolerance of imatinib, nilotinib, or dasatinib.

Ponatinib (Iclusig). Ponatinib was initially developed to be beneficial for CML with a specific gene mutation known as T315I. This mutation makes CML cells resist treatment with imatinib, nilotinib, dasatinib and bosutinib. However, ponatinib can also benefit patients with more advanced and more resistant CML, not just those with the T315I mutation. Ponatinib was initially approved as a treatment for patients with some forms of leukemia in December 2012; it was subsequently temporarily removed from the market to address safety concerns regarding vascular events. After 3 months, it returned to the market with several new safety measures added to the label. Although the side effects of ponatinib carry risk, it may be of benefit for patients with highly resistant CML, and can be an effective treatment strategy for patients who have only limited or higher-risk options.

The most important milestone reached with TKI treatments is called major molecular remission; it occurs when the amount of measurable CML is 1,000 times smaller than when it was first diagnosed. Doctors look for this level of remission within the first 12 to 18 months of continuous treatments. There are also interim milestones—blood cell counts returning to normal, the spleen enlargement resolving, an early (after three to six months of treatment) reduction in measurable CML, and no cells with the Ph chromosome found in the blood or bone marrow.

Other Treatment Options

Omacetaxine (Synribo). Approved by the FDA in October 2012, Synribo is an injectable medicine used to treat adults with CML who are no longer responding to, or could not tolerate, two or more TKIs. It can stabilize CML for a period of time by bringing back blood remission and, in some patients, a deeper (cytogenetic) response; this includes patients with the T315I mutation. The most common side effects of Synribo include a low level of platelets in the blood (thrombocytopenia); low red blood cell count (anemia); a decrease in infection-fighting white blood cells (neutropenia), which may lead to infection and fever, diarrhea, nausea, weakness and fatigue; injection site reaction; and a decrease in the number of lymphocytes in the blood (lymphopenia).

Chemotherapy. Older medications such as hydroxyurea can still be useful to control high blood cell counts. Doctors now mostly prescribe hydroxyurea very early in the diagnosis process (before Ph chromosome testing results are available) and subsequently only if all other treatments have stopped working. Often, the vitamin folic acid is taken with hydroxyurea. Common side effects of this drug include skin ulcers, nail changes, and low blood counts.

Immune system modulators. Before imatinib was approved, the standard treatment for CML was interferon. Interferon may work by stimulating an immune response as well as by blocking the division of cancer cells and slowing tumor growth. Researchers continue to study ways of incorporating interferon and a number of other medications designed to strengthen the body’s immune response to CML, including vaccines. The ability to “reprogram” a patient’s or donor’s immune cells so they can recognize and destroy cancer cells has generated great interest as to whether this approach will work for other white blood cell (myeloid) disorders.

Stem cell/bone marrow transplant. This treatment is usually recommended for younger patients who have already tried a number of other treatments that either did not work or caused side effects that could not be tolerated. It is also an option for any patient whose CML advances under treatment or presents in an advanced stage; in both cases, control of the CML prior to transplant is important. Also, to be eligible for a transplant, patients need a well-matched donor; this is usually a close relative, such as a brother or sister. Because the risks associated with bone marrow transplants increase with age, and TKI therapy can offer significant long term benefit for most, the number of patients going on to transplant is low.

No matter what treatment option is chosen, continual monitoring is essential. CML is a chronic disease, and patients will see their doctor and other members of their health care team many times—in the first several years after diagnosis, likely every 3 to 6 months. Monitoring may consist of complete blood count tests, EKGs to assess heart rhythms, liver function tests, and molecular testing (in particular, a test called quantitative Polymerase Chain Reaction, or qPCR). Patients should talk to their doctor to seek the best molecular testing available; they should also receive the test results and make sure they understand what the results mean.

While CML has become a chronic, highly treatable disease, there are still questions that can only be answered in clinical trials. For instance, the current guidance is that TKIs must be taken continuously, even if the patient is in major molecular remission. Investigations into whether it is ever safe to discontinue treatments should take place only in the well-monitored environment of a clinical trial.

