Chronic myelogenous leukemia: Encyclopedia - Chronic myelogenous leukemia

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.

Chronic myelogenous leukemia - 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).

Chronic myelogenous leukemia - Diagnosis

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.

Chronic myelogenous leukemia - Pathophysiology

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.

Chronic myelogenous leukemia - Epidemiology

CML occurs in all age groups, but most commonly in the middle-aged and elderly. Its annual incidence is about 1 per million.

Chronic myelogenous leukemia - Treatment

Chronic myelogenous leukemia - Chronic phase

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.

Various combinations of the different treatment modalities are being explored, such as interferon and imatinib together.

In 2005, Bocchia et al reported favourable results of vaccination with the bcr-abl p210 fusion protein in patients with stable disease, with GM-CSF as an adjuvant.

Three new drugs dasatinib (BMS-354825), ceflatonin (homoharringtonine) and AMN 107 are currently in active clinical trials in patients with chronic myeloid leukemia (CML) who have developed resistance to imatinib. [1][2]

Chronic myelogenous leukemia - Blast crisis

Blast crisis carries all the symptoms and characteristics of acute myelogenous leukemia, and has a very high mortality rate. This stage can most effectively be treated by a bone marrow transplant after high-dose chemotherapy. In young patients in the accelerated phase, a transplant may also be an option. However the likelihood of replapse after a bone marrow transplant is higher in patients in blast crisis or in the accelerated phase as compared to patients in the chronic phase.

Chronic myelogenous leukemia - Prognosis

The prognosis of CML depends on a number of different parameters. Two different scoring systems are in use: one by Sokal et al (1984) and one by Hasford et al (1998).

Adapted from the Wikipedia article "Chronic myelogenous leukemia", under the G.N U Free Docmentation License. Please also see http://en.wikipedia.org/wiki