Chronic myelogenous leukemia
Chronic myelogenous leukemia (or CML) is a form of chronic leukemia characterised by increased production of myeloid cells in the bone marrow. It is a type of myeloproliferative disease associated with a characteristic chromosomal translocation termed the Philadelphia chromosome. It is traditionally treated with chemotherapy, interferon and bone marrow transplantation, although a specific inhibitor (imatinib mesylate) has radically changed the management. more...
Signs and symptoms
Patients are often asymptomatic at diagnosis, presenting incidentally with an elevated white blood count on a routine laboratory test. Symptoms may include: malaise, low grade fever, increased susceptibility to infections, anemia and thrombocytopenia with resultant bruising (although an increased platelet count, thrombocytosis, may be a feature). Splenomegaly may also be seen.
The disease may remain dormant for years, but a proportion proceed to accelerated phase (in which the diseases progresses rapidly) or overt blast crisis, which has the symptoms and risks of acute myelogenous leukemia (AML).
CML is often suspected on the basis on the full blood count, which shows increased granulocytes of all types (including basophils). When the index of suspicion is high, a bone marrow biopsy is required to distinguish CML from other diseases that feature the same symptoms.
Ultimately, CML is diagnosed by detecting the Philadelphia chromosome (a translocation between the 9th and 22nd chromosome leading to an aberrant protein that drives cell division). This translocation leads to bcr-abl fusion and activation of protein tyrosine kinase cascade.
Disease activity can be determined on the basis of the bone marrow examination, cytogenetics and by quantitative PCR.
CML was the first malignancy to be linked to a clear genetic abnormality, the chromosomal translocation named Philadelphia chromosome, in 1960. The fusion of two genes on chromosomes 9 and 22, termed abl and bcr respectively, leads to a protein that propels mitosis and causes genomic instability (leading to further mutations).
CML progresses to accelerated phase, and then blast crisis, when additional genetic abnormalities speed up the rate at which new malignant cells are produced in the bone marrow. A second Philadelphia chromosome may appear, as well as deletions of (parts of) chromosomes.
CML occurs in all age groups, but most commonly in the middle-aged and elderly. Its annual incidence is about 1 per million.
Chronic phase CML is treated with imatinib (marketed as Gleevec or Glivec; previously known as STI-571). In the past, hydroxyurea, alkylating agents (e.g. cytarabine), interferon alfa 2b and steroids were used, but this has been replaced by imatinib. Imatinib is a new agent which specifically targets the abnormality caused by the Philadelphia chromosome. It is better tolerated and more effective than previous therapies. Bone marrow transplants were also used as initial treatment for CML before imatinib and can be curative. In patients who fail to achieve a cytogenetic remission with imatinib or who relapse while on imatinib, a bone marrow transplant should be considered.
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