Chronic myelocytic leukemia (CML) is a cancer of white blood cells in which too many white blood cells are made in the bone marrow. Chronic myelogenous leukemia and chronic myeloid leukemia are other names for CML and refer to the identical disease. In CML, there is an increased proliferation of white blood cells called granulocytes.
Description
Chronic leukemia is a cancer that starts in the blood cells made in the bone marrow. The bone marrow is the spongy tissue found in the large bones of the body. The bone marrow makes precursor cells called "blasts" or "stem cells" that mature into different types of blood cells. Unlike acute leukemias, in which the process of maturation of the blast cells is interrupted, in chronic leukemias, the cells do mature and only a few remain as immature cells. However, even though the cells appear normal, they do not function as normal cells.
The different types of cells produced in the bone marrow are red blood cells (RBCs), which carry oxygen and other materials to all tissues of the body; white blood cells (WBCs), which fight infection; and platelets, which play a part in the clotting of the blood. The white blood cells can be further subdivided into three main types: the granulocytes, monocytes, and the lymphocytes.
The granulocytes, as their name suggests, have granules (particles) inside them. These granules contain special proteins (enzymes) and several other substances that can break down chemicals and destroy microorganisms such as bacteria. Monocytes are also important in defending the body against pathogens.
The lymphocytes form the third type of white blood cell. There are two main types of lymphocytes: T lymphocytes and B lymphocytes. They have different functions within the immune system. The B cells protect the body by making antibodies. Antibodies are proteins that can attach to the surfaces of bacteria and viruses. This attachment sends signals to many other cell types to come and destroy the antibody-coated organism. The T cell protects the body against viruses. When a virus enters a cell, it produces certain proteins that are projected onto the surface of the infected cell. The T cells can recognize these proteins and produce certain chemicals (cytokines) that are capable of destroying the virus-infected cells. In addition, the T cells can destroy some types of cancer cells.
Chronic leukemias develop very gradually. The abnormal lymphocytes multiply slowly, but in a poorly regulated manner. They live much longer than normal cells and thus their numbers build up in the body. The two types of chronic leukemias can be easily distinguished under the microscope. Chronic lymphocytic leukemia (CLL) involves the T or B lymphocytes. In chronic myelocytic leukemia (CML), the cells affected are the granulocytes. In addition, CML involves abnormalities of both the blood platelets, structures that help blood to clot, and the red blood cells, the blood cells that carry oxygen.
Very rarely will CML appear in children. Juvenile CML is a distinct disease of children younger than 14
years of age. There is a decrease in the number of blood platelets, substances that help the blood to clot. And there is an increase in certain white blood cells.
Demographics
Slightly more men than women are affected by CML. The average patient is between 50 and 60 years of age. However, CML can affect people of any age. Chronic leukemias account for 1.2% of all cancers. Chronic myelocytic leukemia is generally seen in people in their mid-40s. According to the estimates of the American Cancer Society (ACS), approximately 4, 400 new cases of leukemia were diagnosed in the year 2000, 2, 600 in men and 1, 800 in women. Between 1973 and 1991, the rate at which CML appeared in the United States decreased slightly.
Causes and symptoms
People exposed to nuclear and other radiation are at increased risk for CML. Thus, people who have had higher exposure to radiation for medical reasons are at increased risk of developing this cancer. Parents with CML do not have children who are more than normally likely to develop CML. However, it is possible that people whose immune system exhibits certain characteristics are at increased risk for the disease.
CML develops in a two-or three-stage progression. First, the chronic phase appears. Between 60 and 80 percent of patients next exhibit the symptoms of what is called the accelerated phase. The final stage of CML is the terminal blastic phase.
Symptoms of chronic phase CML appear in 60%-85% of patients. This means 15% to 40% of all the people diagnosed with CML have no symptoms at all and are diagnosed with the disease only because of the results of a routine blood test. Patients who do have symptoms most frequently find themselves to have fatigue, weight loss, or pain. Some patients have a mass of tissue or an enlarged liver that the doctor is able to feel. Some patients experience strokes, visual problems, a lowering of alertness or responsiveness, priapism, and ringing in the ear. Many patients in accelerated phase CML have no specific symptoms. However, fever, weight loss, and night sweats may appear.
Patients with terminal, blastic phase CML often experience symptoms. There may be fever, weight loss, night sweats, and bone pain. Many patients develop infections. Many have anemia (low counts of red blood cells) and many bleed easily.
