NORD gratefully acknowledges Olivia Lanes, NORD Editorial Intern and Thomas P. Loughran, Jr., MD, Director, University of Virginia Cancer Center, for assistance in the preparation of this report.
Chronic myelogenous leukemia (CML) accounts of about 20% of all leukemias affecting adults. It typically affects middle-aged individuals and rarely adolescents or children. CML is a slowly progressing blood and bone marrow disorder, characterized by the excessive development of white blood cells in the spongy tissue found inside large bones of the body (bone marrow), spleen, liver and blood. As the disease progresses, the leukemic (blast) cells invade other areas of the body including the intestinal tract, kidneys, lungs, gonads and lymph nodes. These diseased cells do not grow old and eventually die like normal cells. They build up in huge numbers, overwhelm healthy blood cells and damage the bone marrow. Since CML progresses slowly, many people are first diagnosed during routine blood exams before they even show symptoms. There is no cure for CML because it is not possible to eliminate all of the diseased cells in the body, however, there are many approved treatments that can achieve a long-term remission. Patients respond best to treatment when CML is in its earliest stage, so it is important to diagnose the disease as early as possible. Possible symptoms that may indicate CML are fever, night sweats, fatigue, pain below the ribs on the left side, and inexplicable weight loss. If an individual is experiencing any of the above symptoms or other signs, it is important they make an appointment with their doctor to be tested for CML. Introduction There are three phases of chronic myelogenous leukemia.
The first phase, or the chronic phase, is characterized by a slow, progressive overproduction of white blood cells. In chronic CML, fewer than 10% of the cells in the blood and bone marrow are blast (leukemic) cells. Patients in this phase have the best response to treatment. The next phase is transitional, and is called the accelerated phase, which occurs when 10%-19% of the cells are blast cells. The most advanced phase is the blastic phase. At this point, over 20% of the blood cells are blast cells). In the blastic phase, the leukemia is very aggressive and does not respond well to therapy. Approximately 85% of all individuals with chronic myelogenous leukemia enter this phase.
Many individuals with CML show nonspecific symptoms at the time of diagnosis. The most common symptoms are fatigue, weakness, itchiness, night sweats, abdominal discomfort, and weight loss. An abnormally enlarged spleen (splenomegaly) is usually discovered upon physical examination. CML is commonly diagnosed when an affected individual is undergoing blood tests for a different reason. Sometimes, no symptoms are present at all.
When the accelerated or blastic phase of CML occurs, an affected individual may experience severe weight loss, high fever, bone pain, enlargement of the liver and spleen, pain in the joints (arthralgia), and hemorrhages appearing as patches of purplish discoloration on the skin and mucous membranes.
The exact cause of CML is not known. Blood samples of patients with CML show the presence of abnormal cells that reproduce more rapidly than normal cells. Ninety percent of these neoplastic cells show a consistent rearrangement of chromosomes. This rearrangement is the result of a transfer of genetic material from chromosome 22 to chromosome 9 and vice versa. As a result of this transference, chromosome 22 ends up shorter than normal. This shortened chromosome is known as the Philadelphia chromosome, and is present in the blood cells of 90% of people with CML. Formation of the Philadelphia chromosome results in a fused gene, called BCR-ABL. This gene contains instructions that make the disease blood cells produce far too much of a protein called tyrosine kinase. This protein causes the cancer by allowing the diseased blood cells to grow out of control.
Family history is not a risk factor for CML. The chromosome rearrangement resulting in the Philadelphia chromosome is believed to be acquired, meaning it develops after birth. It is believed that in some cases, excessive exposure to radiation increases an individual’s chances of developing the disease.
CML is slightly more prevalent in males than in females. It may occur at any age, but predominantly affects people in their 40s and 50s. There are more than 4,000 new cases of the 30,000 new cases of leukemia, diagnosed each year. There is an increased incidence rate of CML among people who have been exposed to radiation, such as the survivors of the atomic bombs dropped in Nagasaki and Hiroshima.
Although very rare in young patients, ages 20-29, CML may present itself in a more aggressive form, such as the accelerated phase or the blastic phase.
A diagnosis of CML is made based upon a thorough clinical evaluation, a detailed patient history and a variety of tests including blood tests, bone marrow examination, and chromosome analysis.
Routine blood tests may reveal abnormally high levels of white blood cells along with high numbers of immature white blood cells. If this is the case, a complete blood count (CBC) will be conducted. This test can provide a more detailed account of the abnormalities in the blood cells.
A sample of tissue taken from the bone marrow is needed to confirm a diagnosis. In individuals with advanced stage CML, the bone marrow has very little fat and numerous leukemic cells.
A fluorescence in situ hybridization (FISH) analysis and a polymerase chain reaction (PCR) test can identify the Philadelphia chromosome or the fused BCR-ABL gene that results from the chromosome translocation.
Clinical Testing and Work-Up
When treating CML, it is crucial to know what stage of the disease the individual is in. To determine staging, the following tests and procedures may be used:
Cytogenetic analysis: A test in which cells in a sample of blood or bone marrow are viewed under a microscope to look for certain changes in the chromosomes, such as the Philadelphia chromosome.
