Leukemias

Adult Chronic Myeloid Leukemia

Adult chronic myeloid leukemia (CML), also called chronic myelogenous leukemia or chronic granulocytic leukemia, is a cancer of the blood and bone marrow that progresses slowly and usually occurs during or after middle age but rarely in childhood.

The role of bone marrow, the soft tissue inside bones, is to make immature blood stem cells that develop into mature blood cells. In people who have CML, too many stem cells develop into abnormal white blood cells known as blast cells or granulocytes that build up in bone marrow. These cells do not function normally and they interfere with the production of healthy white blood cells, red blood cells and blood platelets.

CML occurs when a genetic mutation alters the normal development of blood cells. The cells in your body contain 23 coiled pairs of chromosomes made up of DNA that contains genes which control development. About 90% of people with CML have a translocation (an exchange of chromosome material) of genetic material between human chromosome 9 and chromosome 22, resulting in a short chromosome 22 and a long chromosome 9.

The short chromosome 22 is known as the Philadelphia chromosome, named for the city where it was discovered. This chromosome creates a new gene that contains instructions telling the abnormal white blood cells to produce too much of a protein named tyrosine kinase, which in turn allows abnormal white blood cells to be overproduced.

Symptoms and Diagnosis

In the early developmental phase of this disease, up to 20% of people with chronic myeloid leukemia may not have obvious symptoms and can live for months or years without knowing they have CML. Eventually, as the disease progresses, symptoms do occur.

Because people with CML do not have enough healthy white blood cells, they may be susceptible to infections. Because they do not have enough red blood cells, they may develop anemia with symptoms of fatigue (feeling tired), weakness and shortness of breath. Because they do not have enough blood platelets, they may bruise and bleed easily. Other symptoms may include weight loss for no known reason, night sweats, fever, bone or joint pain, excessive blood clotting and stroke. If the cancerous cells spread to the spleen, the spleen becomes enlarged and may cause pain on the left side of the abdomen.

In addition to a physical exam and medical history, a diagnosis of CML is usually made based on information from blood and bone marrow tests, including blood cell counts, blood chemistry studies and bone marrow samplings, that is, a bone marrow biopsy and aspiration (removal of tissue samples for study). A cytogenetic analysis is also usually done in which a sample of blood or bone marrow is examined under a microscope to look for changes in chromosomes, such as the Philadelphia chromosome.

Phases of CML

CML develops in three phases based on the number of abnormal white blood cells seen in the blood or bone marrow: chronic, accelerated and blastic.

In the chronic phase, less than 10% of the cells in blood and bone marrow are blast cells. Symptoms in this phase are typically very mild, if they occur at all. About 81% of CML patients are diagnosed in the chronic phase.

In the accelerated phase, from 10% to 19% of blood and bone marrow cells are blast cells and there are fluctuations in the number of other white blood cells and blood platelets as well. Symptoms may include fever and weight loss.

In the blastic phase, 20% or more of these cells are blast cells. This is the most advanced and aggressive phase of the disease. It usually means the cells have spread beyond the bone marrow to other tissues and organs. Patients often have symptoms of fever, weight loss and decreased appetite.

Treatment

Many patients with CML in the chronic phase receive treatment with a targeted therapy drug known as imatinib mesylate (trade name Gleevec) as the standard first treatment. This drug has revolutionized therapy for CML.

The Philadelphia chromosome in CML patients creates an abnormal gene called Bcr/Abl that stimulates the overproduction of tyrosine kinase and blast cells. Imatinib is a tyrosine kinase inhibitor that blocks the tyrosine kinase enzyme (protein) from signaling bone marrow to make too many blast cells.

A large clinical trial begun in 2000 compared the response rates among chronic-phase CML patients to imatinib with the response rates to the best standard chemotherapy treatment given at the time (interferon plus cytarabine). The study found that the response rates were much higher in the patients who received imatinib and that these patients had fewer side effects. A five-year update of this trial published in 2006 reported that most patients given imatinib continued to have good results.

In June 2010, the U.S. Food and Drug Administration approved nilotinib (Tasigna), a second generation tyrosine kinase inhibitor, for the first-line treatment of adult patients with newly diagnosed Philadelphia-positive CML in the chronic phase, providing patients with an option to imatinib for the initial treatment of CML. Like imatinib, nilotinib targets the Bcr/Abl gene.

In October 2010, the Food and Drug Administration also approved another second-generation tyrosine kinase inhibitor, dasatinib (Sprycel), for the treatment of newly diagnosed CML patients in the chronic phase. The FDA approval of both of these newer drugs was based on phase 3 clinical trials comparing dasatinib or nilotinib therapy with treatment by imatinib. In both trials, patients who received one of the newer drugs had higher rates of complete cytogenetic response, meaning a complete disappearance of cells that contain the Philadelphia chromosome.

Both drugs-which were previously approved by the FDA to treat CML that no longer responds to or is resistant to imatinib-are more potent than imatinib. In addition, fewer mutations in the Bcr/Abl gene appear capable of conferring resistance to these drugs than to imatinib.

Although one of the two clinical studies of these drugs showed statistically significant decreased rates of progression to the accelerated or blastic phase of CML, which may ultimately translate into improved survival, the follow-up period with nilotinib and dasatinib has not been long enough to detect and confirm this prolonged survival with these agents. The preferred initial treatment for newly diagnosed patients with chronic-phase CML could now be any one of these tyrosine kinase inhibitors.

Treatment options for CML patients in the accelerated phase of the disease include bone marrow transplantation, imatinib, interferon-alpha and high-dose cytarabine. Options for blase'-phase therapy include imatinib and chemotherapy.