Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor 3/2020
Chronic myeloid leukemia (CML) is the abnormal growth of relatively mature myeloid (white blood) cells. Half of all patients with CML are diagnosed after the age of 67.
CML is associated with a chromosomal abnormality in which genetic material from chromosome 9 is transferred to chromosome 22. The chromosome containing the genetic switch is called the Philadelphia chromosome; this chromosome plays a role in the development of CML.
The exchange of genetic information that produces the Philadelphia chromosome brings together two genes: the BCR (breakpoint cluster region) gene on chromosome 22 and the ABL (Ableson leukemia virus) gene on chromosome 9. The combination of these two genes into the single BCR-ABL gene results in the production of a protein that contributes to uncontrolled cell growth.
Initially in CML, there is a gradual increase in mature, abnormal myeloid cells in the bone marrow. These cells eventually spill into the blood and other organs, causing symptoms such as fatigue from anemia or an enlarged spleen. The increase in leukemic cell numbers occurs slowly at first and is referred to as the chronic phase, but these cells invariably begin to increase more rapidly and/or include less mature cells, resulting in the accelerated or blastic phase. In order to understand the best treatment options available for chronic myeloid leukemia, it is important to know the phase of leukemia, since all new treatment information concerning chronic myeloid leukemia is categorized and discussed by the phase of disease.
Staging of Chronic Myeloid Leukemia
Chronic Phase: Patients in the chronic phase of CML have stable disease with only minor symptoms, no cancer outside the bone marrow or spleen and white blood cell and platelet blood counts that are usually greater than normal.
Accelerated Phase: When chronic myeloid leukemia is difficult to control with Gleevec® (imatinib) or other therapies, the white blood count begins to increase. New symptoms may appear and old symptoms may worsen. The spleen may enlarge and/or new abnormal chromosomes can be detected in the bone marrow cells. Eventually, the leukemia becomes completely resistant to treatment and the bone marrow becomes overburdened with large numbers of immature white blood cells known as “blasts”. A diagnosis of accelerated phase requires at least one of the following:
- The persistent presence of 10-30% myeloblasts in the bone marrow or peripheral blood.
- A major increase of the white blood cell count to over 50,000, platelet counts that are increased or decreased and red blood cell levels that are low despite treatment.
- Progressive enlargement of the spleen.
- Growth of leukemia outside the bone marrow or spleen.
- The presence of any cytogenetic abnormality in addition to a Philadelphia chromosome.
- Persistent unexplained fever or bone pain.
Blastic Phase: Greater than 30% myeloblasts in marrow or blood
Treatment of Chronic Phase Chronic Myeloid Leukemia
The diagnosis of CML is first suggested in approximately 20% of affected individuals by detecting a high white blood cell count on routine blood testing. Patients are usually without symptoms and often have difficulty understanding the serious nature of their disease since they do not feel ill.
The hallmark of CML is the Philadelphia chromosome or the BCR-ABL gene, which is not found in normal blood cells and is not passed down from parents to children. The BCR-ABL gene is a fusion gene—a new gene that is formed when two genes are joined together. The BCR-ABL gene makes the BCR-ABL protein, a type of protein called a tyrosine kinase. Tyrosine kinases are proteins that are located on or near the surface of cells and send signals telling cells when to grow and divide. The BCR-ABL protein is abnormal. It is locked in the “on” position so that it always sends signals for cells to keep growing and dividing. This causes blood stem cells to make too many white blood cells.
Historically the only curative treatment for individuals diagnosed with CML was an allogeneic stem cell transplant. This changed when Gleevec® (imatinib) was approved by the FDA for treatment of CML in 2001. Gleevec® is a targeted medicine that belongs to a class of drugs called tyrosine kinase inhibitors (TKI) and these drugs now form the basis for the overall management of CML. TKI’s are well tolerated and prolong survival. Allogeneic stem cell transplantation can eradicate the abnormal clone in CML cells and cure many patients who fail or are intolerant to initial treatment but is associated with significant treatment related morbidity and mortality. All current therapies, other than stem cell transplantation, are aimed at controlling the growth of abnormal cells and attempting to delay the transformation or progression from the chronic phase of CML to the blastic phase resembling acute leukemia.
