Version May 2024
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CHRONIC MYELOID LEUKEMIA OVERVIEW — Chronic myeloid leukemia (also called CML or chronic myelogenous leukemia) is a chronic (long-term, slowly developing) form of leukemia. Leukemia is a type of cancer of cells in the blood and bone marrow (the spongy, red tissue that fills large bones).
People with CML have an increase in the number of immature (young) white blood cells in their blood, bone marrow, and spleen. Some people have no symptoms when they are diagnosed with CML, and it is discovered when blood tests are done for another reason. Abnormalities in blood tests include increased platelets, anemia, and a high white blood cell count. Other people have symptoms such as enlargement of the spleen (with a feeling of fullness in the abdomen), fatigue, bone pain, fevers, night sweats, and/or weight loss. Symptoms of CML typically develop gradually. In a small percentage of people, CML transforms into an aggressive form of acute leukemia with more severe symptoms and increasingly abnormal white blood cells (called leukemic blast cells).
CML occurs when a cell in the bone marrow undergoes a breakage of two chromosomes (chromosomes 9 and 22), which then fuse to form a characteristic abnormal chromosome, called the Philadelphia chromosome (named for the city in which it was first identified). The chromosome fusion causes an exchange of genetic information in which two separate genes, BCR and ABL1, are joined together. The resultant abnormal gene, called BCR::ABL1, causes bone marrow cells to produce an abnormal protein (the BCR::ABL1 tyrosine kinase), which stimulates CML cells to grow and survive better than normal blood cells.
People with CML develop the chromosome/gene abnormality during their lifetime; that is, it is not something that you are born with or pass on to your children. Its cause is unknown.
CML cells can crowd out the development of normal blood cells in the bone marrow. The main types of normal blood cells are:
●White blood cells – Neutrophils are a type of white blood cell that help to fight infection. People with neutropenia (low numbers of neutrophils) are more likely to get infections.
●Red blood cells – Red blood cells carry oxygen to the body's organs and tissues. People who are anemic (meaning they do not have enough red blood cells) may be pale, tired, and/or short of breath.
●Platelets – Platelets help to prevent and stop bleeding. People with low platelets (thrombocytopenia) can have bleeding and spontaneous bruising. People with high platelets can have clotting or also increased risk of bleeding.
More detailed information about CML, written for healthcare providers, is available by subscription. (See 'Professional level information' below.)
CANCER CARE DURING THE COVID-19 PANDEMIC — COVID-19 stands for "coronavirus disease 2019." It is an infection caused by a virus called SARS-CoV-2. The virus first appeared in late 2019 and has since spread throughout the world. Getting vaccinated lowers the risk of severe illness; experts recommend COVID-19 vaccination for anyone with cancer or a history of cancer.
In some cases, if you live in an area with a lot of cases of COVID-19, your doctor might suggest rescheduling or delaying medical appointments. But this decision must be balanced against the importance of getting care to screen for, monitor, and treat cancer. Your doctor can talk to you about whether to make any changes to your appointment schedule. They can also advise you on what to do if you test positive or were exposed to the virus.
PHASES OF CHRONIC MYELOID LEUKEMIA — There are three phases of CML:
●Chronic phase – Approximately 85 percent of people are in the chronic phase of CML when they are initially diagnosed. In chronic phase CML, there are less than 5 percent immature leukemic blast cells (the abnormal white blood cells) in the bone marrow. Chronic phase CML is well controlled with oral medications in nearly all cases.
●Accelerated phase – During the accelerated phase, the white blood cells become increasingly unable to mature normally, and there are between 10 and 19 percent leukemic blast cells in the blood or bone marrow. Accelerated phase CML is more difficult to control with medications, probably because of new mutations that develop in the CML cells.
●Blast phase – In blast phase of CML (also called "blast crisis"), there are more than 20 percent blast cells in the blood or bone marrow. CML can progress to blast phase from the chronic or accelerated phase, or in some cases a person is already in the blast phase at the time of diagnosis. Blast phase CML is difficult to control with medications.
