Patient information: Chronic myeloid leukemia (CML) in adults (Beyond the Basics)
- Robert S Negrin, MD
Robert S Negrin, MD
- Section Editor — Bone Marrow Transplantation
- Professor of Medicine
- Stanford University School of Medicine
- Charles A Schiffer, MD
Charles A Schiffer, MD
- Professor of Medicine and Oncology
- Barbara Ann Karmanos Cancer Institute
- Wayne State University School of Medicine
CHRONIC MYELOID LEUKEMIA OVERVIEW
Chronic myeloid leukemia (also called CML or chronic myelogenous leukemia) is a chronic (long-term) disorder of the bone marrow. Bone marrow is the spongy, red tissue that fills the large bones. All of the blood cells are produced in the bone marrow.
People with CML have acquired an abnormality that causes a section of one chromosome (a strand of genes) to break off and attach to another chromosome; this results in an abnormally short chromosome, known as the Philadelphia chromosome. This exchange of genetic information causes two genes, BCR and ABL, to fuse into one gene, called BCR-ABL.
The BCR-ABL gene causes bone marrow cells to produce an abnormal enzyme (the BCR-ABL tyrosine kinase); this enzyme stimulates white blood cells to grow out of control, resulting in elevations of the white blood cell count and an increase in the size of the spleen. Eventually, the disease can transform into a more aggressive disease, called acute leukemia.
People with acute leukemia have an increased number of immature white blood cells (called blast cells). The overgrowth of blast cells leads to an inadequate number of mature white blood cells, which limits production of other vital blood cells, including red blood cells and platelets. Having a decreased number of blood cells and platelets can increase the risk of developing infections or bleeding excessively.
PHASES OF CHRONIC MYELOID LEUKEMIA
There are three phases of CML:
Chronic phase — In the chronic phase, there are less than 5 percent immature blast cells in the bone marrow. Approximately 85 percent of people are in the chronic phase when they are initially diagnosed. This phase generally lasts several years and is readily controlled with oral medications.
Accelerated phase — During the accelerated phase, maturation of white blood cells becomes progressively impaired, and there are between 10 and 19 percent blast cells in the blood or bone marrow. The number of abnormal cells in the body is more difficult to control with medications, likely because of new mutations that develop in the blast cells.
Blast phase — In blast crisis (blast phase), there are more than 20 to 30 percent blast cells in the blood or bone marrow. Before recent advances in treatment, blast crisis typically occurred within four to five years after diagnosis and was often unresponsive to treatment.
CHRONIC MYELOID LEUKEMIA TREATMENT OPTIONS
Treatment decisions for people with chronic myeloid leukemia (CML) are complex due to the variety of available options. Currently, the most frequently used treatment options include:
●Disease control with oral tyrosine kinase inhibitors (TKIs) such as imatinib (brand name: Gleevec), dasatinib (brand name: Sprycel), or nilotinib (brand name: Tasigna)
●Potential cure with hematopoietic cell transplantation (also called bone marrow transplantation), usually after the disease stops responding or relapses during treatment with a TKI
●Treatment to reduce symptoms with chemotherapy (hydroxyurea, busulfan, or interferon alpha with or without cytarabine)
The choice of therapy depends upon the phase of CML, the availability of a stem cell donor, the patient's candidacy for stem cell transplantation, and the patient's preference.
Response to treatment — The primary goal of treatment is to reduce or eliminate the cells with the abnormal Philadelphia chromosome. This is measured as the cytogenetic response. Such treatment, if effective, will also return the blood counts to normal. This is measured as the hematologic response.
While achieving a hematologic response will reduce the severity of symptoms associated with CML, progression to the accelerated or blast phase will continue unless a cytogenetic response is achieved. Achieving a hematologic response is important, but does not ensure that the disease is adequately controlled.
Another way to determine how well the disease is controlled is to perform sensitive molecular testing. A person is said to have a complete molecular response when there is no evidence of the BCR-ABL gene. The goal of hematopoietic cell transplantation is to achieve this level of response. A molecular response is sometimes seen during longer term follow up of people treated with TKIs. Chemotherapy rarely, if ever, produces such a response.