The following is a general overview of the management of chronic phase CML. Each person with CML is different, and the specific characteristics of your condition will determine how it is managed. The information on this Web site is intended to help educate you about treatment options and to facilitate a shared decision-making process with your treating physician. New treatments for CML are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of this cancer.
Treatment of CML with Tyrosine Kinase Inhibitors
The majority of CML cases are caused by a specific genetic abnormality, referred to as the Philadelphia chromosome. The Philadelphia chromosome occurs through a switching of specific genetic information. The gene that results from this genetic switching produces a protein called the Bcr-Abl tyrosine kinase. The Bcr-Abl tyrosine kinase influences cellular function and growth in an uncontrolled manner, leading to excessive replication and growth of cells – the hallmark trait of CML and cancer.
TKI’s bind to a specific site on the Bcr-Abl tyrosine kinase and block the growth effects of the protein. This, in turn, halts the excessive replication and growth of leukemia cells. There are currently several TKI’s approved for the treatment of CML.
Recent studies have demonstrated that newer generation TKI's are superior to Gleevec® for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia. (2,3)
The ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients) directly compared three treatments: Tasigna® 300 mg twice daily to Tasigna® 400 mg twice daily or Gleevec®, 400 mg once daily in adult patients with newly diagnosed Ph+ CML in chronic phase. The estimated rates of patients whose disease did not progress on study at 72 months in the Gleevec®, Tasigna 300 mg and Tasigna® 400 mg twice-daily arms were 92.2%, 95.8% and 97.8%, respectively.
The estimated rates of freedom from death due to a CML-related cause at 72 months in the Gleevec®, Tasigna® 300 mg and Tasigna® 400 mg treatment groups were 93.9%, 97.7% and 98.5%, respectively demonstrating all three treatments to be highly effective and suggesting Tasigna® 400 mg may be the optimal treatment for newly diagnosed patients with chronic phase CML.
Measuring Response to Treatment
Initial response to therapy is indicated by normalization of the peripheral blood counts (white blood cells, platelets and red blood cells) and return of increased bone marrow cellularity to normal. Most patients are followed with peripheral blood tests rather than repeated bone marrow examination. Cells collected from the bone marrow or peripheral blood will contain the Philadelphia chromosome, and cytogenetic tests (tests that detect chromosomal abnormalities) are used to monitor response to therapy. Currently the majority of newly diagnosed patients with CML will achieve a complete cytogenetic remission (no evidence of Philadelphia chromosome-positive cells). More importantly, in patients with a complete cytogenetic remission a test called polymerase chain reaction (PCR) can determine the completeness of a “molecular” remission by measuring the presence of the BCR-ABL gene. As a general rule, the greater the degree of molecular response the longer the survival of an individual patient.
Monitoring TKI Treatment
Monitoring of treatment with cytogenetics and PCR is essential for optimal treatment of patients with CML. Unfortunately adequate monitoring is reported to be underutilized by many physicians and their patieients. It is recommended that monitoring with laboratory testing occur at three-month intervals. Patients need to understand that the treatment goal is to achieve a complete hematologic response first, followed by a complete cytogenetic response, ideally within the first 12-month period. Following that, the goal is to achieve a major molecular response, which can be assessed by PCR testing. Monitoring is made easier by performing tests on peripheral blood rather than bone marrow when available.
Allogeneic Stem Cell Transplant
Useful Definitions for Chronic Myelogenous Leukemia (CML)
Blood stem cell: An immature cell from which other types of blood cells develop.
Bone marrow: The soft, sponge-like tissue in the center of most bones where blood cells are made.
Chromosomes: Long strands of bundles of coded instructions in cells for making and controlling cells.
