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Clinical Description
Leukemia is a general term used to describe a group of cancers caused by abnormal production of blood cells from the bone marrow. The bone marrow is the spongy tissue inside the large bones that produces all the different types of blood cells. Chronic Myeloid Leukemia (also known as CML or chronic myelogenous leukemia) is a type of leukemia that is slow-growing and caused by an acquired abnormality of the chromosomes (strands of genes) in the white blood cells of the bone marrow. CML cells carry a characteristic chromosome called the “Philadelphia” or Ph chromosome, discovered by investigators in Philadelphia about half a century ago, that results from part of one chromosome breaking off and attaching to another chromosome. This abnormality results in the formation of a fusion gene called BCR-ABL1. This gene produces an abnormal BCR-ABL1 enzyme that stimulates the leukemia cells to grow out of control, causing high white blood cell counts in the blood and an enlarged spleen. CML is diagnosed in approximately 1-2 out of 100,000 people each year in the United States. The average age of people with CML is around 50-60 years old.
Symptoms of Chronic Myeloid Leukemia
Patients with CML may not have any symptoms at the time of diagnosis.
Often an abnormally high white blood cell count is found on routine blood testing for yearly check-ups or blood tests done for other reasons. Symptoms usually develop slowly, and can include fatigue, shortness of breath with usual activity, pale skin, pain or fullness in the left upper abdomen caused by an enlarged spleen, drenching night sweats, inability to tolerate warm temperatures, or weight loss.
CML has three phases: chronic, accelerated, and blast phases.
· The chronic phase is the earliest stage of disease, and most people are diagnosed in this phase. During this time, symptoms are mild, the white blood cells can still fight infection, and the disease is usually controllable with an oral medication. This phase can last many years, particularly now that there are new medications available to control the disease.
· In the accelerated phase, a low red blood cell count or anemia may develop, the number of white cells may go up or down, and the number of platelets may drop. The number of abnormal immature cells in the bone marrow may increase and the spleen may swell. People in this phase can often feel ill.
· Patients in blast crisis have an increased number of abnormal immature cells (blasts) in their bone marrow and circulating in the blood, as well as low red blood cell and platelet counts. This makes patients more at risk for infection and bleeding. Symptoms in this phase often include fatigue, shortness of breath, stomach pain, or bone pain.
Risk Factors of Chronic Myeloid Leukemia
Though CML is caused by a chromosome abnormality, it is not a hereditary disease. The Ph chromosome occurs only in the cancer cells and is not present in the other cells of the body. The only known environmental risk factor for CML is exposure to high doses of radiation. There is no link between dental or medical x-rays and increased risk of CML.
How Chronic Myeloid Leukemia is Diagnosed
Testing required for the diagnosis of CML include peripheral blood testing with a complete blood count and blood cell examination under the microscope, as well as a bone marrow biopsy. Results often seen in CML include a high white blood cell count, a low red blood cell count (or a low hemoglobin and hematocrit), and either a high or low platelet count. Bone marrow biopsy is done to confirm the diagnosis and to determine stage of disease. In addition to looking at bone marrow cells under the microscope, the marrow cells are sent for special testing to determine if the Philadelphia chromosome and any additional abnormalities are present.
Treatment Options for Chronic Myeloid Leukemia at Tufts Medical Center
In the chronic phase of CML, the initial treatment is usually an oral medication called a “tyrosine kinase inhibitor” (TKI). It is taken once daily, and can be purchased with a prescription at any major pharmacy. Currently there are three tyrosine kinase inhibitors approved by the FDA for treatment of CML. Imatinib (trade name Gleevec) was the first drug to be approved in 2001, and soon thereafter two others, nilotinib (Tasigna) and dasatinib (Sprycel), were approved for use in CML. Although generally well-tolerated, TKI treatment can sometimes be associated with some side effects, including swelling of face and legs, upset stomach, accumulation of fluid in the chest cavity, and abnormalities of the heart rhythm. The decision regarding which drug to use should be made with the prescribing doctor, with careful monitoring of side effects.
Most patients remain on a TKI for six months to one year before it can be clear whether the disease is responding to treatment. A physician can determine a patient’s response to treatment based on blood tests that check for levels of the Ph chromosome or BCR-ABL1, which are expected to decrease during treatment. Most responding patients should remain on their TKI indefinitely. It is not yet known whether TKI treatment can cure CML, but the disease recurs quickly in the majority of patients who stop TKI treatment. In about a third of patients, a relapse occurs with an increase in the Ph chromosome or in the white blood cell count. A major caus of relapse is the appearance of a mutant form of the BCR-ABL1 enzyme that is resistant to the TKI, which can be detected by a blood test. In many cases, switching to a different TKI can bring the disease under control again. However, there are some BCR-ABL1 mutations where the patient does not respond to any of the currently prescribed TKIs. In that case, a bone marrow stem cell transplant may be necessary.
Several other treatments may be required for the initial treatment of CML. If the white blood cell count initially is very high, a drug called Hydroxyurea is often used to bring the white blood cell count down to a normal range before starting a TKI. If a patient has a dangerously high white blood cell count at any phase of the disease, a procedure called leukapheresis may be needed. This is a procedure in which the patient’s blood is filtered in order to quickly remove the excess white blood cells. This is done by inserting a large intravenous catheter in either the neck or the groin, and attaching the patient via an IV to a special pheresis machine that filters the blood.
Occasionally, CML does not respond to the oral TKIs, or the disease becomes resistant to treatment with these drugs. CML that is resistant to oral TKIs or that has progressed to an accelerated or blast phase may require treatment with intravenous systemic chemotherapy. Once the disease is controlled with chemotherapy, a bone marrow stem cell transplant (bone marrow donated from a matched relative or matched unrelated donor) is usually recommended.
All of the above mentioned therapies are available and commonly performed at Tufts Medical Center. Tufts Medical Center continues to be at the forefront of research into new treatments of this disease. A new TKI called DCC-2036 was jointly developed with the pharmaceutical industry and is currently in an early (phase I) clinical trial at Tufts. Two investigators at Tufts are funded by the National Institutes of Health to develop new treatments that make use of engineered human immune cells to attack the leukemic stem cell.
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