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A blood sample is examined under the microscope and from it the proportion of white blood cells circulating in the blood stream is determined. Identification of abnormally high numbers of fully matured and maturing white blood cells (myelocytes and neutrophils) is the first step towards a diagnosis of CML. A CBC (complete blood count) shows increased white blood cell count and a CBC differential is consistent with increased numbers of white blood cells, either mature or immature. The diagnosis of CML is confirmed by performing a bone marrow aspiration to look for the presence of the Philadelphia chromosome, which is a diagnostic marker in 90% of CML patients.
Other tests done to diagnose CML are the leukocyte alkaline phosphatase score (LAP), which is lower than normal values for CML patients. Vitamin B12 and uric acid usually appear elevated in CML patients. A CML patient's lactate dehydrogenase (LDH) is also likely to be elevated.
See a table, which clinically differentiates the three phases of CML:
Some patients may present fibrosis of the marrow, especially in advanced phases. The marrow is hypercellular at diagnosis, meaning overproduction of white cells. In a handful of patients, the diagnosis marrow may show other clonal changes, which mean chromosomal abnormalities other than the Ph chromosome, and this becomes marked in advanced phases denoting marrow instability.
Treatment
1. Cytotoxic drugs like Hydroxyurea may be used to lower the white blood cell count. This drug is a chemotherapy drug and brings about 3-7 years survival without cytogenetic response.
2. Interferon-alpha can induce cytogenetic remission in a few patients (10-15% complete) and reduce the percentage of the Ph chromosome. It can give 1-2 years median survival advantage over Hydroxyurea treatment.
3. Allogeneic Stem Cell Transplantation (SCT) is the only proven curative treatment to date.
4. An inhibitor of the BCR-ABL tyrosine kinase activity called STI-571 or Gleevec (Imatinib Mesylate) has proven to induce a higher rate of major and complete cytogenetic remissions in CML patients than Interferon-alpha. In newly diagnosed patients, the drug induces a dramatic ~70% complete cytogenetic remission rate and provides much hope for the future for CML patients. It is a relatively new drug so long-term data is not collected yet but this molecular inhibitor is an exciting new approach to CML treatment. Gleevec is now more or less first-line CML therapy worldwide.
5. A handful of patients have shown Gleevec resistance and relapse in the 4 years of Gleevec therapy necessitating in the development of combination therapies and new drugs. Some of these are a) Gleevec + Interferon b) Gleevec + Ara-C c) Gleevec + Genasense (an antisense drug) d) Decitabine e) Velcade and other new drugs which remain in clinical trials offering hope to Gleevec-resistant or relapsed patients.
Next page--Genetic Tools of CML Diagnosis
Phases of CML Criteria
Table
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