Philadelphia Chromosome: CML is associated with a chromosomal abnormality in which genetic material from chromosome 9 is transferred to chromosome 22. The chromosome containing the genetic switch is called the Philadelphia chromosome; this chromosome plays a role in the development of CML.
BCR-ABL: The exchange of genetic information that produces the Philadelphia chromosome brings together two genes: the BCR (breakpoint cluster region) gene on chromosome 22 and the ABL (Ableson leukemia virus) gene on chromosome 9. The combination of these two genes into the single BCR-ABLgene results in the production of a protein that contributes to uncontrolled cell growth.
Gene: Set of coded instructions in cells for making and controlling cells.
Human leukocyte antigens (HLA): Special proteins on the surface of white blood cells that help the body to identify its own cells from foreign cells.
HLA type: A unique set of HLA proteins on a person’s white blood cells. HLA types differ among people just like blood types differ among people. HLA testing is used to determine a person’s HLA type. HLA testing is done before a type of treatment that transfers blood stem cells from another person to the patient. It’s very important that their HLA types are a near-perfect match for this treatment to work. This is because the HLA type affects how the body responds to foreign substances.
Understanding DNA Damage Response or DDR and Cancer Treatment
What is DNA Damage Response or DDR?
Cytogenetics: The study of chromosomes the long strands of bundles of coded instructions for making and controlling cells. Cytogenetics involves examining a sample of cells with a microscope to look for changes in the cells’ chromosomes. This type of test is used to detect abnormal chromosomes and measure the number of cells that have them. The pathologist will use a microscope to examine a “map” of the chromosomes, called a karyotype. The pathologist will assess the size, shape, number, arrangement, and structure of the chromosomes on the karyotype to look for any abnormal changes. Cytogenetics is used to diagnose leukemia and other cancers. It is also used to monitor how well treatment is working. Cytogenetic testing can be performed on cells from the peripheral blood, but bone marrow is preferred because the yield from peripheral blood is very poor.
Fluorescence in situ hybridization (FISH): A test used to detect the Philadelphia chromosome and the BCR-ABL fusion gene. This test may be used on a peripheral blood sample if a bone marrow sample can’t be collected. FISH uses color “probes” to find the BCR gene and the ABL gene in chromosomes. The BCR-ABL fusion gene, located on the Philadelphia chromosome, is shown by the overlapping colors of the two probes. FISH analysis of peripheral blood may be used to diagnose CML when bone marrow cytogenetics isn’t possible. But, FISH is not recommended for monitoring the response to treatment.
QPCR (Quantitative reverse transcriptase polymerase chain reaction): A very sensitive test that detects and measures the BCR-ABL gene. QPCR makes thousands of copies of the DNA in cells from a blood or marrow sample to see how many cells have the BCR-ABL gene. Copies of BCR-ABL found by QPCR are also called BCR ABL transcripts. The number of BCR-ABL copies detected by QPCR is called the transcript level. The transcript level reflects the number of BCR-ABL genes in your body. Changes in BCR-ABL levels are measured in logs—a log reduction means the BCR-ABL level has decreased by a certain amount. QPCR can detect one CML cell among more than 100,000 normal cells. This test is used to confirm (diagnose) CML as well as to monitor the treatment response. The QPCR test should always be done in the same lab, preferably a lab that uses the International Scale. The International Scale is a standardized scale for measuring and reporting QPCR test results. QPCR test results from different labs are converted to the International Scale so that all test results are consistent and can be compared between labs.
Flow cytometry: A test looks at certain substances on the outside surface of cells to identify the specific type of cells present. This test is used for advanced phases of CML to determine if the leukemia cells are mostly myeloid or lymphoid cells. This test is important because the cell type may affect which treatment option is best. Flow cytometry can be performed on a sample of bone marrow or peripheral blood.
BCR-ABL gene mutation analysis: Sometimes new changes (mutations) develop in the part of the BCR-ABL gene that makes the BCR-ABL protein. These mutations change the shape of the BCR-ABL protein, affecting how and which targeted cancer drugs can bind to it to block the growth signals. A mutation analysis is a test that looks for new mutations in the BCR-ABL gene that may occur during treatment for CML. This test may be performed on a peripheral blood or bone marrow sample after months of treatment based on how well treatment is working. Mutational analysis is important because new or different gene mutations can affect which treatment option is best for you.
