Leukemia - Chronic Myeloid - CML

Treatment Options

This section outlines treatments that are the standard of care (the best proven treatments available) for this specific type of cancer. When making treatment plan decisions, patients are also encouraged to consider clinical trials as an option. A clinical trial is a research study to test a new treatment to prove it is safe, effective, and possibly better than standard treatment. Your doctor can help you review all treatment options. 

Treatment overview

In cancer care, different types of doctors often work together to create a patient's overall treatment plan that combines different types of treatments. This is called a multidisciplinary team.

Descriptions of the most common treatment options for CML are listed below, followed by information on measuring treatment effectiveness and the common treatment recommendations outlined by the disease phase. Treatment options and recommendations depend on several factors, including the phase of the disease, possible side effects, and the patient's preferences and overall health. 

Targeted therapy

Targeted therapy is a treatment that attacks 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 normal cells. Targeted therapy is given by a medical oncologist, a doctor who specializes in treating cancer with medication, or a hematologist, a doctor who specializes in treating blood disorders.

Recent studies show that 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. As a result, doctors can better match each patient with the most effective treatment whenever possible. In addition, many research studies are taking place now to find out more about specific molecular targets and new treatments directed at them. 

For CML, the target is the unique protein called the BCR-ABL tyrosine kinase enzyme. There are four types of targeted therapy used to treat CML: imatinib (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), bosutinib (Bosulif). All four drugs can stop the BCR-ABL enzyme from working, which causes the CML cells to die quickly. These drugs are described in more detail below.

Imatinib was the first targeted therapy approved (in 2001) by the U.S Food and Drug Administration (FDA) for CML. Dasatinib and nilotinib were later approved for patients who either had severe side effects from imatinib or when imatinib was not working. In 2010, dasatinib and nilotinib were approved by the FDA as an initial treatment for patients with newly diagnosed chronic phase CML. Most recently, bosutinib was approved in 2012 for patients who cannot take other tyrosine kinase inhibitors or when these other drugs no longer work. It is not clear whether any of these drugs can cure CML, and the disease usually comes back if treatment is stopped. If treatment with one of these drugs has worked, a patient no longer has evidence of the Philadelphia chromosome and has normal levels of blood cells, called a complete cytogenetic remission. However, these drugs should be continued throughout the person’s life. To find the best treatment for them, 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.

Imatinib. Imatinib is given in pill form once or twice a day and causes fewer side effects than the chemotherapy (see below) used previously to treat CML. Nearly all patients with chronic phase CML have blood counts return to normal 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 the Philadelphia chromosome.

The recurrence rate for patients whose CML completely responds to imatinib is very low, and patients with few numbers of cells with the Philadelphia chromosome remaining will stay in chronic phase longer by taking imatinib than with previous treatments. Although it is too soon to know how long these responses will last or if patients will be cured with this medication alone, there are many patients who were treated with imatinib in the first clinical trials in 1999 who are still in complete cytogenetic remission.

The side effects of imatinib are mild but can include slight nausea, changes in blood counts, fluid retention, swelling around the eyes, fatigue, and muscle cramps.

Imatinib may also be used to treat some adults with other types of cancer, such as acute lymphoblastic leukemia (ALL) and the Philadelphia chromosome.

Dasatinib. Dasatinib is a pill that may be taken once or twice a day, depending on the dose. The side effects include anemia, neutropenia (low levels of white blood cells), thrombocytopenia (low platelet counts), and the build-up of fluid around the lungs or heart. The doctor will monitor a patient's blood counts frequently after starting dasatinib and may adjust dosing 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 anti-acid medications.

Nilotinib. Nilotinib is a capsule that patients take by mouth twice a day. Common side effects include low blood counts, rash, headache, nausea, and itching. Other possible but uncommon serious side effects include high blood sugar levels, fluid accumulation, and swelling of the pancreas. The most serious side effect of nilotinib includes possible life-threatening heart problems that can lead to an irregular heartbeat and possible sudden death. However, this side effect is very rare.

Bosutinib. Bosutinib is a pill taken once a day. The most common side effects are diarrhea, nausea and vomiting, abdominal pain, thrombocytopenia, anemia, rash, and fatigue.   

Measuring treatment effectiveness. Patients receiving imatinib, dasatinib, or nilotinib should receive regular check-ups with the health care team to see how well the treatment is working. The response of CML includes:

A complete hematologic response: the white blood cell and platelet counts have returned to normal, the spleen is of normal size and cannot be felt on physical examination, and the patient has no symptoms of CML

A partial response: the blood counts are still abnormal, there may still be some immature blasts in the blood, and the spleen may still be enlarged, but the symptoms and blood test results are improved compared with those before treatment

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 cells. Once a person's cancer shows a complete hematologic response, the doctor then looks for a cytogenetic response.

A complete cytogenetic response means that there are no cells with the Philadelphia chromosome found on the cytogenetic tests.

A partial cytogenetic response means that between 1% and 34% 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.

An important goal of treatment is to achieve a complete cytogenetic response. This requires performing a bone marrow biopsy and is generally done 3 to 6 months after starting treatment when blood tests suggest that there are fewer leukemia cells.

