This article is a more specific discussion of CML. Please be sure to read Leukemia: The Basics first, so you have a basic understanding of leukemia.
The discovery of CML
CML is a chronic blood cancer that starts with a defect in two chromosomes and results in an overgrowth of white blood cells; it is one of the only cancers with a known specific gene mutation. Each person has 23 chromosomes, which contain DNA and a person's genetic makeup (genes). While CML has been recognized since the late 1800's, it was the discovery of the Philadelphia chromosome in 1960 that changed the face of CML.
Drs. Peter Nowell and David Hungerford, two Philadelphia researchers, were experimenting with cells from various types of leukemia when one noticed a smaller-than-normal chromosome number 22 on the cancer cells of 2 individuals with CML. With the far less sophisticated techniques of the time, they were unable to tell what happened to the material missing from the small chromosome.
Nowell and Hungerford published their research in 1960, describing the abnormality that had then been found in 9 out of 10 CML patients they studied. The findings were confirmed by a group in the United Kingdom, and the abnormality was subsequently named the Philadelphia Chromosome, for the city in which it was discovered. Nowell and Hungerford had demonstrated that this genetic change was required for the development of CML a novel and often unaccepted concept at that time.
It would be 1972 before another researcher; Janet Rowley, MD, would discover the missing piece of chromosome number 22 attached to chromosome number 9, thereby identifying the first known chromosomal translocation. The 9;22 translocation is found on the leukemic cells of more than 95% of patients with CML. As the field of genetics grew, it was discovered that the gene abl (pronounced “able”), normally located on chromosome 9, had attached itself to the gene bcr (pronounced “b-c-r”) on chromosome 22. The bcr-abl gene encodes a protein (called tyrosine kinase), whose activity results in too many stem cells developing into white blood cells, leaving a shortage of other cell types. This genetic change to bcr-abl occurs during a person's lifetime and is not passed on to future generations or inherited from parents.
You may wonder why all of this is important. Well, these discoveries led to the development of a drug, called imatinab (Gleevec®), which changed the lives of people with CML and how the disease is treated, which we will discuss later.
The facts about CML
CML accounts for about 10% of all leukemia cases in the United States, with an estimated 6,660 new cases to be diagnosed in 2015, for an annual incidence of about 1 in 555. It can occur at any age, but the average age at diagnosis is 64. Only 10% of people diagnosed with CML are under the age of 20. It is slightly more common in men than women.
What causes CML?
In most cases, the cause of CML is not known. Although a genetic mutation (bcr-abl rearrangement) has been identified, it is not clear what causes this mutation. Exposure to high doses of radiation (such as those after an atomic bomb or older radiation treatment methods for cancer) raises the risk for getting the disease. Chemical exposure has not been shown to cause CML, nor is there a hereditary link. Although the bcr-abl gene is sometimes found in other leukemias, in a person with clinical signs of CML, the finding of the bcr-abl gene rearrangement confirms the diagnosis.
How is CML “staged”?
CML is not staged like other cancers, but rather is broken down into three phases: chronic, accelerated, and blast. The phases are identified by the number of immature white blood cells (called blasts) that are present in the blood stream. This is also a sign of how aggressive the disease is at that point. Chronic phase is defined as less than 10% blast cells in the blood and is the least aggressive of the phases, accelerated phase is defined as 10-19% blast cells in the blood, and blast phase is defined as 20% or more blast cells seen in the blood and is the most aggressive phase of the disease.
How do people with CML present?
Chronic phase is also called the stable phase, and about 90% of people will be diagnosed in this phase. Almost half of newly diagnosed chronic phase patients will have no symptoms, and the disease will be detected by an elevated white blood cell count on a routine blood test. The most common symptoms (regardless of stage) are a result of a low red blood cell count (anemia) and an enlarged spleen (splenomegaly). Anemia leads to fatigue, shortness of breath with activity, and a pale appearance. Splenomegaly, which tends to be present in the blast phase, causes abdominal fullness or discomfort, feeling full early when eating (the spleen is pressing on the stomach), and weight loss. Bone pain, fever, sweats, and fatigue are other symptoms that may appear prior to the diagnosis.
