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The World Health Organization (WHO) classifies chronic myeloid leukaemia (CML) as a myeloproliferative disease characterised by the presence of the Philadelphia chromosome (Ph) or the BCR-ABL fusion oncogene10. The diagnosis is generally easily made on the basis of morphological examination of a peripheral blood smear, but confirming genetic studies have become essential with the advent of molecularly targeted therapy.
Haematological Analysis
A peripheral blood smear (Figures 1 and 2) from a patient in the chronic phase of disease is characterised by excessive numbers of myeloid cells. Mature granulocytes generally predominate and account for the elevated white blood cell (WBC) count, but all stages of differentiation are found. A bone-marrow (BM) aspirate will reveal significant myeloid hyperplasia, sometimes with fibrosis17, 19, 22.
Figure 1. Peripheral blood smear of a patient with chronic-phase CML. The low-power view (left) and the cell count show evidence of a marked increase in the number of WBCs. The high-power view (right) shows that the cells are at all stages of maturity. Compare this with Figure 2.
Figure 2. Sample sections of normal peripheral smear. These sections from a normal peripheral smear show areas with no WBCs (left). There are occasional platelets seen. Where WBCs are visible (right), they are predominantly mature neutrophils (shown) or lymphocytes (not shown). There are no immature WBCs present, except 5%-10% band forms.
Cytogenetic Testing
Philadelphia Chromosome
The Ph chromosome can be detected by standard cytogenetic techniques in most patients23,24. In patients who are cytogenetically negative for the Ph chromosome, molecular techniques such as fluorescence in situ hybridisation (FISH) or reverse transcriptase polymerase chain reaction (RT-PCR) may be useful in detecting BCR-ABL24. In addition, the use of these special techniques may have implications in disease staging or assessing residual disease3.
Other Genetic Targets
Additional cytogenetic and molecular alterations are often found in patients with CML during the progression from chronic to blast-crisis phase, including mutated and overexpressed genes. It is unclear whether the transformation of CML from chronic to blast-crisis phase involves cooperation between BCR-ABL and additional abnormal genes. Current research is investigating potential cooperation between BCR-ABL and secondary genetic defects and the role of these secondary fusion-gene products in leukaemogenesis25.
Other Philadelphia Chromosome-Positive (Ph+) leukaemias
In addition to CML, a subset of acute lymphoblastic leukaemia (ALL) and some acute myeloid leukaemia (AML) cases may also be Ph+ leukaemias. ALL accounts for 80% of the acute childhood leukaemias, but fewer than 20% of adult cases. Approximately 70% of ALL cases arise from the B-cell lymphoid lineage at varied stages of differentiation. Chromosomal abnormalities are detected in approximately 90% of paediatric and 75% of adult patients. The translocation unique to the Ph chromosome occurs in approximately 25% of adult cases, and the fusion product is the p190BCR-ABL protein. AML accounts for up to 90% of the acute leukaemias in adults, but is uncommon in children. Although traditionally classified by morphological type, cytogenetic appearance, and cytochemical stains, most AML cases show blast cells derived from myeloid or monocytic lineage. The Ph chromosome is detected in approximately 5% of cases of AML in adults.
Read about Treatment Options for CML, including prognostic risk group assessment and criteria, goals of therapy, and historical and current treatment options.
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