More sensitive blood tests, such as FISH and PCR , are usually done several times a year 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, which means that amount of cells with the BCR-ABL gene have been greatly reduced and further bone marrow tests are not necessary.

Sometimes, a tyrosine kinase drug stops working and the CML develops resistance to it. Resistance can occur if patients do not take their medication regularly, as prescribed. Even if patients do take the medication correctly, CML may become resistant to tyrosine kinase inhibitors, which is why it is important that the patient receives regular monitoring with cytogenetic testing, FISH, or PCR to monitor how well the drug is continuing to work. When used as the initial treatment, both dasatinib and nilotinib have been shown to produce a complete cytogenetic response sooner and in more patients when compared with imatinib; however, imatinib has been used for longer. If the medication you start with stops working, a different tyrosine kinase drug may still be effective.

Chemotherapy

Chemotherapy is the use of drugs to kill cancer cells, usually by stopping the cancer cells' ability to grow and divide. In systemic chemotherapy, the drugs travel through the bloodstream to reach cancer cells throughout the body. A chemotherapy regimen (schedule) usually consists of a specific number of cycles given over a set period of time. A patient may receive one drug at a time or combinations of different drugs at the same time.

A drug called hydroxyurea (Hydrea, Droxia) is often given to lower the number of white blood cells until the definite diagnosis of CML is made with the tests described in the Diagnosis section. Given in pill 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 number of cells with the Philadelphia chromosome and does not prevent blast crisis alone. Although hydroxyurea has few side effects, most patients newly diagnosed with chronic phase CML receive imatinib or other tyrosine kinase inhibitors (see above) as soon as possible. Side effects of chemotherapy depend on the specific drug and the dosage and usually go away when treatment is complete.

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. 

Stem cell transplantation/bone marrow transplantation

A stem cell transplant is a medical procedure in which diseased bone marrow is replaced by highly specialized cells, called hematopoietic stem cells. Hematopoietic stem cells are 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 blood stem cells 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 and consider several other factors, such as the type of leukemia, results of any previous treatment, and patient's age and general health.

There are two types of stem cell transplantation depending on the source of the replacement blood stem cells: allogeneic (ALLO) and autologous (AUTO). Only ALLO transplants are used to treat of CML and may be a primary treatment option for some younger patients.

In both types, the goal of transplantation is to destroy cancer cells in the marrow, blood, and other parts of the body and allow replacement blood stem cells to create healthy bone marrow. In most stem cell transplants, the patient received high doses of chemotherapy and/or radiation therapy to destroy as many cancer cells as possible. 

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 bolster, target, or restore immune system function. Interferon 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 and 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 therapy was the primary treatment for chronic phase CML before imatinib became available. A clinical trial showed that imatinib worked better to treat CML than interferon with fewer side effects. Therefore, interferon is no longer recommended as the first treatment for CML. 

Palliative/supportive care

Leukemia and its treatment often cause side effects. In addition to treatment to slow, stop, or eliminate the disease, an important part of care is relieving a person's symptoms and side effects. This approach is called palliative or supportive care, and it includes supporting the patient with his or her physical, emotional, and social needs.

Palliative care can help a person at any stage of illness. People often receive treatment for the leukemia and treatment to ease side effects at the same time. In fact, patients who receive both often have less severe symptoms, better quality of life, and report they are more satisfied with treatment.

Before treatment begins, talk with your health care team about the possible side effects of your specific treatment plan and supportive care options. And during and after treatment, be sure to tell your doctor or another health care team member if you are experiencing a problem, so it is addressed as quickly as possible. 

Treatment by phase

Chronic phase

The immediate goals of treatment are to alleviate any symptoms the patient may be have. The longer-term goals are to decrease or get rid of the cells with the Philadelphia chromosome to slow down or prevent the disease from moving to blast crisis. Treatment may include one or more of the drugs mentioned above or an ALLO stem cell transplantation.

Accelerated phase

The same drugs used for chronic phase CML may also be used in the accelerated phase. Although treatment with a tyrosine kinase inhibitor can work well during this stage, it is less likely to work as well as it does for chronic phase CML, and many patients have a recurrence within about two years. Dasatinib or nilotinib are more effective in providing longer remissions. Therefore, an ALLO stem cell transplantation should be considered when possible. If an ALLO stem cell transplantation is not recommended or if a matched donor cannot be found, the treatment plan may include a different tyrosine kinase inhibitor or a clinical trial.

Blastic phase

Treatment with a tyrosine kinase drug only works well for a few months for patients in blast crisis, but it can help to control the CML while a stem cell/bone marrow transplantation is being arranged. If the transplant can be done while imatinib or dasatinib is working, then the long-term results are better. Stem cell/bone marrow transplantation in the blast phase is less successful than in chronic phase, but this approach as worked well for some patients. Many people with CML in blastic phase receive imatinib or dasatinib plus the chemotherapy, an approach usually used for patients with acute myeloid leukemia (AML). The chance of remission from this approach is about 20%; most patients' leukemia recurs within weeks to a few months. Hydroxyurea (see Chemotherapy, above) is often given to patients because it can help control blood cell levels. If stem cell/bone marrow transplantation is not an option, the doctor may recommend a clinical trial.