Chronic Myeloid Leukemia Screening/Prevention
Information about the prevention of cancer and the science of screening appropriate individuals at high-risk of developing cancer is gaining interest. Physicians and individuals alike recognize that the best “treatment” of cancer is preventing its occurrence in the first place or detecting it early when it may be most treatable.
Chronic myeloid leukemia (CML) is the abnormal growth of relatively mature myeloid (white blood) cells. The disease is associated with a chromosomal abnormality, where genetic material from chromosome 9 is transferred to chromosome 22. This forms what is called the Philadelphia chromosome, which plays a role in the development of the disease. This translocation results in the fusion of two proteins, BCR and ABL, which confers a selective advantage to the growth of CML cells over normal cells. The cause of this translocation is unknown.
The average age at diagnosis of CML is 67 years. Initially, there is a gradual increase in mature myeloid cells in the bone marrow. These cells eventually spill into the blood and other organs causing symptoms such as fatigue resulting from anemia and an enlarged spleen. The increase in leukemic cell numbers occurs slowly at first and is referred to as the chronic phase, but cell numbers will invariably begin to increase more rapidly and/or include less mature cells, resulting in the accelerated or blastic phase.
At this time, researchers do not know what causes CML and are trying to solve this problem. Scientists know that CML occurs in males more often than in females and in Caucasians more often than in African-Americans. However, they cannot explain why one person gets CML and another does not. Because the average age at diagnosis is over 67 years, it is suspected that unknown environmental exposure over a long period of time is required to cause CML. By learning what causes this disease, researchers hope to better understand how to prevent and treat it.
The chance of an individual developing cancer depends on both genetic and non-genetic factors. A genetic factor is an inherited, unchangeable trait, while a non-genetic factor is a variable in a person’s environment, which can often be changed. Non-genetic factors may include diet, exercise, or exposure to other substances present in our surroundings. These non-genetic factors are often referred to as environmental factors. Some non-genetic factors play a role in facilitating the process of healthy cells turning cancerous (i.e. the correlation between smoking and lung cancer) while other cancers have no known environmental correlation but are known to have a genetic predisposition, meaning a person may be at higher risk for a certain cancer if a family member has that type of cancer.
Heredity or Genetic Factors
There are no clear hereditary factors associated with CML. Identical twins of patients with CML are at no greater risk of developing CML than other siblings. This strongly suggests that environmental factors are much more important than genetic factors in the development of CML. It is a scientific mystery as to why only one of a pair of identical twins will develop CML, since the genetics are identical and environmental exposures are similar, if not the same.
HLA is the histocompatibility system that is used to match people for bone marrow, liver and kidney transplants. One study has found that a specific HLA type, DR4, is associated with a lower incidence of CML, however researchers have not yet identified the reason for this decrease.
Environmental or Non-Genetic Factors
The fact that only one of a pair of identical twins usually develops CML suggests that finding the specific cause for leukemia will be difficult if not impossible. However, by studying large numbers of people all over the world, researchers have found certain factors that increase a person’s risk of developing CML.
Exposure to large amounts of high-energy radiation increases the risk of CML. Such radiation was produced by the atomic bomb explosions in Japan during World War II.
Therapy Related Chronic Myeloid Leukemia: Some of the drugs and radiation used to treat other types of cancer may increase an individual’s risk of CML. Low-dose radiation used in the past to treat a variety of non-malignant conditions has been associated with an increased incidence of leukemia, of which 20-30% were CML. Various chemotherapy and immunosuppressive drugs have been associated with an increase in CML. Radioactive iodine treatment of thyroid cancer is also associated with an increased incidence of CML. CML has also been reported after heart transplants where radiation therapy was given.