TREATMENT OF CHRONIC MYELOID LEUKEMIA — The most common treatments for CML are:
●Tyrosine kinase inhibitors – For most people, CML is treated with an oral medication, called a tyrosine kinase inhibitor (TKI). This medication blocks the effects of BCR::ABL1 (the abnormal protein found in people with CML).
TKIs include imatinib mesylate (brand name: Gleevec), dasatinib (brand name: Sprycel), nilotinib (brand name: Tasigna), bosutinib (brand name: Bosulif), ponatinib (brand name: Iclusig), and asciminib (brand name: Scemblix). (See 'Tyrosine kinase inhibitors' below.)
●Stem cell transplantation – Stem cell transplantation (also called bone marrow transplantation or hematopoietic cell transplantation) is usually used after the disease stops responding or relapses during treatment with a TKI. (See 'Stem cell transplant' below.)
●Symptom control – Certain chemotherapy medications (hydroxyurea, busulfan, omacetaxine, or interferon alfa) may be used to reduce symptoms of CML in special circumstances, although they do not cure the disease.
The choice of therapy is influenced by the phase of CML, whether you are a candidate for stem cell transplantation, the availability of a bone marrow donor, and your personal values and preferences.
Goals of treatment — The primary goals of treatment are to relieve symptoms, help you live as long as possible, and prevent your CML from progressing to the blast phase. Achieving these goals generally requires markedly reducing the number of cells that contain the abnormal "Philadelphia chromosome" and enabling the return of normal (non-leukemic) blood cells.
There are several ways to measure how well your treatment is working, using various blood tests:
●The hematologic response refers to the disappearance of CML cells from the blood and a return to normal blood cell counts.
●The cytogenetic response refers to the disappearance of cells that contain the Philadelphia chromosome from the blood or bone marrow. Measurement of the cytogenetic response can detect as few as one CML cell among 100 normal blood or bone marrow cells.
●The molecular response indicates whether the abnormal BCR-ABL1 gene is present, using a sensitive molecular test called RT-PCR (reverse transcriptase polymerase chain reaction). PCR can detect as few as one BCR-ABL1-positive CML cell among 10,000 to 100,000 normal cells.
A hematologic response is typically associated with a decrease in the severity of symptoms but, alone, it does not ensure that CML is adequately controlled. Unless a cytogenetic response is achieved, there is a continued risk of progression to accelerated phase or blast phase of CML.
The term "complete molecular response" has been used to describe cases in which the BCR-ABL1 gene is no longer detectable, but various PCR tests have different sensitivities (ie, differences in their ability to detect very small numbers of CML cells). Although a complete molecular response reflects disappearance of all detectable CML cells, it does not ensure cure of the disease.
Choosing an approach based on disease phase — Treatment for CML depends in part on the phase of disease:
●Chronic phase CML – For most people with chronic phase CML, initial treatment should be with a TKI, because these medications are well-tolerated and generally effective (often for 10 years or longer). (See 'Tyrosine kinase inhibitors' below.)
●Accelerated/blast phase CML – In accelerated phase/blast phase, responses to TKIs are considerably less favorable than in chronic phase. Although most patients will have an initial response to a TKI, most people in accelerated or blast phase will eventually relapse if they are treated with a TKI alone, especially if they develop while on treatment with a TKI. Treatment in these phases should include stem cell transplantation, if possible. A TKI is usually given first to try to control the disease prior to transplantation. Stem cell transplantation is discussed in more detail separately. (See 'Stem cell transplant' below and "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)", section on 'Hematopoietic cell transplantation side effects'.)
Tyrosine kinase inhibitors — Tyrosine kinase inhibitors (TKIs) are the initial treatment of choice for most people with CML. The Philadelphia chromosome, which is a defining characteristic of CML, produces an abnormal protein called BCR-ABL1. TKI treatment blocks the effects of BCR-ABL1, which rapidly kills CML cells. People who are treated with TKIs generally have fewer and milder side effects than those treated with traditional chemotherapy. However, TKIs are not recommended for use during pregnancy or breastfeeding. (See 'Pregnancy/Nursing' below.)
