CHRONIC MYELOID LEUKEMIA
Chronic myeloid leukemia (CML) arises from a mutation in the myeloid stem cell. Normal myeloid cells continue to be pro-duced, but there is a preference for immature (blast) forms. Therefore, a wide spectrum of cell types exists within the blood, from blast forms through mature neutrophils. Because there is an uncontrolled proliferation of cells, the marrow expands into the cavities of long bones (eg, the femur), and cells are also formed in the liver and spleen (extramedullary hematopoiesis), resulting in enlargement of these organs that is sometimes painful. In 90% to 95% of patients with CML, a section of DNA is found to be missing from chromosome 22 (the Philadelphia chromosome [Ph1]); it is, in fact, translocated onto chromosome 9. The spe-cific location of these changes is on the BCR gene of chromosome 22 and the ABL gene of chromosome 9. When these two genes fuse (BCR-ABL gene), they produce an abnormal protein (a ty-rosine kinase protein) that causes WBCs to divide rapidly. This BCR-ABL gene is present in virtually all patients with this disease.CML is uncommon in people younger than 20 years of age, but the incidence increases with age (median age, 40 to 50 years).
Patients diagnosed with CML in the chronic phase have an overall median life expectancy of 3 to 5 years. During that time, they have very few symptoms and complications from the disease itself. Problems with infections and bleeding are rare. However, once the disease transforms to the acute phase (blast crisis), the overall survival time rarely exceeds several months.
The clinical picture of CML varies. Many patients are asympto-matic, and leukocytosis is detected by a CBC performed for some other reason. The WBC count commonly exceeds 100,000/mm3. Patients with extremely high WBC counts may be somewhat short of breath or slightly confused due to decreased capillary perfusion to the lungs and brain from leukostasis (the excessive amount of WBCs inhibits blood flow through the capillaries). Patients may complain of an enlarged, tender spleen. The liver may also be en-larged. Some patients have somewhat insidious symptoms, such as malaise, anorexia, and weight loss. Lymphadenopathy is rare. There are three stages in CML: chronic, transformation, and ac-celerated or blast crisis. Patients have more symptoms and com-plications as the disease progresses.
Advances in understanding of the pathology of CML at a molecu-lar level have led to dramatic changes in its medical management. An oral formulation of a tyrosine kinase inhibitor, imatinib mesy-late (Gleevec) works by blocking signals within the leukemia cells that express the BCR-ABL protein, thus preventing a series of chemical reactions that cause the cell to grow and divide (Tennant, 2001; Goldman & Melo, 2001). Gleevec appears to be more use-ful in the chronic phase of the illness. In clinical trials, it has been generally well tolerated. Antacids and grapefruit juice may limit drug absorption, and large doses of acetaminophen can cause hepatotoxicity. The long-term effects of Gleevec, its impact on sur-vival, and the optimal length of treatment are being determined.
Conventional therapy depends on the stage of disease. In the chronic phase, the expected outcome is correction of the chromo-somal abnormality (ie, conversion of the malignant stem cell pop-ulation back to normal). Agents that have been used successfully for this purpose are interferon-alfa (Roferon-A) and cytosine, often in combination. These agents are administered daily as subcuta-neous injections. This therapy is not benign; many patients cannot tolerate the profound fatigue, depression, anorexia, mucositis, and inability to concentrate. A less aggressive therapeutic approach fo-cuses on reducing the WBC count to a more normal level, but does not alter cytogenetic changes. This goal can be achieved by using oral chemotherapeutic agents, typically hydroxyurea (eg, Hydrea) or busulfan (eg, Myleran). In the case of an extreme leukocytosis at diagnosis (eg, WBC count higher than 300,000/mm3), a more emergent treatment may be required. In this instance, leukophere-sis (in which the patient’s blood is removed and separated, with the leukocytes withdrawn, and the remaining blood returned to the pa-tient) can temporarily reduce the number of WBCs. An anthracy-cline chemotherapeutic agent (eg, daunomycin) may also be used to bring the WBC count down quickly to a safer level, where more conservative therapy can be instituted.
The transformation phase can be insidious, but it marks the process of evolution (or transformation) to the acute form of leukemia (blast crisis). In the transformation phase, the patient may complain of bone pain and may report fevers (without any obvious sign of infection) and weight loss. Even with chemother-apy, the spleen may continue to enlarge. The patient may become more anemic and thrombocytopenic; an increased basophil level is detected by the CBC. Despite its being a myeloid stem cell dis-ease, CML will transform in up to 25% of patients to resemble not AML, but acute lymphoid leukemia (ALL), with lymphoid-appearing blasts (Derderian et al., 1993). Transformation into the acute phase can be gradual or rapid.
In the more acute form of leukemia (blast crisis), treatment may resemble induction therapy for acute leukemia, using the same medications as for AML or ALL. Patients whose disease evolves into a “lymphoid” blast crisis are more likely to be able to reenter a chronic phase after induction therapy. For those whose disease evolves into AML, therapy is largely ineffective in achieving a sec-ond chronic phase. Life-threatening infections and bleeding occur frequently in this phase. CML is a disease that can potentially be cured with BMT or PBSCT. Patients who receive such transplants while still in the chronic phase of the illness tend to have a greater chance for cure than those who receive them in the acute phase. The transplantation procedure may now be considered for other-wise healthy patients who are younger than 70 years of age.
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