Viruses and Chronic Myeloid Leukemia: Scientists have identified a virus that seems to increase the risk for one very uncommon type of leukemia. However, this virus has no known association with common forms of leukemia including CML. Scientists throughout the world continue to study viruses and other possible risk factors for leukemia.
Prevention of Chronic Myeloid Leukemia
Cancer is largely a preventable illness. Two-thirds of cancer deaths in the U.S. can be linked to tobacco use, poor diet, obesity, and lack of exercise. All of these factors can be modified. Nevertheless, an awareness of the opportunity to prevent cancer through changes in lifestyle is still under-appreciated. The overwhelming majority of cases of CML cannot be prevented since we do not know the cause of this disease.
Diet: Diet is a fertile area for immediate individual and societal intervention to decrease the risk of developing certain cancers. Numerous studies have provided a wealth of often-contradictory information about the detrimental and protective factors of different foods.
There is convincing evidence that excess body fat substantially increases the risk for many types of cancer. While much of the cancer-related nutrition information cautions against a high-fat diet, the real culprit may be an excess of calories. Studies indicate that there is little, if any, relationship between body fat and fat composition of the diet. These studies show that excessive caloric intake from both fats and carbohydrates lead to the same result of excess body fat. The ideal way to avoid excess body fat is to limit caloric intake and/or balance caloric intake with ample exercise.
It is still important, however, to limit fat intake, as evidence still supports a relationship between cancer and polyunsaturated, saturated and animal fats. Specifically, studies show that high consumption of red meat and dairy products can increase the risk of certain cancers. One strategy for positive dietary change is to replace red meat with chicken, fish, nuts and legumes.
High fruit and vegetable consumption has been associated with a reduced risk for developing at least 10 different cancers. This may be a result of potentially protective factors such as carotenoids, folic acid, vitamin C, flavonoids, phytoestrogens and isothiocyanates. These are often referred to as antioxidants.
There is strong evidence that moderate to high alcohol consumption also increases the risk of certain cancers. One reason for this relationship may be that alcohol interferes with the availability of folic acid. Alcohol in combination with tobacco creates an even greater risk of certain types of cancer.
Exercise: Higher levels of physical activity may reduce the incidence of some cancers. According to researchers at Harvard, if the entire population increased their level of physical activity by 30 minutes of brisk walking per day (or the equivalent energy expenditure in other activities), we would observe a 15% reduction in the incidence of colon cancer.
Screening and Early Detection of Chronic Myeloid Leukemia
For many types of cancer, progress in the areas of cancer screening and treatment has offered promise for earlier detection and higher cure rates. The term screening refers to the regular use of certain examinations or tests in persons who do not have any symptoms of a cancer but are at high risk for that cancer. When individuals are at high risk for a type of cancer, this means that they have certain characteristics or exposures, called risk factors that make them more likely to develop that type of cancer than those who do not have these risk factors. The risk factors are different for different types of cancer. An awareness of these risk factors is important because 1) some risk factors can be changed (such as smoking or dietary intake), thus decreasing the risk for developing the associated cancer; and 2) persons who are at high risk for developing a cancer can often undergo regular screening measures that are recommended for that cancer type. Researchers continue to study which characteristics or exposures are associated with an increased risk for various cancers, allowing for the use of more effective prevention, early detection, and treatment strategies.
Approximately 20% of CML cases are diagnosed during routine examinations or examinations for other illnesses. The most common symptoms are fatigue and weight loss associated with a high white blood cell count, large spleen and low red blood cell levels. Another common occurrence is bleeding which is unrelated to low or high platelet counts in the blood, but is related to the fact that the platelets don’t work well. Young male patients tend to present with more advanced symptoms than older individuals.
In order for screening to be effective, patients at risk need to be identifiable and this is currently impossible. The average age for developing CML is over 67 years. People over the age of 65 should probably have a physical examination and routine screening every 6 months. Screening is best done by a careful physical examination and determination of blood counts. A bone marrow examination is not necessary unless the blood counts are abnormal or there is some definable abnormality upon physical examination.
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