Recurrent CML

It is not yet proven whether imatinib, dasatinib, or nilotinib can cure CML. A remission is when leukemia cannot be detected in the body by cytogenetic testing and there are no symptoms. This may also be called “no evidence of disease” or NED.

A remission can be temporary or permanent. This uncertainty leads to many survivors feeling worried or anxious that the leukemia will come back. While many remissions are permanent, it is important to talk with your doctor about the possibility of the disease returning. Understanding the risk of recurrence and the treatment options may help you feel more prepared if the leukemia does return. 

If the leukemia does return despite the original treatment, it is called recurrent leukemia. When this occurs, a cycle of testing will begin again to learn as much as possible about the recurrence. After testing is finished, you and your doctor will talk about your treatment options. Often the treatment plan will include the therapies described above (such as targeted therapy, chemotherapy, and immunotherapy) but may be used in a different combination or given at a different pace. Your doctor may also suggest clinical trials that are studying new ways to treat this type of recurrent leukemia.

People with recurrent leukemia often experience emotions such as disbelief or fear. Patients are encouraged to talk with their health care team about these feelings and ask about support services to help them cope. 

Refractory CML

If the leukemia worsens after treatment or does not respond appropriately, it is called refractory leukemia. Patients with this diagnosis are encouraged to talk with doctors who are experienced in treating this type of leukemia, because there can be different opinions about the best treatment plan. 

For many patients, a diagnosis of refractory leukemia can be very stressful and, at times, difficult to bear. Patients and their families are encouraged to talk about the way they are feeling with doctors, nurses, social workers, or other members of the health care team. It may also be helpful to talk with other patients, including through a support group.

Coping with Side Effects

Fear of treatment side effects is common after a diagnosis of leukemia, but it may help to know that preventing and controlling side effects is a major focus of your health care team. This is called palliative or supportive care, and it is an important part of the overall treatment plan, regardless of the stage of disease.

Common side effects from each treatment option for CML are described in detail within the Treatment section.  Side effects depend on a variety of factors, including the phase, the length and dosage of treatment(s), and your overall health.

Before treatment begins, talk with your doctor about possible side effects of each type of treatment you will be receiving. Ask which side effects are most likely to happen, when they are likely to occur, and what can be done to prevent or relieve them. And, ask about the level of caregiving you may need during treatment and recovery, as family members and friends often play an important role in the care of a person with CML. 

In addition to physical side effects, there may be psychosocial (emotional and social) effects as well. Patients and their families are encouraged to share their feelings with a member of their health care team who can help with coping strategies. 

During and after treatment, be sure to tell the health care team about the side effects you experience, even if you feel they are not serious. Sometimes, side effects can last beyond the treatment period, called a long-term side effect. A side effect that occurs months or years after treatment is called a late effect. Treatment of both types of effects is an important part of survivorship care. 

After Treatment

As treatment for CML is completed (such as after a successful stem cell/bone marrow transplantation) or continues long-term (such as treatment with targeted therapy), talk with your doctor about developing a follow-up care plan. This plan may include regular physical examinations and/or medical tests to monitor your recovery for the coming months and years.

People treated for CML and in remission should receive lifelong follow-up examinations on a regular basis to watch for signs or symptoms of recurrence or late effects. People treated for CML are encouraged to follow established recommendations for good health, such as not smoking, eating a balanced diet, maintaining a healthy weight, and receiving appropriate screening for other types of cancer. 

For many patients, targeted therapy, such as imatinib, dasatinib, and nilotinib, is an ongoing cancer treatment. Any decision to discontinue these drugs should be decided by a patient and doctor together, based these how well the drug continues to work and the side effects.

Latest Research

Doctors are working to learn more about CML, ways to prevent it, how to best treat it, and how to provide the best care to people diagnosed with this disease. The following areas of research may include new options for patients through clinical trials. Most cancer centers are actively involved in clinical trials aimed at increasing the number of people who are cured of CML. Always talk with your doctor about the diagnostic and treatment options best for you.

Imatinib resistance. Sometimes, CML becomes resistant to imatinib when the BCR-ABL gene develops new changes, which prevent imatinib from blocking the enzyme. Research focused on increasing the effectiveness of this treatment are listed below:

Switching to another tyrosine kinase drug

Using higher doses of imatinib as the first treatment

Combining imatinib with other drugs, including low-dose cytarabine (Cytosar-U), alpha interferon (Roferon-A, Intron A, Alferon), pegylated interferon, or other BCR-ABL inhibitors

Other chemotherapy drugs such as omacetaxine

Testing new drugs that have been made specifically to block new mutations in the BCR-ABL fusion gene, such as ponatinib.

Creating vaccines against BCR-ABL

Developing newer methods of stem cell transplantation aimed at decreasing the side effects

Evaluating other new tyrosine kinase inhibitors for CML that does not respond to imatinib

Safely stopping tyrosine kinase drug treatment without the CML coming back.

Supportive care. Clinical trials are underway to find better ways of reducing symptoms and side effects of current CML treatments in order to improve patients' comfort and quality of life.