Chronic myelogenous leukemia (also called CML, chronic myelocytic leukemia, or chronic myeloid leukemia) is a chronic (long-term) disorder of the bone marrow. Bone marrow is the spongy, red tissue that fills the large bones. All of the blood cells are produced in the bone marrow.

Patients with CML have acquired an abnormality that causes one chromosome (a strand of genes) to break off and attach to another chromosome; this results in an abnormally short chromosome, known as the Philadelphia chromosome. This exchange of genetic information causes two genes, BCR and ABL, to fuse into one gene, called BCR-ABL.

The BCR-ABL gene causes bone marrow cells to produce an abnormal enzyme; this enzyme stimulates white blood cells to grow out of control, resulting in elevations of the white blood cell count and an increase in the size of the spleen. Eventually, the disease may transform into a more aggressive disease, called acute leukemia.

People with acute leukemia have an increased number of immature white blood cells (called blast cells). The overgrowth of blast cells leads to an inadequate number of mature white blood cells, which limits production of other vital blood cells, including red blood cells and platelets. Having a decreased number of blood cells and platelets can increase the risk of developing infections or bleeding excessively.

There are three phases of CML:

Chronic phase — In the chronic phase, there are less than 5 percent immature blast cells circulating in the bone marrow. Approximately 85 percent of patients are in the chronic phase when they are initially diagnosed. This phase generally lasts several years and is readily controllable with oral chemotherapy medications.

Accelerated phase — During the accelerated phase, maturation of white blood cells becomes progressively impaired, and there are between 10 and 19 percent blast cells in the blood or bone marrow. The number of abnormal cells in the body is more difficult to control with medications, likely because of new mutations that develop in the blast cells.

Blast phase — In blast crisis (blast phase), there are more than 20 to 30 percent blast cells in the blood or bone marrow. Before recent advances in treatment, blast crisis typically occurred within four to five years after diagnosis and was often unresponsive to treatment.

TREATMENT OPTIONS — Treatment decisions for patients with CML are complex due to the variety of available options and the lack of long term follow-up results for the newer, simpler options. Currently, the most frequently used treatment options include: oral tyrosine kinase inhibitors such as imatinib (Gleevec®), dasatinib (Sprycel®), or nilotinib (Tasigna®); stem cell transplant in select cases, and other chemotherapies (hydroxyurea or interferon alpha with or without cytarabine).

The primary goal of treatment is to reduce or eliminate the cells with the abnormal Philadelphia chromosome. This is measured as the cytogenetic response. Such treatment, if effective, will also return the blood count to normal. This is measured as the hematologic response. While achieving a hematologic response will reduce the severity of symptoms associated with CML, progression to the accelerated or blast phase will continue unless a cytogenetic response is achieved. Achieving a hematologic response is important, but it does not ensure that the disease is adequately controlled.

The only way to ensure that the disease is controlled is to have sensitive molecular testing. A person is said to have a molecular response when there is no evidence of the BCR-ABL gene. The goal of bone marrow transplantation is to achieve this level of response. Longer term follow up of people treated with imatinib indicate that some of these patients have a molecular response as well. Chemotherapy, on the other hand, only occasionally produces such a response.

TYROSINE KINASE INHIBITORS — The consequence of the Philadelphia chromosome is the formation of a unique gene product, an abnormal enzyme called the BCR-ABL tyrosine kinase. As a result, researchers directed their efforts at developing compounds that could selectively inhibit this abnormal enzyme. Tyrosine kinase inhibitors slow or stop the actions of BCR-ABL, which leads to the rapid death of cells containing the abnormal Philadelphia chromosome. Normal cells suffer less toxic effects from tyrosine kinase inhibitors as compared to traditional chemotherapy treatments.

Although they have not been proven to cure the disease, tyrosine kinase inhibitors are able to achieve long-term control of the disease in the majority of patients; thus, they have become the initial treatment of choice for almost all people who are newly diagnosed with CML

Imatinib (Gleevec®) — Imatinib mesylate is a tyrosine kinase inhibitor that can be used in patients with all phases of CML. It is proven to have significant benefits; one study comparing imatinib to interferon plus cytarabine (a form of chemotherapy) for patients with newly diagnosed, chronic phase CML found that 97 percent of patients receiving imatinib had a complete hematologic response rate, and 76 percent achieved a complete cytogenetic response.

Further follow-up is needed to determine how long responses will last, although the relapse rate has been remarkably low in patients followed for six or more years who achieved a complete cytogenetic response. At the current time, experts recommend continuing imatinib treatment indefinitely because the disease recurs, often within months, in the majority of people who stop taking it. Progression to blast crisis can occur despite imatinib treatment in people with advanced disease and in those who acquire new genetic mutations.

The recommended initial starting dose of imatinib is 400 mg/day for patients in chronic phase and 600 mg/day for patients in accelerated phase or blast crisis. The medication should be taken by mouth once daily, with a meal and a large glass of water. A higher dose of imatinib (400 mg twice a day) may be associated with a faster response. However, this dose is generally reserved for people enrolled in clinical trials.

Side effects — Imatinib is generally very well tolerated; most side effects are mild to moderate and do not cause the person to stop taking it. Common side effects include: Nausea and vomiting, although this is not usually a problem when the drug is taken with meals. Diarrhea is usually mild to moderate, but can be severe. It generally responds to treatment with loperamide (Imodium®). Muscle cramps are perhaps the most bothersome long-term symptom associated with imatinib, most commonly affecting the calves, feet, and hands. There is no definitive treatment, although some patients benefit from treatment with calcium or magnesium supplements, or the use of quinine. Skin rash is uncommon. When it occurs, it is usually mild and often resolves with continued treatment. Breast enlargement (gynecomastia) may occur in a small number of men. Mild anemia is not uncommon in patients who use imatinib for long periods.

Acetaminophen (Tylenol®) and St. John's wort (hypericum perforatum) should be avoided while taking imatinib due to the risk of a drug interaction.

Newer second generation tyrosine kinase inhibitors are now available for patients who do not tolerate imatinib or for those patients who are refractory or resistant to imatinib, specifically dasatinib and nilotinib. In addition, there are an increasing amount of clinical trials looking at new agents which may also prove to be beneficial.

OTHER TREATMENTS: Stem cell transplant is primarily reserved for very young patients, patients who fail imatinib, and for patients in accelerated or blast phase. Hydroxyurea, cytarabine, and interferon also are examples of some chemotherapy agents which have activity in CML and are sometimes used.

Websites:

www.leukemia-lymphoma.org

www.cancer.gov/cancerinfo/pdq/treatment/CML

www.marrow.org/PATIENT/Undrstnd_Disease_Treat/Lrn_about_
Disease/CML/index.html