TYROSINE KINASE INHIBITORS (TKIs)
The Philadelphia chromosome, characteristic of chronic myeloid leukemia (CML), gives rise to the formation of a unique gene product, an abnormal enzyme called the BCR-ABL tyrosine kinase. Researchers directed their efforts at developing compounds that could selectively inhibit this abnormal enzyme, resulting in the development of a class of medications known as tyrosine kinase inhibitors (TKIs). TKIs slow or stop the actions of BCR-ABL, which leads to the rapid death of cells containing the abnormal Philadelphia chromosome. Normal cells suffer fewer toxic effects from TKIs compared with traditional chemotherapy treatments.
Although they have not been proven to cure the disease, TKIs are able to achieve long-term control of CML in the majority of people; thus, they have become the initial treatment of choice for almost all people who are newly diagnosed with CML. All of the available TKIs are able to induce hematologic and cytogenetic responses in all stages of the disease [1-3]. As a result, a choice among these medications is usually based upon the patient's medical history and the potential side effects of each medication (table 1).
Many prescription and non-prescription medications can interact with TKIs, potentially making the treatment less effective or dangerously increasing the amount of drug in the bloodstream. Two non-prescription medications that should be avoided are acetaminophen (brand name: Tylenol) and St. John's wort (also called hypericum perforatum). Grapefruit juice should also be avoided.
Imatinib (brand name: Gleevec) — Imatinib mesylate is a TKI that can be used in people with all phases of CML. It is proven to have significant benefits. One study comparing imatinib versus interferon plus cytarabine (a form of chemotherapy) for people with newly diagnosed, chronic phase CML found that 97 percent of people who were given imatinib had a complete hematologic response rate, and 76 percent achieved a complete cytogenetic response .
Further follow-up is needed to determine how long responses will last, although the relapse rate has been remarkably low in people followed for seven or more years who achieved a complete cytogenetic response. At present, experts recommend continuing imatinib treatment indefinitely because the disease recurs, often within months, in the majority of people who stop taking it. Progression to blast crisis can occur despite imatinib treatment in people with accelerated phase disease and in those who acquire new genetic mutations.
The medication should be taken by mouth once daily, with a meal and a large glass of water.
It is extremely important to take every single scheduled dose of your imatinib. Skipping pills can seriously jeopardize your chances of having a good response. One study showed that you need to take over 90 percent of your pills to have a chance of a sustained complete response . (See "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy", section on 'Resistance'.)
Side effects — Imatinib is generally very well tolerated; most side effects are mild to moderate and do not cause the person to stop taking it. Less than 5 percent of people will be unable to tolerate long-term treatment with imatinib.
Common side effects include:
●Nausea and vomiting, although this is not usually a problem when the drug is taken with meals.
●Diarrhea is usually mild to moderate, but can be severe. It generally responds to treatment with loperamide (brand name: Imodium).
●Muscle cramps are perhaps the most bothersome long-term symptom associated with imatinib, most commonly affecting the calves, feet, and hands. There is no definitive treatment, although some people benefit from treatment with calcium or magnesium supplements.
●Skin rash is uncommon. When it occurs, it is usually mild and often resolves with continued treatment.
●Breast enlargement (gynecomastia) may occur in a small number of men.
●Mild anemia, which manifests as fatigue or listlessness, is not uncommon in people who use imatinib for long periods.
●Some patients note mild to moderate fatigue.
Pregnancy — Women and men who take imatinib usually have no increased difficulty achieving pregnancy. However, the risk of miscarriage and birth defects while taking imatinib is uncertain. Thus, men and women who take imatinib are strongly advised to use a birth control method during treatment.
Women who take imatinib and become pregnant are left with a difficult choice:
●Continuing imatinib may result in damage to the developing fetus.
●Stopping imatinib may allow CML to relapse in the mother.
In one series of women exposed to imatinib during pregnancy, 50 percent delivered a healthy baby, 28 percent elected to have a termination, 14 percent had a miscarriage, and approximately 10 percent had a baby with a birth defect . In addition, imatinib is passed into breast milk, and breastfeeding women are advised to avoid imatinib. Women who become pregnant while taking imatinib should speak with their healthcare provider as soon as possible.
Dasatinib (brand name: Sprycel) — Dasatinib is a second generation TKI that may be recommended for treatment of CML after imatinib. It can also be used as initial treatment instead of imatinib. It is taken by mouth once or twice daily.
Side effects — Up to 35 percent of people who take dasatinib for advanced phase CML can develop a pleural effusion, a collection of fluid in space between the lining of the lung (the pleura) and the chest wall. In some cases, this complication requires a reduction in the dose of dasatinib, a temporary break in treatment, or a procedure to drain the fluid. Pleural effusions occur in approximately 10 percent of patients treated with dasatinib in chronic phase and generally tend to be of less clinical severity than in patients with advanced CML.
