Skip to: site menu | section menu | main content
Chronic Myelogenous Leukemia...
Chronic myelogenous leukemia is a slowly progressing disease in which too many white blood cells are made in the bone marrow.
Also called chronic granulocytic
leukemia. Most cases of CML appear in adults, but about 2 to 4% of CML patients
are children.
Chronic Myelogenous Leukemia
CML results from an acquired (not inherited) injury to the DNA of a stem cell
in the marrow. This injury is not present at birth. Scientists do not yet understand
what produces this change in the DNA in patients with CML. Chronic myelogenous
leukemia (CML) accounts for only 5% of all childhood leukemia, and 80% of the
cases occur after 4 years of age. The cytogenetic abnormality most characteristic
of CML is the Philadelphia chromosome, which represents a translocation of chromosomes
9 and 22 [t(9;22)] resulting in a bcr-abl fusion protein.
CML is characterized by a marked leukocytosis and is often associated with thrombocytosis,
sometimes with abnormal platelet function. Bone marrow aspiration or biopsy reveals
hypercellularity with relatively normal granulocytic maturation and no significant
increase in leukemic blasts. Although reduced leukocyte alkaline phosphatase
activity is seen in CML, this is not a specific finding.
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 disease progresses rapidly) or overt blast crisis, which
has the symptoms and risks of acute myelogenous leukemia (AML).
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.
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.
Epidemiology
CML occurs in all age groups, but most commonly in the middle-aged and elderly.
Its annual incidence is about 1 per million.
Treatment:
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.
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 relapse 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.
NOTE: This web site is designed for educational purposes only and is not engaged in rendering medical advice. The information provided through this site should not be used for diagnosing or treating a health problem or a disease. If you have or suspect you may have a health problem, you should consult your health care provider