Etiology and pathogenesis
The development of chronic myeloid leukemia is based on a specific genetic anomaly: the appearance of the Philadelphia chromosome (Ph chromosome). This marker is detected not only in neutrophils, but also in other myeloid cells: erythroid elements and megakaryocytes.
The main difference between the chronic form and acute leukemias lies in the degree of differentiation of the tumor pool. In the chronic course, cells retain the ability to mature, so mature and intermediate forms of leukocytes, rather than blasts, predominate in the bloodstream and bone marrow. A characteristic cytochemical feature of pathological neutrophils is a sharp decrease in the activity of the enzyme alkaline phosphatase in them.
Clinical presentation
In the early stages, the disease is often asymptomatic and is an incidental finding on a complete blood count. As the tumor process progresses, pronounced clinical manifestations develop:
- General intoxication syndrome: unmotivated weakness, fatigue, fever, and weight loss.
- Splenomegaly: a significant enlargement of the spleen causes discomfort and a feeling of heaviness in the left upper quadrant. The condition may be complicated by the development of splenic infarctions.
- Hepatomegaly: secondary enlargement of the liver.
- Extramedullary infiltration: leukemic cells are able to infiltrate various organs, affecting the heart, lungs, and skin.
- Neurological disorders: infiltration of the epidural adipose tissue can lead to compression of the spinal nerve roots, resulting in corresponding neurological symptoms.
Laboratory diagnostics
Confirmation of the diagnosis requires a comprehensive evaluation of peripheral blood and bone marrow aspirate.
Peripheral blood changes: Pronounced leukocytosis with a predominance of neutrophils is revealed. A classic "left shift of the leukocyte formula" is characteristic: immature forms—promyelocytes and myelocytes—appear in the smear, isolated blasts may be present, but all intermediate transitional forms are invariably preserved. In the later stages of the process, anemia (decreased red blood cell count) naturally joins.
Bone marrow changes: Bone marrow examination reveals a total predominance of granulocytic cells. Yellow (fatty) bone marrow is pathologically replaced by active hematopoietic tissue. The platelet count can vary from marked thrombocytopenia to thrombocytosis.
Terminal stage (blast crisis)
Blast crisis is a sudden, fatal deterioration of the patient's condition. This process is caused by the genetic instability of the tumor: new subclones of cells appear that completely lose the ability to differentiate and rapidly crowd out the original clone.
Clinically, the terminal stage is accompanied by:
- Increase in hemorrhagic syndrome and the onset of severe infections.
- Rapid enlargement of the spleen with frequent organ infarctions.
- Appearance of fever and intense bone pain (ossalgia).
- Formation of dense leukemic infiltrates in the thickness of the skin.
- Enlargement of peripheral lymph nodes.
- Transition of the hematological blood picture to signs of acute leukemia (dominance of blasts).
Treatment approaches
The choice of treatment tactics depends on the stage of the disease and the general status of the patient.
The "gold standard" and the only radical method of therapy is considered to be bone marrow stem cell transplantation, which is performed if a genetically compatible donor is available. If transplantation is impossible, patients are prescribed chemotherapy. According to available data, the highest clinical efficacy is demonstrated by a regimen combining $\alpha$-interferon and cytarabine.
Briefly: answers to topical questions
What genetic mechanism (which chromosomes and genes) underlies the formation of the Philadelphia chromosome?
The formation of the Philadelphia chromosome is based on a reciprocal translocation of genetic material between the long arms of chromosomes 9 and 22. This process is described by the genetic formula t(9;22) (q34; q11).
As a result of this translocation, a pathological chimeric gene BCR-ABL is formed. This gene encodes a specific protein that causes increased tyrosine kinase enzyme activity and dysregulation of its function. As a result, proliferation is enhanced in the affected cell, terminal differentiation is slowed down, and the response to physiological regulatory stimuli is impaired.
What are the three main phases (stages) into which the course of chronic myeloid leukemia is conventionally classified?
The course of chronic myeloid leukemia is classified into 3 stages.
- Chronic phase — blasts constitute 1–3%; the majority of cases are diagnosed at this stage.
- Accelerated phase — the stage of disease progression; lasts an average of several months, accompanied by an increase in leukocytosis, immature granulocytes, and blasts.
- Blast crisis (blast transformation) — characterized by decreased cell maturation/differentiation and high treatment resistance; also described in sources as the terminal stage of CML.
What targeted drugs (tyrosine kinase inhibitors) are used in the modern treatment of chronic myeloid leukemia?
Among the targeted drugs of the tyrosine kinase inhibitor group for chronic myeloid leukemia cited in the sources, imatinib is indicated.
- Imatinib is a drug pathogenetically associated with the Philadelphia chromosome in CML. Its pharmacodynamics includes the inhibition of the synthesis of the oncoprotein associated with the Philadelphia chromosome and the blockade of platelet-derived growth factor receptors. The drug is used for chronic myeloid leukemia, prescribed orally, metabolized in the liver by CYP3A4 enzymes, and is incompatible with grapefruit juice, as the latter inhibits CYP3A4 and impairs the metabolism of the drug.
Class and exam questions
What is the main difference between chronic myeloid leukemia and acute leukemias?
In chronic myeloid leukemia, tumor cells retain the ability to mature, so mature and intermediate forms predominate in the blood, whereas in acute leukemia, the substrate consists exclusively of blasts (immature cells).
Why do neurological disorders occur in chronic myeloid leukemia?
This is due to the fact that leukemic cells can infiltrate the epidural tissue, leading to mechanical compression of the spinal nerve roots.
What is a blast crisis?
This is the terminal stage of the disease characterized by the appearance of new, differentiation-incapable subclones of tumor cells, causing a sharp deterioration in condition (ossalgia, rapid spleen enlargement, bleeding).
What else to study on this topic
- The mechanism of formation and pathogenetic role of the Philadelphia chromosome (Ph chromosome).
- Differential diagnosis of chronic myeloid leukemia versus leukemoid reactions.
- Features of the hematological picture of a blast crisis in a blood smear.
- Pathogenesis of splenic infarctions in massive splenomegaly.
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