Rarely, patients have developed pulmonary hypertension-high blood pressure in the blood vessels that carry blood to the lungs. Pulmonary hypertension causes people to have trouble breathing and to feel very tired.
Women who are pregnant or breastfeeding should not use dasatinib due to the potential risk of harm to the infant; men and women are strongly encouraged to use a birth control method during treatment.
Nilotinib (brand name: Tasigna) — Nilotinib is another second generation TKI that may be recommended for treatment of CML after imatinib. It can also be used as initial treatment instead of imatinib. It should be taken by mouth on an empty stomach (one hour before or two hours after eating) every 12 hours; taking the medication with food can lead to excessive amounts of the drug in the bloodstream and is not recommended.
Side effects — The most common side effects of nilotinib include rash, itching, nausea, and constipation. An abnormal heart rhythm, known as QT prolongation, is a potential side effect of both dasatinib and nilotinib. QT prolongation can potentially cause sudden cardiac death, although this complication is very rare. People who have an electrolyte imbalance (low blood level of potassium or magnesium), an abnormal heart rhythm, or who take medication to regulate their heart rhythm should talk with their doctor about the need for additional monitoring while taking dasatinib or nilotinib.
There is a higher rate of cardiovascular complications in patients receiving nilotinib compared with those receiving imatinib, particularly in individuals with cardiovascular risk factors (high blood pressure, high blood cholesterol, diabetes, smokers). These complications include stroke, heart attacks, and symptoms related to decreased blood flow to the legs. The latter is called "peripheral artery disease" and can cause leg pain that gets worse with activity. Muscle pain that gets worse with activity and improves with rest is called "claudication."
Women who are pregnant or breastfeeding should not use nilotinib; men and women are strongly encouraged to use a birth control method during treatment.
Bosutinib (brand name: Bosulif) — Bosutinib is another TKI that may be recommended for treatment of CML after failure of another TKI. It should be taken daily by mouth with food. Major side effects include diarrhea, abnormalities in liver function tests, and nausea and vomiting. Some patients have fluid retention. Fluid retention includes swelling in the legs (called edema) and fluid around the lungs (called pleural effusion). Women who are pregnant or breastfeeding should not use bosutinib; men and women are strongly encouraged to use a birth control method during treatment.
Ponatinib (brand name: Iclusig) — Ponatinib is another TKI that may be recommended for treatment of CML that has relapsed or is unresponsive to treatment with other TKIs. It is the only TKI that is active in CML with certain mutations (eg, T315I). Due to concerns regarding dangerous side effects, ponatinib is reserved for use in patients who are not candidates for other TKIs. Potentially life-threatening side effects include cardiovascular problems (stroke, heart attack, peripheral artery disease), inflammation of the pancreas (pancreatitis), and liver failure. Women who are pregnant or breastfeeding should not use ponatinib; men and women are strongly encouraged to use a birth control method during treatment.
If the tyrosine kinase inhibitor fails — People who cannot tolerate, fail to respond, or stop responding to an initial TKI are faced with the decision of what treatment to try next. The options include:
●Control the disease with another TKI, and then proceed as soon as possible with hematopoietic cell transplantation.
●Control the disease with another TKI with plans to proceed with transplantation if the disease relapses a second time.
●If the disease relapses despite treatment with another TKI and transplantation is not an option, treatment with interferon alpha can help to reduce symptoms and prolong survival. (See 'Interferon alpha' below.)
Relapses during treatment with a TKI are often due to the development of a new mutation in the BCR-ABL gene, which allows the disease to become resistant to treatment. Testing to determine whether additional mutations have developed in the BCR-ABL gene (called mutation analysis) can be performed. Some mutations (eg, T315I) will not respond to commonly available tyrosine kinase inhibitors (imatinib, dasatinib, or nilotinib); people with these mutations are generally encouraged to consider transplantation. (See 'Hematopoietic cell transplantation' below.)
If transplantation is not an option, options include treatment with omacetaxine (brand name: Synribo), ponatinib, or enrollment on a clinical trial. Omacetaxine is a chemotherapy that can be given as an injection under the skin daily for two weeks and repeated every four weeks for a maximum of six cycles. Side effects include infection, diarrhea, nausea, fever, and fatigue. (See 'Ponatinib (brand name: Iclusig)' above and 'Clinical trials' below.)