Clinical trials will also be essential as new questions arise, and as new treatment approaches are being researched and developed. The search for newer targeted drugs and immune-based therapy is ongoing.

Patients who are interested in participating in clinical trials should talk to their doctor; availability of clinical trials can be found at, a service of the U.S. National Institutes of Health.

Because so many people with CML are treated with TKIs for years and even decades, they face a number of challenges, including coping with the side effects of their medication and staying on a drug for a long time. Doctors now have a great deal of experience helping patients manage their symptoms.

Fatigue (extreme tiredness not helped by sleep) is one of the most common side effects for people living with CML. In some cases, doctors can lower the dose of the drug, as long as it does not make the treatment less effective. Sometimes switching to a different drug may be needed. If you are experiencing fatigue, talk to your doctor about whether taking a smaller dose is right for you.

There are a number of other tips for reducing fatigue:
• Take several short naps or breaks.
• Take short walks or do some light exercise, if possible.
• Try easier or shorter versions of the activities you enjoy.
• Ask your family or friends to help you with tasks you find difficult or tiring.
• Save your energy for things you find most important.

Fatigue can be a symptom of other illnesses, such as diabetes, thyroid problems, heart disease, rheumatoid arthritis, and depression; it may also be associated with problems related to CML, such as anemia. So be sure to ask your doctor if he or she thinks any of these conditions may be contributing to your fatigue. Also, it could be very valuable to talk to an oncology social worker or oncology nurse. These professionals can also help you manage fatigue. They can work with you to manage any emotional or practical concerns that may be causing symptoms and help you find ways to cope.

Digestive tract symptoms are also common but usually not severe: mild nausea, occasional vomiting, loss of appetite, or diarrhea. CML medicines are prescribed with specific instructions; some are best taken with a meal, while others should be taken on an empty stomach. Your doctor can prescribe medications for digestive tract side effects.

The following tips also may help:

Nausea and vomiting:
• Avoid food with offending odors, as well as overly sweet, greasy, fried or highly seasoned food.
• Eat meals cold or at room temperature, which often makes food more easily tolerated.
• Nibble on dry crackers or toast; these bland foods are easy on the stomach.

Loss of appetite:
• Because it’s important to maintain your weight, eat small meals throughout the day. That’s an easy way to take in more calories and protein.
• To keep from feeling full early, avoid liquids with meals or take only small sips (unless you need liquids to help swallow). Drink most of your liquids between meals.
• Be as physically active as you can. Sometimes, taking a short walk an hour or so before meals can help you feel hungry.
• Keep high-calorie, high-protein snacks on hand such as hard-boiled eggs, peanut butter, cheese, ice cream, granola bars, liquid nutritional supplements, puddings, nuts, trail mix, or canned tuna.
• Eat your favorite foods any time of the day. For example, if you like breakfast foods, eat them for dinner.

• Drink plenty of water. Ask your doctor about using drinks such as Gatorade which provide electrolytes as well as liquid. Electrolytes are body salts that must stay in balance for cells to work properly.
• Over-the-counter medicines such as loperamide (Imodium A-D and others) and prescription drugs are available for diarrhea but should be used only if necessary. If the diarrhea is bad enough that you need medicine, discuss it with your doctor or nurse.
• Avoid sweetened foods and alcohol.
• Choose fiber-dense foods such as whole grains, fruits and vegetables, all of which help form stools.

Skin rash. People being treated for CML with TKIs are sometimes affected by skin rash. In general, the rash is mild and can be treated with antihistamines or, rarely, topical steroids. Before you treat a rash with over-the-counter medications, talk to your doctor. It’s important to closely monitor this and other symptoms to make sure they do not worsen and affect your health or quality of life.