If CML is suspected, blood and bone marrow samples will be sent to a lab to check for the Philadelphia chromosome or bcr-abl gene.
How is CML treated?
In 2001, the U.S. Food and Drug Administration approved imatinib (Gleevec) for the treatment of CML, and it has become the standard of care for newly diagnosed CML patients. Imatinib is a tyrosine kinase inhibitor (TKI); tyrosine kinase is a type of protein called an enzyme. The specific enzyme of interest in CML is abnormal because it is produced by an abnormal gene associated with CML called the bcr-abl gene, also known as the Philadelphia chromosome. By blocking the function of the tyrosine kinase protein, the drug effectively reduces the abnormal effects of this “bad” bcr-abl gene, (i.e. the Philadelphia chromosome). In addition, the drug can also cause direct death of the bcr-abl -expressing cells to die (a process known as apoptosis).
Patients can continue to take imatinib for as long as the disease continues to respond and as long as they are able to tolerate any side effects, which are generally mild. In many patients, the Philadelphia chromosome becomes undetectable by current testing methods, but studies have shown that the abnormality will return quickly if the medication is stopped. Patients must have the presence and amount of Philadelphia chromosome monitored every 3-4 months while on the medication.
Dasatinib and Nilotinib are “second generation” TKIs that are effective in some patients whose CML has grown resistant to imatinib, and in some cases are used as “first line” treatment. These medications may be used before proceeding to transplant, or in patients not able to undergo transplant (due to age, health issues or lack of a donor). Unfortunately, the three available tyrosine kinase inhibitors work best in chronic phase CML, and their efficacy decreases for accelerated and blast phases. In addition, some patients have an abnormality (called a T315I mutation) in which the medication ponatinib, a “third generation” TKI, may be useful. Research is trying to find the optimal dose and schedule of TKIs, for example, using larger doses intermittently.
Prior to the discovery of imatinib, patients with CML were often offered allogeneic stem cell transplant, which remains the only known cure for CML. However, the procedure itself carries a 10-20% risk of death, making it a difficult treatment to choose when the patient has no symptoms and feels well. Because CML can usually be managed with TKIs alone, transplant is reserved for patients who no longer are responding to TKI medication in the first chronic phase of the disease or as a salvage treatment for advanced disease. It is suggested that at the time of diagnosis of CML, a patient should undergo a “work-up” for allogeneic stem cell transplant including HLA typing, a transplant risk assessment, and evaluation of the likelihood of finding a donor. This will shorten the time needed to prepare for a stem cell transplant if it is decided to be the chosen course of treatment.
Omacetaxine mepesuccinate (Synribo™) is a synthetic form of hommoharringtonine, a compound purified from a Chinese evergreen tree, has been approved for the treatment of CML that has failed 2 or more TKIs. This medication has been studied specifically in patients with T315I mutations and may be an option for those patients. Interferon alfa was also commonly used before imatinib and was effective in 30-55% of patients, but few had the Philadelphia chromosome eliminated (the necessary step to cure). This therapy may be used in patients who are not able to undergo transplant. Research is also investigating the use of interferon alfa in conjunction with imatinib. Arsenic trioxide had also been previously studied, but newer, safer versions of the medication have renewed interest in this medication. Researchers continue to look for ways to improve the tyrosine kinase inhibitors or to target the disease from other angles with the hope of achieving a cure for all patients.
What is Blast Phase?
CML eventually progresses, or speeds up, and transforms to an acute form of leukemia, which most often resembles AML (acute myeloid leukemia). This may also be referred to as “blast phase” or “blast crisis”. Patients may be treated with imatinib or other TKI, chemotherapy drugs similar to those used in AML, or transplant. This phase of the disease is particularly difficult to treat and prognosis is poor.
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