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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