There are other side effects that can occur soon after TKI treatments have begun, or after they have been in place for a longer period of time. Some of these include:

Muscle pain and cramps. Talk to your doctor if this occurs; he or she may recommend taking supplements such as magnesium or calcium.
Liver function tests. Talk to your doctor about including a liver function test in your routine monitoring. Liver function changes often occur in the first 12 to 18 months of treatment.
Fluid retention. Fluid retention can cause edema (swelling) around the eyes and in the legs, and pleural effusion (a build-up of fluid between the tissues that line the lungs and the chest). Fluid retention can develop at any point, so it needs to be monitored throughout TKI treatment.
Vascular problems. Reports have shown that some patients taking nilotinib (Tasigna), or ponatinib (Iclusig) have experienced vascular problems, including coronary artery disease and heart attacks, stroke, and peripheral artery disease. Talk to your doctor about these possible effects at the time you are prescribed any TKI (especially ponatinib), and if you experience any vascular problems.

There may be other options available to you. All of your doctors should know what medications you are taking, as there can be interactions between TKIs and other medications, even those you might consider harmless (e.g. antibiotics). It is important to know that treatment with TKIs is very well tolerated by most patients. Not every patient develops every side effect, and many do not develop any at all.

Taking medication over many years means maintaining a schedule and staying on track. That’s especially crucial for people living with CML. Doctors have found that missing even two or three doses a month can reduce the odds of achieving treatment milestones, including major molecular remission (the most significant milestone).

Your doctor and other members of your health care team understand that you may be facing hurdles that impact your ability to adhere to your medication schedule. If you are having difficulty, talk to one of them. With their help, and the following tips, you should be able to stay on your medication:

Get a plan on paper. When you start taking your pills, have your doctor provide written instructions that you can take home and review.

Fit the drug into your usual routine. Check with your doctor about the best way to take your pills, including the time of day, before or after meals, or with food. It is always best to swallow your pills with water. If you are taking many pills, ask your doctor or pharmacist how best to space your pills, as some pills cannot be taken together. Take your prescribed pills the same time every day.

Consider using a pill sorter (available at drug stores) to sort your medication; fill it with a week’s supply of medicine. Place reminders on your calendar to refill your prescriptions several days before they run out.

If you are going on a trip, be sure to have plenty of medication with you, including extra pills in case your stay is extended or your return is delayed. Keep your medication with you at all times in your personal bag, rather than checking it with luggage, which could be lost. If you are on a road trip, make sure your pills don’t sit for long periods in a hot car trunk or in a locked car.

Know what to do if you miss a dose. Discuss this with your health care team. Do not take a double dose to make up for a missed one.

If you have trouble swallowing pills, ask your oncologist, nurse or pharmacist for suggestions on what to do. Your health care team can advise you on the best method to use.

Know what to expect. Medications often have side effects. Review with your health care team the expected side effects. If you experience any unusual or unexpected symptoms, call your doctor immediately. Do not try to treat these side effects on your own, and do not stop taking your medication without talking to your doctor.

As you manage your CML, it’s important to remember that you are a consumer of health care.

The best way to make decisions about health care is to educate yourself about your diagnosis and who is on your health care team, including nurses, social workers and patient navigators. In addition to creating a treatment summary, here are some tips for improving communication with your health care team:

Start a health care journal. Having a health care journal or notebook will allow you to keep all of your health information in one place. You may want to write down the names and contact information of the members of your health care team, as well as any questions for your doctor. Keep a diary of your daily experiences with your CML and its treatment. You can separate your journal or notebook into different sections to help keep it organized.

Prepare a list of questions. Before your next medical appointment, write down your questions and concerns. Because your doctor may have limited time, you should ask your most important questions first, and be as specific as possible.

Bring someone with you to your appointments. Even if you have a journal and a prepared list of questions or concerns, it’s always helpful to have support when you go to your appointments. The person who accompanies you can serve as a second set of ears. He or she may also think of questions to ask your doctor or remember details about your symptoms or treatment that you may have forgotten.

Write down your doctor’s answers. Taking notes will help you remember your doctor’s responses, advice and instructions. If you cannot write down the answers, ask the person who accompanies you to do that for you. If you have a mobile device, you can use it to take notes. Writing notes will help you review the information later.

Record your visit if your doctor allows it. Recording the conversation with your doctor gives you a chance to hear specific information again or share it with family members or friends.