A major cause of treatment "failure" is poor compliance with taking the medication, meaning the patient has been skipping doses or not taking the medication as directed. Therefore, it is critical that the doctor be certain that the patient was actually taking the TKI treatment before switching therapies.
HEMATOPOIETIC CELL TRANSPLANTATION
In hematopoietic cell transplantation (pronounced "hee-mah-toh-poy-ET-ick"), also referred to as bone marrow transplantation or stem cell transplantation, the patient's diseased bone marrow (hematopoietic) cells are replaced with healthy ones from a donor. (See "Patient information: Bone marrow transplantation (stem cell transplantation) (Beyond the Basics)".)
Choice of donor — The donor is a person other than the patient; this is called an allogeneic transplant. Allogeneic transplants can come from a relative (eg, sibling) or from an unrelated donor. Within a family, the best chance for a match comes from siblings who have the same parents as the patient. Each sibling has a one in four chance of matching an individual patient. Since many people do not have a sibling who matches, unrelated donors may be used. Related or unrelated donors who are fully HLA-matched are preferred. Under some circumstances, partially or half-matched (haploidentical) donors can be used.
In chronic myeloid leukemia (CML), the chances of success with hematopoietic cell transplantation are directly related to the phase of disease at the time of the transplant. In the past, transplantation of people in chronic phase within the first year resulted in the best outcomes. Several studies have suggested that treatment with a tyrosine kinase inhibitor (TKI) prior to transplantation does not reduce the chance that transplantation will be successful, although additional studies are needed to confirm this finding.
If a matched sibling donor can be found, 50 to 85 percent of people with CML transplanted in the first or second chronic phase of their disease achieve long-term remissions. Disease-free survival falls to 30 to 40 percent in people transplanted in the accelerated phase, and to 10 to 20 percent in people transplanted in blast phase.
A patient's age has a major influence on the outcome after transplantation with cells from a sibling donor. In the subgroup of people under age 50 who undergo this procedure during the first year of diagnosis, 70 to 85 percent will be alive and free of disease five years later. However, people up to 60 years of age have successfully undergone allogeneic transplantation with treatments that completely destroy the bone marrow (myeloablative treatment). The development of reduced intensity regimens, which have reduced toxicity, has permitted even older people to be successfully transplanted.
Relapse after transplant — Relapse or recurrence of CML may occur if cells containing the Philadelphia chromosome remain after the transplant procedure. However, finding residual disease with sensitive molecular tests in the first six months following transplantation is not associated with eventual relapse because the anti-tumor effects of the graft may eventually prevail.
Relapse can be treated with a TKI or with infusions of leukocytes from the original donor, with the hope of mounting a more effective graft-versus-tumor effect. Donor leukocyte infusions (DLIs) can be extremely effective, and remissions attained after DLI appear to be quite durable. However, graft-versus-host disease, and in some instances graft failure, may complicate DLI.
DECIDING BETWEEN TRANSPLANTATION AND A TYROSINE KINASE INHIBITOR
Initial treatment with a tyrosine kinase inhibitor (TKI) is well-tolerated and effective for at least eight years in most people with chronic phase chronic myeloid leukemia (CML). Successful allogeneic transplantation can produce long-term suppression of CML with a very low chance of relapse because such people have a molecular, cytogenetic, and hematologic response.
However, transplantation has some potentially serious risks, including graft-versus-host disease and even death. While there have not been any randomized clinical trials directly comparing TKIs with hematopoietic cell transplantation in people newly diagnosed with chronic phase disease, most experts recommend initial treatment with a TKI, reserving transplantation for if/when the disease relapses.
Transplantation may be recommended as a part of the initial treatment in people who are diagnosed with accelerated or blast phase disease. Giving chemotherapy or a TKI prior to transplantation (to achieve chronic phase) is preferable to transplanting during the blast phase; the chance of a cure is greater when transplantation is done during the chronic phase.
Interferon alpha (IFNa, brand name: Pegasys) was commonly used in the past for treatment of chronic myeloid leukemia (CML). In up to 90 percent of people, interferon can induce a hematologic response, improve symptoms, and reduce or eliminate enlargement of the spleen (splenomegaly). However, tyrosine kinase inhibitors (TKIs) are clearly superior to IFNa in studies comparing the two treatments.