More than two-thirds of patients with chronic phase CML achieve long-term control of the disease with TKIs. Although TKIs have not been proven to cure CML, people who have an excellent response to TKI therapy have expectations for survival that are similar to age-matched individuals without CML.
Available TKIs include imatinib (brand name: Gleevec), nilotinib (brand name: Tasigna), dasatinib (brand name: Sprycel), bosutinib (brand name: Bosulif), ponatinib (brand name: Iclusig), and asciminib (brand name: Scemblix). Imatinib was the first TKI to become available, so doctors have the most information about its efficacy and related side effects. Ponatinib and asciminib are newer TKIs that are generally reserved for people who have not responded to other TKIs. The decision of which TKI to use is usually based on potential side effects (table 1), your medical history, and cost. Most people can return to their usual daily activities after starting treatment with a TKI.
It is very important to take your TKI exactly as directed and to avoid other medications or supplements that may impair efficacy. People who take every dose are more likely to have better outcomes; skipping doses can jeopardize your chances of having a good response. Some TKIs should to be taken with food, while one (nilotinib) needs to be taken on an empty stomach. 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 the herb St. John's wort (also called Hypericum perforatum). Grapefruit juice should be avoided.
Side effects — TKIs do come with side effects, which vary depending on which drug is used (table 1). Many side effects, such as nausea, diarrhea, constipation, rash, and liver test abnormalities, are generally most troublesome in the first one to two months of treatment and disappear or become much milder over time. Other side effects, such as cardiovascular problems, can develop after months or years of treatment.
For people who continue to have severe side effects, your physician may make careful adjustments to the dose or schedule of the TKI. It is important that you do not make these adjustments without the approval of your doctor, because this may affect your response to treatment and long-term benefits of TKI therapy.
TKI failure — For people who do not have an adequate response to TKI therapy, who stop responding to treatment, or who have intolerable side effects, your physician may suggest treatment with a different TKI.
Your doctor needs to be certain that you have been taking your TKI properly before switching to a different TKI. Not taking the medication properly is a major cause of treatment "failure". It is critical to take your medications exactly as directed and tell your doctor if you have missed any doses, what other medications you are taking, and when you take the TKI relative to meals.
For people who did not have an adequate initial response to the TKI or who initially responded, but later had a relapse (stopped responding), the cause may be development of a new mutation in the BCR-ABL1 gene, which allows the disease to become resistant to treatment. Testing for additional mutations in the BCR-ABL1 gene (called mutation analysis) should be done at the time of relapse because this may affect the choice of a different TKI. Some mutations of BCR-ABL1 (eg, a mutation called "T315I") will not respond to most commonly available TKIs (imatinib, dasatinib, nilotinib, or bosutinib); people with this mutation may be treated with ponatinib or asciminib and are generally encouraged to consider transplantation. (See 'Stem cell transplant' below.)
Treatment options may also include enrollment on a clinical trial or other treatments (interferon alfa, omacetaxine). As an example, omacetaxine (brand name: Synribo) is a form of chemotherapy that is given as an injection under the skin daily for two weeks, and repeated every four weeks for a maximum of six cycles. Side effects of omacetaxine include infection, diarrhea, nausea, fever, and fatigue. (See 'Clinical trials' below.)
Pregnancy/Nursing — Special considerations are needed for women with CML who are pregnant, may become pregnant, or are breastfeeding, and for men who may be able to get their partner pregnant.
Women and men who take TKIs usually have no increased problems with fertility. However, the risk of miscarriage and birth defects while taking TKIs is increased. As a result, women who take a TKI are strongly advised to use birth control during treatment.
Women who take a TKI and become pregnant must choose between ending the pregnancy, continuing the TKI (which may cause problems in the developing fetus), and stopping the TKI temporarily (which may allow CML to relapse). For women who choose to stop TKI treatment and continue with the pregnancy, many doctors recommend temporarily switching to interferon alfa.
