Chronic Myeloid Leukemia (CML) is a type of cancer that originates in the blood-forming cells of the bone marrow. This condition is characterized by the overproduction of abnormal white blood cells, which accumulate in the blood and marrow. The diagnostic process involves initial suspicion based on physical signs or routine tests, followed by definitive genetic confirmation and an assessment of the disease’s extent.
Recognizing the Signs of CML
Many people diagnosed with CML do not experience symptoms because the disease progresses slowly. It is frequently discovered incidentally when a routine blood test, ordered for an unrelated health concern or general check-up, reveals an abnormal blood cell count. This finding often raises the first suspicion of a blood disorder.
When symptoms do occur, they are often vague and non-specific, resembling those of many less serious conditions. Common indicators include persistent fatigue, unexplained weight loss, low-grade fevers, and excessive night sweats. Some individuals may notice abdominal fullness or discomfort in the upper left side, caused by an enlarged spleen, a common physical finding in CML.
Initial Diagnostic Blood Tests
The first step in a formal investigation is a Complete Blood Count (CBC) with a differential, which provides a detailed breakdown of the blood’s components. In a patient with CML, the CBC typically shows a significantly elevated white blood cell (WBC) count, sometimes reaching very high levels due to the overproduction of myeloid cells.
A peripheral blood smear is then performed to microscopically examine the blood cells’ appearance and maturity. This analysis often reveals an increase in basophils and a spectrum of immature white blood cells, known as granulocyte precursors or myelocytes, circulating in the blood. While these findings are suspicious for CML, they are not sufficient to confirm the diagnosis, as other conditions can cause similar blood count abnormalities.
Confirming the Diagnosis with Genetic Markers
The definitive diagnosis of CML relies on identifying a specific genetic abnormality known as the Philadelphia chromosome (Ph chromosome). This is a shortened chromosome 22 resulting from a reciprocal exchange of genetic material between chromosome 9 and chromosome 22. This rearrangement creates the BCR-ABL1 fusion gene, which produces an abnormal protein that drives the uncontrolled growth of myeloid cells.
Several specialized tests are used to detect this fusion gene and the Philadelphia chromosome. Cytogenetics, or karyotyping, involves growing blood or bone marrow cells in a lab and examining them under a microscope to visually confirm the presence of the shortened chromosome 22. Since this process requires cell division, results can take a few weeks.
A faster technique is Fluorescence In Situ Hybridization (FISH), which uses fluorescent probes that attach to the BCR and ABL1 genes. When the two genes are fused, the resulting signal confirms the presence of the BCR-ABL1 gene, even if the Ph chromosome is not visible through traditional cytogenetics. The most sensitive test is the Polymerase Chain Reaction (PCR), specifically quantitative real-time PCR (qPCR). This molecular test detects and measures the amount of the BCR-ABL1 gene transcript, even at very low levels, and is important for both initial diagnosis and monitoring treatment response.
To gather the necessary cells for these genetic and chromosomal analyses, a bone marrow aspiration and biopsy is usually performed. This procedure involves withdrawing a small amount of liquid marrow (aspiration) and a piece of solid bone tissue (biopsy), typically from the hip bone. Although blood samples can be used for some molecular tests, the bone marrow sample provides the most comprehensive information, including the cellularity and the extent of the disease within the marrow.
Assessing Disease Status
Once CML is confirmed by the presence of the BCR-ABL1 fusion gene, the next step is to determine the disease’s phase. This assessment is based primarily on the percentage of immature white blood cells, called blasts, found in the blood or bone marrow. This measure of disease progression helps guide treatment decisions, and CML is categorized into three phases: chronic, accelerated, and blast.
Chronic Phase
The chronic phase is the most common at diagnosis and is characterized by having less than 10% blasts in the blood and bone marrow. Patients in this phase often have mild or no symptoms and generally respond well to standard therapy, such as tyrosine kinase inhibitors.
Accelerated Phase
If the disease progresses, it enters the accelerated phase, defined by a blast count between 10% and 19%. Other indicators for the accelerated phase include a high percentage of basophils in the blood or new chromosomal changes in the leukemia cells.
Blast Phase
The most advanced stage is the blast phase, sometimes referred to as blast crisis, which resembles acute leukemia. This phase is defined by having 20% or more blasts in the blood or bone marrow, or the presence of blast cells spreading to tissues outside of the marrow. Recognizing the specific phase is important, as the urgency and intensity of initial treatment are dictated by the disease status.