As a result, interferon is considered to be a "palliative" treatment for CML since it is not curative and only rarely results in a prolonged complete cytogenetic response. A patient who cannot tolerate TKIs might be offered IFNa with or without another chemotherapy medication, cytarabine.
Side effects — Side effects are a major problem with IFNa, and include fever, chills, and flu-like symptoms. Typically, the drug is started at a relatively low dose three days per week and then slowly increased. IFNa must be injected, and many people prefer to take their injection at night along with acetaminophen (brand name: Tylenol) and an antihistamine such as diphenhydramine (brand name: Benadryl) to minimize the side effects.
RECOMMENDATIONS FOR TREATMENT OF CHRONIC MYELOID LEUKEMIA
The treatment of chronic myeloid leukemia (CML) is complex, and the optimal treatment is a source of considerable debate. Therefore, consultation with a physician familiar with the latest data is critical.
●Tyrosine kinase inhibitors (TKIs) are preferred by most healthcare providers and people, and an expert panel has recommended their use as the initial treatment for people with newly diagnosed chronic phase CML.
●Allogeneic hematopoietic cell transplantation remains the only treatment that is known to cure CML. People who relapse during treatment with a TKI should discuss this option in detail with their physician. (See 'If the tyrosine kinase inhibitor fails' above.)
●Because relapses occur frequently in people with accelerated phase CML and in virtually all people with blast phase CML who are treated with a TKI, allogeneic transplantation should be considered when possible, preferably after the person's disease has responded to the TKI.
Many people with chronic myeloid leukemia (CML) will be asked about enrolling in a clinical (research) trial. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask your healthcare provider for more information, or read about clinical trials at:
●National Cancer Institute
●National Library of Medicine
WHERE TO GET MORE INFORMATION
Your healthcare provider is the best source of information for questions and concerns related to your medical problem.
This article will be updated as needed on our website (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.
Patient level information — UpToDate offers two types of patient education materials.
The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.
Patient information: Leukemia in adults (The Basics)
Patient information: Chronic myeloid leukemia (CML) (The Basics)
Patient information: Neutropenia and fever in people being treated for cancer (The Basics)
Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.
Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.
Cellular and molecular biology of chronic myeloid leukemia
Clinical manifestations and diagnosis of chronic myeloid leukemia
Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia
Genetic abnormalities in hematologic and lymphoid malignancies
Hematopoietic cell transplantation in chronic myeloid leukemia
Initial treatment of chronic myeloid leukemia in chronic phase
Interferon alpha for the treatment of chronic myeloid leukemia
Molecular genetics of chronic myeloid leukemia
Overview of the myeloproliferative neoplasms
Overview of the treatment of chronic myeloid leukemia
Treatment of chronic myeloid leukemia in accelerated phase
Treatment of chronic myeloid leukemia in blast crisis
Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy
The following organizations also provide reliable health information.
●National Library of Medicine
●National Cancer Institute
●American Cancer Society
●The Leukemia & Lymphoma Society
●National Marrow Donor Program
●American Society of Clinical Oncology
- O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348:994.
- Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010; 362:2260.
- Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010; 362:2251.
- Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010; 28:2381.
- Pye SM, Cortes J, Ault P, et al. The effects of imatinib on pregnancy outcome. Blood 2008; 111:5505.
- O'Hare T, Eide CA, Deininger MW. Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 2007; 110:2242.
- Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006; 354:2542.
- Schiffer CA. BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N Engl J Med 2007; 357:258.
- Kantarjian H, O'Brien S, Talpaz M, et al. Outcome of patients with Philadelphia chromosome-positive chronic myelogenous leukemia post-imatinib mesylate failure. Cancer 2007; 109:1556.
All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.
- CHRONIC MYELOID LEUKEMIA OVERVIEW
- PHASES OF CHRONIC MYELOID LEUKEMIA
- CHRONIC MYELOID LEUKEMIA TREATMENT OPTIONS
- TYROSINE KINASE INHIBITORS (TKIs)
- HEMATOPOIETIC CELL TRANSPLANTATION
- DECIDING BETWEEN TRANSPLANTATION AND A TYROSINE KINASE INHIBITOR
- INTERFERON ALPHA
- RECOMMENDATIONS FOR TREATMENT OF CHRONIC MYELOID LEUKEMIA
- CLINICAL TRIALS
- WHERE TO GET MORE INFORMATION