People who have CML have an unusually high number of white blood cells. Somewhat less than half of these people also have high numbers of blood platelets. Most patients have mild anemia. The composition of the bone marrow in CML patients also differs from that of a healthy person. The marrow is described as being hyper-cellular. This means that the number of cells present in the bone marrow is unusually great.
If the doctor has reason to suspect leukemia, he or she will conduct a very thorough physical examination to look for enlarged lymph nodes in the neck, underarm, and pelvic region. Swollen gums, an enlarged liver or spleen, bruises, or pinpoint red rashes all over the body are among the signs of leukemia. Urine and blood tests may be ordered to check for microscopic amounts of blood in the urine and to obtain a complete differential blood count. This count will give the numbers and percentages of the different cells found in the blood.
Standard imaging tests such as x rays, computed tomography scans (CT scans), and magnetic resonance imaging (MRI) may be used to check whether the leukemic cells have invaded other organs of the body, such as the bones, chest, kidneys, abdomen, or brain.
Many doctors consider the presence of the Philadelphia (Ph) chromosome to be a crucial factor in the diagnosis of CML. The Ph chromosome is formed if some of the genetic material in two specific parts of two specific genetic units, called chromosomes, have exchanged
some content in a particular way and created an arrangement of genetic material characteristic of CML patients.
Laboratory findings indicate when a patient enters the accelerated phase of CML. There may be more than 15% blasts (immature cells) in the blood. Alternately, the accelerated phase has started when more than 30% of the blood may be composed of a combination of blasts and promyelocytes. Promyelocytes are immature granulocytes. Another marker for the start of the accelerated phase is when the blood contains more than 20% of another white blood cell, called a basophil. Finally, the accelerated phase may be heralded by there being more than 100, 000, 000, 000 platelets per liter of blood. The terminal, blastic phase of CML is heralded by measurements of 30% or more of blasts in either the bone marrow or the blood.
Clinical staging, treatments, and prognosis
Staging
Several different staging systems are in use. Most of these make use of the fact that a number of factors relevant to patients with CML say something about the patient's prognosis. Among these factors are the patient's age, the white blood cell count, the platelet count, the percentage of blast cells and basophil cells in either the blood or the bone marrow, the size of the liver, the size of the spleen, population of red blood cells that have a central portion called a nucleus, and the evolution of certain cell clones.
Treatment
It is very fortunate that several years ago the American Society of Hematology convened an Expert Panel on Chronic Myeloid Leukemia. This panel reviewed available therapies and published its findings in 1999. The findings were rigorously based upon evidence provided by the best research. The panel, comprised of top doctors from around the world, carefully sifted through all of the studies on treatment for CML and put aside all those studies performed with questionable methodology. This is a most important document relevant to CML therapy.
Since the publication of the findings of the expert panel, however, a new medicine has demonstrated great success in studies. This new medicine is known as STI571, Imatinib mesylate, or Gleevec. Since Gleevec was such a new drug in 2001, few studies have been conducted to evaluate its long-term effects. Furthermore, researchers have not had an opportunity to view the effects of imatinib mesylate over a period of five, 10, or 20 years.
In terms of CML therapy, the situation in 2001 was the following: physicians have the reliable report of the
Expert Panel and a little bit of new information about a new medication. How the Expert Panel's findings and this new information should be integrated with the results of recent studies of imatinib mesylate is an issue that cancer doctors are currently resolving.
The Expert Panel looked at treatment of the chronic phase of CML. One therapy examined by the panel is busulfan (BUS). Another is hydroxyurea (HU). Both BUS and HU are chemotherapy medications. Studies have demonstrated that CML patients in chronic phase given HU live longer than patients given BUS.
Another therapy examined by the expert panel is interferon-alpha. Interferon is a chemical normally made in the cells of the body. It helps protect the body against viruses and also seems to have some effect against certain cancers. The interferon used as medicine is a laboratory-manufactured copy of the interferon produced by the body. The Expert Panel concluded that patients in chronic phase CML who have received interferon live longer than those given HU or BUS. This conclusion applies, in particular, to patients who have had little prior treatment for CML, who start interferon treatment soon after diagnosis, and who have certain other characteristics. However, side effects of interferon therapy are greater than those of therapy with HU or BUS. Patients who develop the side effects of interferon may feel like they have the flu. Patients receiving interferon seem to do
better if they also receive chemotherapy with either HU or a medicine called Ara-C, or cytarabine.
