Chronic Myelogenous Leukemia (CML)

About 4,600 new cases of chronic myelogenous leukemia (CML) are diagnosed each year in the United States. Chronic myelogenous leukemia may be called by several names, including chronic granulocytic, chronic myelocytic or chronic myeloid leukemia.CML results from an acquired (not inherited) injury to the DNA of a stem cell in the marrow. This injury is not present at birth. Scientists do not yet understand what produces this change in the DNA in patients with CML. This change in the stem cell's DNA confers a growth and survival advantage on the malignant stem cell. The result of this injury is the uncontrolled growth of white cells leading, if unchecked, to a massive increase in their concentration in the blood. Unlike acute myelogenous leukemia (AML), chronic myelogenous leukemia permits the development of mature white blood cells that generally can function normally. This important distinction from acute leukemia accounts for the less severe early course of the disease. Most cases of chronic myelogenous leukemia occur in adults. Only 2.6 percent of leukemias in children ages 0-19 are CML. The frequency of the disease increases with age from about one in 1 million children in the first 10 years of life to nearly two in 100,000 people at age 50, to one in 10,000 people at age 80 and above . The disease in children is similar in behavior to that of adults; however, the outcome of stem cell transplantation is better in younger individuals.

Chronic myelogenous leukemia is distinguished from other leukemias by the presence of a genetic abnormality in blood cells, called the Philadelphia chromosome. The changes that result in this chromosome "causing" chronic myelogenous leukemia have been studied intensively. In 1960, two physicians studying chromosomes in cancer cells noticed that a chromosome in CML patients was shorter in length than that of the same chromosome in normal cells. They named this shortened chromosome the Philadelphia chromosome, because the observation was made at the University Of Pennsylvania School Of Medicine in that city. The total of 46 chromosomes in normal human cells is composed of 22 pairs of chromosomes numbered 1 to 22 and two sex chromosomes (either an X and Y in males or two X's in females). The Philadelphia chromosome (No. 22), which is an abnormally short chromosome, is usually referred to as the Ph-chromosome. Further studies established that two chromosomes, usually chromosome Nos. 9 and 22, were abnormal. Pieces of the chromosomes, which are broken off in the blood cells of patients with chronic myelogenous leukemia, switch with each other. The detached portion of chromosome 9 sticks to the broken end of chromosome 22, and the detached portion of chromosome 22 sticks to the broken end of chromosome 9. This abnormal exchange of parts of chromosomes is called a translocation. This translocation of chromosome pieces occurs only in the stem cell and in the various blood cells derived from that stem cell. The chromosomes of the cells in other tissues are normal.

The breakage on chromosome 9 disrupts a gene referred to as "ABL" (for Abelson). The breakage on chromosome 22 involves a gene referred to as "BCR" (for breakpoint cluster region). The human ABL gene is mutated by the breakage of chromosome 9. The mutated gene is translocated to chromosome 22 and fuses with the remaining part of the BCR gene. This fusion between BCR and ABL leads to an abnormal fused gene, called BCR-ABL. Despite these changes, the BCR-ABL gene can function. The function of a gene is to direct the production of a protein in the cell. In chronic myelogenous leukemia, the protein produced by the BCR-ABL gene is abnormal. The protein produced is an enzyme called tyrosine kinase. The ABL when fused to BCR results in an elongated protein when compared to the protein made by the normal ABL gene. This elongated protein (enzyme) functions abnormally and leads to dysfunctional regulation of cell growth and survival. Evidence points to the abnormal protein as the cause of the leukemic conversion of the hematopoietic stem cell. The mutated gene results in an abnormal or mutated protein, which is responsible for the development of the disease.

The cause of the chromosomal breakage in virtually all CML patients is not known. In a small proportion of patients, the cause of the breakage is exposure to very high doses of radiation. This effect has been most carefully studied in the Japanese survivors of the atomic bomb, whose leukemia risk was significantly increased. A slight increase in risk also occurs in some individuals treated with high dose radiotherapy for other cancers, such as lymphoma. Exposures to diagnostic dental or medical x-rays have not been associated with a heightened risk of chronic myelogenous leukemia.

The onset of chronic myelogenous leukemia is associated with symptoms that usually develop gradually. Most patients feel a loss of well-being. They tire more easily and may feel short of breath when physically active. They may have a pale complexion from anemia. Discomfort on the left side of the abdomen from an enlarged spleen is a frequent complaint. Patients may experience excessive sweating, weight loss and inability to tolerate warm temperatures. Increasingly, the disease is discovered during the course of a "routine" medical examination. Since the disease worsens over weeks or months, most patients would have symptoms develop soon after such a medical examination in any case.

• Medical history and physical examination
• Complete blood counts
• Bone marrow examination
• Cytogenetic Analysis
• Polymerase Chain Reaction (PCR)

To diagnose the disease, the blood and, in most cases, the marrow cells must be examined. The white cell count invariably increases, often to very high levels. Examination of the stained (dyed) blood cells with a light microscope shows a characteristic pattern of white cells: a small proportion of very immature cells (leukemic blast cells), and a larger proportion of maturing and fully-matured white cells (myelocytes and neutrophils). In addition, a sample of marrow is examined to confirm the blood findings and to determine if there is an abnormality of chromosomes. This test, which measures the number and normalcy of chromosomes, is referred to as a cytogenetic analysis. The presence of the Philadelphia chromosome in the marrow cells, a shortened chromosome number 22, high white blood cell counts, and other characteristic blood and marrow findings, confirm that the disorder is chronic myelogenous leukemia. Cytogenetic examination of tissue is the process of analyzing the number and shape of the chromosomes of cells. The individual, who prepares, examines and interprets the number and shape of chromosomes in cells is called a cytogeneticist. In addition to identifying chromosome alterations, the specific genes affected can be identified in some cases. These findings are essential in verifying that the disease is BCR-ABL positive CML.

The chromosome abnormalities that characterize chronic myelogenous leukemia can be detected by other techniques as well. Fluorescence in situ hybridization (FISH) is another method to identify cells in which the nucleus that contains chromosomes with the 9:22 translocation characteristic of CML. FISH is also useful to follow the effects of treatment since it can reveal whether there has been a significant decrease of CML cells in the blood.A very sensitive test of blood cells, the polymerase chain reaction or PCR, can increase very small amounts of either RNA or DNA and make them easier to detect. The alteration in DNA caused by the chromosome breakage in CML can be detected by this very sensitive method. PCR is more sensitive than FISH and can detect one BCR-ABL-positive cell in a background of about 500,000 normal cells.

Here is another view of a peripheral blood smear in a patient with CML. Often, the numbers of basophils and eosinophils, as well as bands and more immature myeloid cells (metamyelocytes and myelocytes) are increased. Unlike AML, there are not many blasts with CML