Bone marrow aspiration and biopsy: The removal of bone marrow, blood, and a small piece of bone by inserting a needing into the hipbone or breastbone. They are then screened by a pathologist for abnormal cells under a microscope.
Tyrosine kinase inhibitors (TKIs) are the frontline therapy for CML.
In 2002, the FDA approved imatinib mesylate (Gleevec), as a therapeutic agent for CML. Gleevec uses a technique known as molecular targeting to block the action of the protein tyrosine kinase, thought to be responsible for most cases of CML. Because it targets the specific cause of the disease, the treatment does not alter healthy tissues, and is thought to be easier on patients than other forms of treatment, such as interferon injections, chemotherapy, and bone marrow transplant. Gleevec is manufactured by Novartis Pharmaceuticals Corporation.
Other drugs that have recently been approved by the FDA are dasatinib (Sprycel) and nilotinib (Tasigna). They work in ways similar to Gleevec, by blocking tyrosine kinase.
In June of 2010, Tasigna was approved by the FDA to treat CML upon initial diagnosis. Tasigna is manufactured by Novartis Pharmaceuticals Corporation.
Sprycel was approved in October of 2010 by the FDA to treat CML when other drugs, such as Gleevec, have been ineffective. Sprycel is manufactured by Bristol Myers Squibb.
Bosulif (bosutinib) was approved by the FDA in 2012 as a treatment for patients with chronic, accelerated or blast phase Philadelphia chromosome positive CML who are resistant to or who cannot tolerate other therapies. Bosulif works by blocking the signal of the tyrosine kinase that promotes the development of abnormal and unhealthy granulocytes. Bosulif is manufactured by Pfizer.
Synribo (omacetaxine mepesuccinate) was approved by the FDA in 2012 under its accelerated approval program to treat adults with CML. This is a new treatment option for patients who are resistant to or cannot tolerate other FDA-approved drugs for chronic or accelerated phases of CML. Synribo blocks certain proteins that promote the development of cancerous cells. Synribo is manufactured by Teva Pharmaceuticals.
The following therapies have been used previously to treat CML:
The orphan drug Idarubicin HCI for injection (Idamycin) was approved by the Food and Drug Administration (FDA) in 1990 for the treatment of CML.
Interferon alfa-2a (Roferon A), administered by injection, received FDA approval for the treatment of CML in 1995.
Drugs that inhibit bone marrow activity (myelosuppressive drugs) may slow the progression of the disease. Hydroxyurea, a medication used to treat CML patients, may lower the white cell count and therefore reduce symptoms.
Radiation therapy of the spleen is another treatment option employed in only relatively few uncontrolled cases, either alone or in combination with chemotherapy, to slow the progression of the disease.
Bone marrow transplant, when performed during the early phase of the disease, can lead to remission and cure of this disease. However, this mode of treatment is not appropriate for all patients and does present some risks. The likelihood of success appears greatest among younger patients who are treated in the early stages of the disease.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
The National CML Society provides current information about emerging drug therapies for CML:
Kantarjian HM, Cortes J. New strategies in chronic myeloid leukemia. Int J Hematol. 2006;83:289-93.
Murgo AJ. Clinical trials of arsenic trioxide in hematologic and solid tumors: overview of the national cancer institute cooperative research and development studies. Oncologist. 2001; 6:22-28.
Druker BJ, et al., Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest. 2000;105:3-7.
Kantarjian HM, et al., Significance of FHIT expression in chronic myelogenous leukemia. Clin Cancer Res. 1999;5:4059-64.
Moracova J, et al., Polymerase chain reaction analyses should be used as a basis for clinical decision making in patients with chronic myelogenous leukemia. Blood. 1999;94:3609-11.
Sacci S, et al., Unexpected high incidence of severe toxicities associated with alpha-interferon, low dose cytosine arabinoside and all-trans retinoic acid in patients with chronic myelogenous leukemia. Leuk Lymphoma. 1999;35:483-89.
Reiter E, et al., Long-term follow-up of patients after related- and unrelated-donor bone marrow transplantation for chronic myelogenous leukemia. Ann Hematol. 1999;78:507-13.
Sacci S, et al., Chronic myelogenous leukemia in nonlymphoid blastic phase: analysis of the results of first salvage therapy with three different treatment approaches for 162 patients. Cancer. 1999;86:2632-41.
Hehlmann R., A chance of a cure for every patient with chronic myeloid leukemia. N Engl J Med. 1998;338:980.
Mayo Clinic Staff. MayoClinic.com. Chronic myelogenous leukemia. http://www.mayoclinic.com/health/chronic-myelogenous-leukemia/DS00564 Updated Jan. 17, 2014. Accessed May 12, 2015.
Besa EC. Medscape. Chronic myelogenous leukemia. http://emedicine.medscape.com/article/199425-overview Updated: Aug 22, 2014. Accessed May 12, 2015.
National Cancer Institute. Chronic Myelogenous Leukemia Treatment. http://www.cancer.gov/cancertopics/pdq/treatment/CML/Patient/allPages Updated March 16, 2015. Accessed May 12, 2015.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100