Chronic myeloid leukemia in 2007

Chronic myeloid leukemia (CML) is a potentially fatal stem cell cancer that comprises approximately 14% of all leukemias. Although it is estimated that 4,600 people will be diagnosed with CML in the United States in 2007, only 12% of those individuals will die from the disease. That low mortality rate is due to the availability and efficacy of the new kinase inhibitors that target the BCR-ABL oncogene and other targets to hold disease progression in check.

To review the molecular pathogenesis of CML, describe the clinical course of the disease, and explain the current application of cytogenetics and molecular testing for diagnosis and treatment.

CML is caused by the translocation of chromosomes 9 and 22 to create what is called the Philadelphia chromosome. This translocation removes a critical regulatory domain from the tyrosine kinase, ABL, such that its protein product is constitutively active. This means that the cell escapes the constraints of normal cell growth and proliferates uncontrollably. The modified protein is known as BCR-ABL, and it causes CML by phosphorylating numerous downstream proteins involved in the activation of cell division, among other functions. during the earliest phase of the disease, the chronic phase, kinase inhibitors that target BCR-ABL are effective in stopping disease progression. However, a minority of patients remain unresponsive to this therapy. Laboratory tests are thus of great importance for this disease. not only are they required for the diagnosis of CML, but during therapy they can establish the degree of response. That response, in turn, can supply the clinician with a good estimate of the prognosis for the patient. The tests used for CML include complete blood count (CBC) with platelets, cytogenetic analysis, fluorescence in situ hybridization (FISH), and quantitative polymerase chain reaction (PCR). These tests vary in the difficulty of application and in the sensitivity. CBC is commonplace within the average hospital laboratory, whereas cytogenetic analysis, FISH, and PCR require specialized equipment, personnel, and training. Hematologic counts are the least sensitive measures of disease, with a limit of detection of a leukemic burden of 1011 cells. Cytogenetics can detect a burden of 109 cells. Finally, quantitative PCr can detect a burden of as few as 105 leukemic cells. The current costs of these tests range from approximately $375 to $1,500 and must be performed every 3 to 6 months to follow the patient's response to therapy.

The advent of kinase inhibitor therapy for CML has greatly increased the importance of sensitive analysis of disease burden. Subsequent testing during therapy greatly improves the ability of the clinician to predict the therapeutic outcome. Signs of early treatment failure can give the patient time to switch therapies before the disease progresses to an advanced stage.