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0 min readIntroduction
Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by the uncontrolled proliferation of granulocytes in the bone marrow and peripheral blood. It represents approximately 15-20% of all adult leukemias. Historically, CML had a poor prognosis, but the advent of tyrosine kinase inhibitors (TKIs) like imatinib has dramatically improved patient outcomes. A key breakthrough in understanding and diagnosing CML was the identification of a specific genetic abnormality, the Philadelphia chromosome, which serves as a hallmark for the disease. This abnormality is crucial for both diagnosis and monitoring treatment response.
The Role of Genetic Markers in CML Diagnosis
The diagnosis of CML relies heavily on identifying the underlying genetic abnormality. The primary genetic marker is the Philadelphia chromosome (Ph chromosome), a reciprocal translocation between chromosomes 9 and 22, denoted as t(9;22)(q34;q11). This translocation results in the formation of a shortened chromosome 22. However, the Ph chromosome is not directly responsible for the leukemic process; rather, it leads to the creation of a novel fusion gene called BCR-ABL1.
The BCR-ABL1 fusion gene encodes a constitutively active tyrosine kinase enzyme. This enzyme drives uncontrolled cell proliferation and inhibits apoptosis, leading to the characteristic features of CML. Diagnostic methods to detect BCR-ABL1 include:
- Cytogenetic analysis (Karyotyping): Detects the Ph chromosome directly.
- Fluorescence In Situ Hybridization (FISH): Uses fluorescent probes to identify the BCR-ABL1 fusion gene.
- Reverse Transcription Polymerase Chain Reaction (RT-PCR): Detects the BCR-ABL1 mRNA transcript, providing a highly sensitive method for monitoring minimal residual disease (MRD) during treatment.
- Quantitative PCR (qPCR): Measures the amount of BCR-ABL1 transcript, allowing for precise quantification of disease burden.
The level of BCR-ABL1 transcript, as measured by qPCR, is used to assess treatment response and predict prognosis.
Clinical Features of CML
CML typically progresses through three phases:
Chronic Phase
- Often asymptomatic, discovered incidentally on routine blood tests.
- Fatigue, weight loss, night sweats, and a feeling of fullness in the abdomen (due to splenomegaly) are common.
- Splenomegaly is present in >75% of patients, often massive.
- Hepatomegaly may also be present.
- Duration of the chronic phase varies, typically lasting 3-5 years without treatment.
Accelerated Phase
Represents a transition from the chronic phase to blast crisis. Features include:
- Increasing white blood cell count despite treatment.
- Splenomegaly worsening or becoming resistant to treatment.
- Development of new cytogenetic abnormalities in addition to the Ph chromosome.
- Symptoms of systemic illness become more pronounced.
- Duration is typically 3-6 months.
Blast Crisis
Represents the most aggressive phase, resembling acute leukemia. Two main types:
- Myeloid Blast Crisis: More common (60-80%), characterized by a predominance of myeloid blasts.
- Lymphoid Blast Crisis: Less common (20-40%), characterized by a predominance of lymphoid blasts.
Patients in blast crisis have a poor prognosis and require aggressive chemotherapy.
Blood Picture in CML
The typical blood picture in CML is characterized by:
| Parameter | Typical Findings |
|---|---|
| White Blood Cell (WBC) Count | Markedly elevated (often >100 x 109/L, can be >300 x 109/L) |
| Differential Count | Significant increase in granulocytes (neutrophils, eosinophils, basophils) in all stages of maturation. Presence of myelocytes, metamyelocytes, and bands. |
| Red Blood Cell (RBC) Count | May be normal or decreased due to bone marrow crowding. |
| Hemoglobin | May be normal or decreased, leading to anemia. |
| Platelet Count | Often elevated (thrombocytosis) in the chronic phase, but can decrease in the accelerated and blast phases. |
| Blood Smear | Demonstrates a full spectrum of myeloid cells, including immature forms. |
Bone marrow aspiration and biopsy are also crucial for diagnosis, showing hypercellularity with a marked increase in myeloid precursors.
Conclusion
In conclusion, the identification of the Philadelphia chromosome and the <em>BCR-ABL1</em> fusion gene is fundamental to the diagnosis of CML. Understanding the clinical phases and characteristic blood picture is essential for appropriate management. The advent of TKIs has revolutionized CML treatment, transforming it from a fatal disease to a chronic condition manageable with long-term therapy. Continued monitoring of <em>BCR-ABL1</em> levels remains critical for assessing treatment response and preventing disease progression.
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