Incorporate other health care professionals into your team. Your oncologist and oncology nurse are essential members of your health care team, but there are other health care professionals who are also critical in ensuring a holistic approach to your care:
• Your primary care physician should be kept updated about your CML treatment and test results.
• Your local pharmacist is a great source of knowledge about the medications you are taking. Have all of your prescriptions filled at the same pharmacy to avoid the possibility of harmful drug interactions.
• Make sure your oncologist knows of any other medical conditions you have, or any pain you are experiencing, so that they can consult with your primary care physician or your specialist if needed.

Remember, there is no such thing as over-communication.

Frequently Asked Questions

Q. Should I be taking the new oral drugs, which may not work for me, or consider getting a bone marrow transplant?

A. This is one of the most important decisions doctors make in treating CML. Most patients do benefit from the newer oral treatments, and there are several to choose from. If none of the new therapies works or if a patient has moved on to a second or third drug and the cancer is still resisting treatment, doctors then consider recommending a bone marrow transplant. The lesson we have learned is not to wait to do a transplant until the cancer advances greatly.

Doctors need to monitor their patients’ progress and make careful decisions along the way. The transplant option is a good one, especially for a younger person with a matched donor. However, most people with CML are middle aged or older, and transplants pose more challenges for them. Although we have made great advances in managing side effects and can reduce the risk of infection and other complications, bone marrow transplants can be difficult procedures.

Q. I took ponatinib [Iclusig] for several weeks, but because of the side effects I experienced, I had to stop using it. I am now waiting to begin on a lower dose. Will it still be effective?

A. We know from clinical trials that lower doses may continue to work and that it may be recommended to lower the dose once the desired response is achieved. For people who experience side effects on any TKI, there are choices—including a brief period off the drug, a dose reduction (either temporarily or for the long term), or a change in therapy. All of this needs to be carefully done under a doctor’s care.

Q. I’m feeling so tired all the time, but I’m not sure if it’s because of the CML drug I’m taking or some other reason. What should I do?

A. It is very important to understand the cause of your fatigue. For example, it may be anemia due to a low red blood cell count or an infection. Discuss your symptoms with your doctor or nurse; they can address the underlying cause. Once the cause of your symptoms has been treated, there are a number of things you can do to prevent or reduce fatigue. Follow the tips listed in this guide and consider using complementary techniques such as yoga, meditation, guided imagery or tai chi. All of these methods encourage deep breathing. Oxygen helps the brain and body function better.

Q. I’m taking a proton pump inhibitor for GERD. Could this reduce the effectiveness of the TKI I am taking?

A. Acid-suppressive drugs such as proton pump inhibitors (PPIs) can reduce the absorption of TKIs into the bloodstream. This is a particular issue for dasatinib (Sprycel). Talk to your oncologist and the doctor who prescribed the PPI. They may recommend alternative strategies instead of a PPI, or in some cases taking the PPI and the TKI several hours apart to minimize interactions.

Q. I was thinking about joining a clinical trial, but I don’t want to replace my treatment with a placebo.

A. Most cancer trials test the addition or substitution of a drug, and will not use placebos. Because continuous treatment is essential in the treatment of CML, talk to your oncologist before joining a trial, to make sure your treatment will not be interrupted. You will also want to find out if he or she has any other concerns about you joining that specific trial.

Q. Is it safe for me to get pregnant while I am on Gleevec?

A. There is very little data available on this topic, but as a general rule TKIs need to be stopped (or not started) during pregnancy. If you are taking a TKI, or are under any other form of treatment, it’s best to talk to your oncologist about family planning as other options may exist.

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This e-booklet has been made possible by Bristol-Myers Squibb; Pfizer; and Teva Oncology.

Last updated July 01, 2015

The information presented in this publication is provided for your general information only. It is not intended as medical advice and should not be relied upon as a substitute for consultations with qualified health professionals who are aware of your specific situation. We encourage you to take information and questions back to your individual health care provider as a way of creating a dialogue and partnership about your cancer and your treatment.

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