Breastfeeding women are advised to avoid TKIs because these medications are passed into breast milk. The effects of TKIs on infants are not well defined. If you become pregnant while taking a TKI, stop taking the drug immediately and contact your healthcare provider as soon as possible. He or she can talk to you about your options.
Stopping TKI treatment — Until recently, continuous (indefinite) treatment with TKIs was recommended, because of concerns that the disease would relapse if therapy is stopped. However, in people who meet specific criteria, it may be possible to consider discontinuation of a TKI.
Discontinuing a TKI is a consideration only in people who have had very low or undetectable levels of BCR/ABL1 for at least two to three consecutive years. The terms "very low" and "undetectable" have specific meaning in this context, and refer to at least a "4-log" reduction of CML cells. As an explanation of this terminology, if only 1 out of every 10,000 CML cells remains, this would be described as a 4-log reduction (10,000 on a logarithmic scale); another way of describing this effect is 0.01 percent (because 99.99 percent of CML cells were killed).
In people who do stop TKI treatment in this setting, molecular relapses occur about half the time (usually within the first six to eight months), but resuming a TKI immediately is almost always successful. Conversely, about half of people who stop TKI treatment have not had recurrence of their CML five years later.
People whose treatment is stopped should have PCR monitoring every four to six weeks for six months and then every two months for another two years.
If you are interested in stopping your TKI, talk to your doctor about whether you might be a candidate. TKI discontinuation should never be undertaken without careful medical supervision, and may be pursued only after carefully weighing the risks of TKI discontinuation and the requirement for additional testing and evaluation.
Stem cell transplant — Stem cell transplantation (also called hematopoietic cell transplantation or bone marrow transplant) may be recommended if CML stops responding or relapses during treatment with a TKI, and for some patients with accelerated phase or blast phase CML.
Stem cell transplantation replaces diseased bone marrow cells with healthy bone marrow. For CML, this requires healthy stem cells donated by another person. The transplanted stem cells generate a new immune system for the person with CML, which recognizes the leukemia cells as foreign and attempts to destroy them. This beneficial reaction against the CML cells is called the graft-versus-tumor effect. However, donor immune cells can also attack other organs in the body, including the skin, liver, and gastrointestinal tract. This is known as "graft-versus-host disease" (GVHD) and can be a severe and sometimes fatal complication. If you receive a stem cell transplant, you will get medications to help prevent GVHD and treat it if it does happen. (See "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)".)
In CML, the chances of successfully controlling CML with stem cell transplantation are related to your age and the phase of disease at the time of the transplant. Younger patients generally tolerate transplantation better than older patients. Transplantation is also more likely to be successful when CML has been restored to chronic phase. Most people will be treated with a TKI before transplantation with the hope of restoring accelerated or blast phase CML to chronic phase.
CLINICAL TRIALS — Many people with 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:
●www.cancer.gov/about-cancer/treatment/clinical-trials
Videos addressing common questions about clinical trials are available from the American Society of Clinical Oncology (www.cancer.net/research-and-advocacy/clinical-trials/welcome-pre-act).
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 education: Leukemia in adults (The Basics)
Patient education: Chronic myeloid leukemia (CML) (The Basics)
Patient education: 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
Genetic abnormalities in hematologic and lymphoid malignancies
Hematopoietic cell transplantation in chronic myeloid leukemia
Initial treatment of chronic myeloid leukemia in chronic phase
Molecular genetics of chronic myeloid leukemia
Overview of the myeloproliferative neoplasms
Overview of the treatment of chronic myeloid leukemia
Accelerated phase chronic myeloid leukemia: Diagnosis and treatment
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
(https://medlineplus.gov/healthtopics.html)
●National Cancer Institute
●American Cancer Society
●The Leukemia & Lymphoma Society
●National Marrow Donor Program
●American Society of Clinical Oncology
(www.cancer.net/cancer-types/leukemia-chronic-myeloid-cml)
●American Society of Hematology
(www.hematology.org/education/Patients)
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