Bone marrow transplantation (BMT) is an effective treatment for CML. In BMT, the patient's diseased bone marrow is replaced with healthy marrow. There are two ways of doing a bone marrow transplant. In an allogeneic bone marrow transplant, healthy marrow is taken from another person (donor) whose tissue is either the same or very closely resembles the patient's tissues. The donor may be a twin, a sibling, or a person who is not related at all. First, the patient's bone marrow is destroyed with very high doses of chemotherapy and radiation therapy. To replace the destroyed marrow, healthy marrow from the donor is given to the patient.
In the second type of bone marrow transplant, called an autologous bone marrow transplant, some of the patient's own marrow is taken out and treated with a combination of anticancer drugs to kill all the abnormal cells. This marrow is then frozen to save it. The marrow remaining in the patient's body is then destroyed with high dose chemotherapy and radiation therapy. Following that, the patient's own marrow that was frozen is thawed and given back to the patient.
Allogeneic BMT may be used soon after diagnosis or after a patient has been treated with interferon or chemotherapy. The Expert Panel found that carefully designed, well-controlled, randomized studies have not been conducted on BMT therapy for CML. In the studies that do exist, scientists performed BMT on a group of patients and then observed the results. These studies show that BMT may lead to long-term remission. Remission is achieved if the disease becomes diminished for a period. Patients appear to live longer if they received chemotherapy followed by BMT. But the Expert Panel cautions that the results of these observational studies cannot be relied upon. One problem with them might be, for example, that the patients chosen to receive BMT might have started out being healthier than patients who did not receive BMT. The side effects of BMT may be severe, and a large number of CML patients receiving BMT die as a direct result of the BMT.
Therefore, one important consideration when BMT is being considered is whether the conditions under which the individual patient might receive BMT are favorable. In other words, is a very suitable marrow donor available? Is the patient within two years of CML diagnosis? It is important that patients understand clearly the ptential benefits and risks of BMT. One comment made by the Expert Panel is that younger patients who hope to live a very long time after CML diagnosis are more likely to benefit from allogeneic BMT. Autologous BMT has not achieved superior long-term results.
The recent studies of imatinib mesylate found it very effective in two groups of CML patients. One group was made up of patients who had unsuccessful results with interferon alfa therapy. The other group of CML patients studied were in the blast phase of the disease. Both studies found the medication to be effective and well tolerated. However, studies reporting on the effectiveness of imatinib mesylate over periods of five years or longer were not yet available in 2001.
Because leukemia cells can spread to all the organs via the blood stream and the lymph vessels, surgery is not considered an option for treating the leukemias.
The Expert Panel was careful to state that patient preferences should be taken into account as a treatment plan is developed. No approach to CML therapy is perfect. Each provides some benefit and is accompanied by certain side effects and risks. Which therapy or therapies is best for each individual patient depends upon on certain facts, such
as the age of the patient and whether the patient is suffering from illnesses other than CML. In addition, the Expert Panel explains that the personal preferences of each patient are an important consideration. For example, some patients would rather avoid potential severe side effects and would be willing to give up the potential of living another few months or years. Other patients would be entirely unwilling to accept this way of looking at risks and benefits. It is important that health care professionals educate patients as to what treatment options are available and the perfections and imperfections associated with each. The opinions of each patient should be an important factor in deciding which treatment is best for that patient.
In the accelerated and blastic phase of CML, aggressive chemotherapy may be given. Combination chemotherapy, in which multiple drugs are used, is more effective than using a single drug for the treatment. Interferon and BMT may be used, although results are not as good as for patients in the chronic phase of CML.
It should be mentioned that during treatment the doctor may order a procedure called leukapheresis. This lowers the numbers of white blood cells circulating in the patient's body. Also, either before or after therapy, it may be necessary to provide the patient with a transfusion of blood platelets. In addition, antibiotics are often used to help prevent infection in leukemia patients.
Prognosis
The most important factor in determining the likelihood that a patient receiving interferon therapy will achieve long-term survival is whether there is a positive response to interferon-alfa. Although experience with imatinib mesylate is being gathered in studies, this drug remains so new that doctors do not know what effect it will have on the prognosis of CML patients. Once the threat of transplantation-related complications has passed, patients receiving BMT may achieve longer survival than patients receiving interferon therapy.
Before the discovery of modern therapies, patients often spent between three-and-a-half and five years in the chronic phase. Then some patients entered an accelerated phase, from which most died within 18 months. Once patients were in the terminal, blastic phase most died within six months. However, all of this has changed with the arrival of newer therapeutic techniques. Just as many patients used to die from heart attack while similar patients may now live for decades, so cancer patients are achieving longer lives.
