CML is a disorder in which myeloid blasts (precursor of myeloid cells) start dividing without control. This is postulated to be caused by a genetic change (reported in more than 95% of all CML patients) in the immature myeloid cells, which is referred to as Philadelphia chromosome (Ph) – a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene.
The fusion gene gives rise to a protein with deregulated tyrosine kinase activity that turns the cells to CML cells (the abnormal myeloid precursors with Ph+), which divide indefinitely and get crowded in the red bone marrow and peripheral blood causing a reduction in the number of normal blood cells.
Chronic Myeloid Leukemia Diagnosis
If a person is suspected to have CML, some investigations are required to confirm the diagnosis of the disease. Further, these investigations can help in determining the phase of CML, organ involvement, cytogenetic abnormalities, etc. which in turn help in selecting an appropriate treatment approach.
Following are some commonly used diagnostic tools for CML:
Blood tests provide very important information that provides direction to the diagnostic workup of CML. Following are the commonly employed blood test for the diagnosis of the CML:
Complete Blood Cells Count (CBC)
This test provides information on the level of RBCs, WBCs, and platelets. In most cases of CML, high level of WBCs and low RBC s and platelets are observed. In some cases, very high level of platelets may also be observed.
In this test, a drop of a blood sample is spread on a glass slide and this is observed under a microscope. This test helps in detecting any change in the appearance of various blood cells. Appearance and relative percentage of myeloid precursors can be estimated by this test, which in turn help in establishing the diagnosis of CML.
Bone Marrow Aspiration/Biopsy
Aspiration samples contain a small number of cells and biopsy contains a tiny piece of tissue collected from the bone with the help of a biopsy needle. The biopsy sample is then tested in a laboratory
and can provide very useful information like phase of CML (chronic, accelerated or blast), cytogenetic abnormalities, etc.
Fluorescent in situ hybridization (FISH)
In this technique, fluorescent RNA probes are used, which bind to a specific portion of a chromosome in the sample cells. Then, the sample can be examined under a microscope to determine the presence of certain chromosomal abnormalities like translocation, addition, or deletion.
This technique is very sensitive, fast, and accurate. It is preferably used for detecting Philadelphia chromosome (Ph), the most common genetic abnormalities in the CML cells.
This test can help in detecting Philadelphia chromosome along with additional chromosomal abnormalities like trisomy 8, isochromosome 17q, second Ph, and trisomy 19. Presence of additional cytogenetic abnormalities is generally associated with poor disease prognosis.
Reverse-transcriptase polymerase chain reaction (RT-PCR)
This is the most sensitive diagnostic tool available today, which can detect a very small number of CML cells with a specific genetic change (BCR-ABL1
gene) in blood or bone marrow sample. This technique can be used either as a qualitative tool to establish the diagnosis of CML or as a quantitative tool after to assess the number of BCR-ABL1 transcripts, and thus, the efficacy of treatment or the minimum residual disease (MRD).
In this technique, the biopsy sample is first treated with some fluorescent antibodies that get attached to certain specific proteins (antigens) on the surface of cells. The treated sample is then analyzed using a laser beam and a detector attached to a computer. It is useful in blast phase of CML to detect the lineage (myeloid or lymphoid).
Diagnosis of the Phase of CML
With the help of various investigations discussed above, CML may be classified into one of the three phases as discussed below-
Chronic Phase (CP) CML
Chronic phase CML is characterized by the presence of less than 10% blast cells in the peripheral blood and bone marrow. The patients with chronic phase CML usually have no or mild symptoms and respond well to standard treatment.
Accelerated Phase (AP) CML
According to WHO criterion, the accelerated phase CML is defined as the presence of 10-19% blast cells in blood or bone marrow, >/=20% basophils in the peripheral blood or bone marrow, persistent thrombocytopenia (platelet count <100 x 10^9/L) unrelated to therapy or persistent thrombocytosis (platelet count >1000 x 10^9/L) unresponsive to therapy, increasing WBCs and spleen size, or clonal cytogenetic evolution in Ph+ cells (trisomy 8, isochromosome 17q, second Ph, and trisomy 19).
Blast Phase (BP) CML
According to the WHO criteria, the blast phase CML is defined as the presence of >/=20% blast cells in the peripheral blood or bone marrow, extramedullary blast proliferation, or large foci or clusters of blasts in bone marrow biopsy.
Scoring Systems for CML Risk Stratification
The Sokal score is calculated based on the patient’s age, spleen size, platelet count, and percentage of blasts in the peripheral blood. CML patients are assigned a risk group (Low, Intermediate, or High) based on the Sokal score (<0.8, 0.8-1.2, and >1.2), respectively.
The Hasford system includes 2 additional prognostic factors to those included in the Sokal system, that is, level of basophils and eosinophils in the blood. CML patients are assigned a risk group (Low, Intermediate, or High) based on the Hasford score (</=780, 781-1480, and >1480), respectively.