Coping with cancer treatment
Cancer patients need supportive care to help them come through the treatment period with physical and emotional strength in tact. Many patients experience feelings of depression, anxiety, and fatigue, and many experience nausea and vomiting during treatment. Studies have shown that these can be managed effectively if discussed with the doctor.
Prevention
Although some cancers are related to known risk factors, such as smoking, in leukemias, there are no definitive risk factors. Therefore, at the present time, there is no way known to prevent the leukemias from developing. People who are at an increased risk for developing leukemia because of proven exposure to ionizing radiation, the organic liquid benzene, or people who have a history of other cancers of the lymphoid system (Hodgkin's lymphoma) should undergo periodic medical checkups.
Braunwald, Eugene, et al. Harrison's Principles of Internal Medicine, 15th ed. New York: McGraw-Hill, 2001.
deWitt, Susan C. Essentials of Medical-Surgical Nursing, 4th ed. Philadelphia: W. B. Saunders, 1998.
Humes, H. David, et al. Kelley's Textbook of Internal Medicine, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2000.
Pazdur, Richard, et al. Cancer Management: A Multidisciplinary Approach: Medical, Surgical, & Radiation Oncology, 4th ed. Melville, NY: PRR, 2000.
Souhami, Robert, Jeffrey Tobias. Cancer and Its Management, 3rd ed. London: Blackwell Science, 1998.
PERIODICALS
Drucker, B. J., et al. "Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia." New England Journal of Medicine, 344 (2001): 1031-1037.
Drucker B. J., et al. "Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome." New England Journal of Medicine, 344 (2001): 1038-1042.
Silver, Richard T., et al. "An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology." Blood, 94 (1999): 1517-1536.
ORGANIZATIONS
The National Cancer Institute publishes useful texts available through the Internet or by mail, and answers questions by telephone. Some publications include: Leukemia, What You Need to Know About Leukemia, PDQ -Treatment -Patients: Chronic Myelogenous Leukemia, and Complementary & Alternative Therapies for Leukemia, Lymphoma, Hodgkin's Disease, & Myeloma. Telephone: 1-800-4CANCER. Web site: <www.nci.nih.gov/>.
The Leukemia & Lymphoma Society (Formerly Leukemia Society of America) publishes useful texts available through the Internet or by mail. Some publications include: Chronic Myelogenous Leukemia (CML), Choosing a Specialist. Choosing a Treatment Facility, Making Intelligent Choices About Therapy, Understanding Blood Counts, Patient Aid Program, and Family Support Group. Telephone:1-800-955-4572. Web site: <www.leukemialymphoma.org/>.
The American Cancer Society publishes useful texts, which include: Adult Chronic Leukemia -Overview, Leukemia -Adult Chronic: Treatment, Leukemia -Adult Chronic: Detection and Symptoms, Leukemia: Adult Chronic FAQ [Frequently Asked Questions], and Leukemia -Adult Chronic: Prevention & Risk. Telephone:1-800-ACS-2345. Web site: <www.cancer.org/>.
National Coalition for Cancer Survivorship. 1010 Wayne Avenue, 7th Floor, Silver Spring, MD 20910-5600. Telephone: (301) 650-9127 and (877)NCCS-YES [877-622-7937). Web site: <www.cansearch.org>.
Lata Cherath, Ph.D.
Bob Kirsch
Accelerated phase
—The middle one of the three-phase course of CML. However, between 20 and 40 percent of patients never enter the accelerated phase but, rather, go directly from the chronic to the terminal blastic phase.
Basophil
—A type of white blood cell
Blast
—An immature cell
Bone marrow
—Spongy tissue found in the large bones of the body
Chemotherapy
—Treatment with drugs that act against cancer.
Chronic phase
—The initial phase of CML.
Hypercellular
—Bone marrow is described as being hypercellular if the number of cells present in the bone marrow is unusually great.
Leukapheresis
—A procedure to remove or extract excessive white blood cells from the blood.
Philadelphia (Ph) chromosome
—The Philadelphia (Ph) chromosome is present if some of the genetic material in two specific parts of two specific genetic units, called chromosomes, have exchanged some content in a particular way.
Remission
—Remission of a disease is achieved if the disease becomes diminished for a period.
Terminal blastic phase
—The final stage of CML.
QUESTIONS TO ASK THE DOCTOR
How can I obtain supportive care so I come through this not only alive but with my family and emotional life intact?
What sort of benefit and what sort of side effects might each of the available treatment options bring?
Would you please inform me about the treatment options and let me tell you about the priorities in my life so I can participate in forming a treatment plan?
What is my prognosis?
Are blasts present?
Has complete remission or partial remission been achieved?
