- Clinical science
Chronic myeloid leukemia (CML) belongs to the group of . It is a malignancy of the hematopoietic stem cells with excessive proliferation of the myeloid lineage (especially granulocytes). It is caused by a cytogenetic aberration (Philadelphia chromosome 22) that results in the formation of a BCR-ABL fusion gene. The increased activity of this gene's product – a tyrosine kinase – promotes unregulated proliferation of myeloid progenitor cells, which eventually differentiate into mature cells. CML has three distinct clinical phases. The chronic phase is characterized by nonspecific symptoms (fever, weight loss, night sweats) and splenomegaly and can persist for up to 10 years. The accelerated phase is characterized by complications secondary to the suppression of the other cell lines (thrombocytopenia, anemia, recurrent infections). The clinical picture of the terminal phase, blast crisis, resembles that of acute leukemia. Important diagnostic features are severe leukocytosis (> 500,000/μl), basophilia, and extreme splenomegaly. The most important therapeutic principle is targeted therapy with imatinib, which selectively inhibits BCR-ABL tyrosine kinase. This drug has revolutionized CML treatment and greatly improved the prognosis of CML.
- Reciprocal translocation between chromosome 9 and chromosome 22 → formation of the Philadelphia chromosome t(9;22) → fusion of the ABL1 gene (chromosome 9) with the BCR gene (chromosome 22) → formation of the BCR-ABL gene → encodes a BCR-ABL non-receptor tyrosine kinase with increased enzyme activity
- Result: inhibits physiologic apoptosis and increases mitotic rate → uncontrolled proliferation of functional granulocytes
|Malignancy||Detection of Philadelphia translocation|
Genetic changes and clinical course
- Additional chromosomal changes and mutations of tumor suppressor genes and oncogenes (p53, Rb1, or Ras), which emerge during the course of the disease, are responsible for the progression from chronic to accelerated phase and, ultimately, the transition to acute leukemia.
- Can persist for up to 10 years and is often subclinical
- When symptomatic, features include:
- Erythrocytopenia: anemia
- Neutropenia: infection and fever
- Extreme pleocytosis
- Extreme splenomegaly : palpable in lower left quadrant or pelvic cavity
The blast crisis is the terminal stage of CML.
- Symptoms resemble those of .
- Rapid progression of bone marrow failure → , bone pain
- Severe malaise
- Subtypes :
Peripheral blood analysis
- CBC and blood smear
- Cytochemistry: ↓ leukocyte alkaline phosphatase (LAP) versus a leukemoid reaction
- Cytogenetics: confirmation of BCR-ABL (Philadelphia chromosome) fusion gene
Low LAP is a distinct feature of CML that distinguishes it from all other forms of leukemia!
- Hyperplastic myelopoiesis: predominantly granulocytosis
- Elevated granulocytic precursor cells (especially myelocytes and promyelocytes)
WHO classification of the CML phases
|CML Phase||Blast count in peripheral blood and bone marrow|
|Blast Crisis||≥ 20%|
- Targeted therapy: first-line for chronic and accelerated phase
Tyrosine kinase inhibitors: e.g., imatinib, dasatinib, nilotinib
- Mechanism of action: selectively inhibit the enzyme tyrosine kinase by binding to its active ATP site → no transfer of phosphate (from ATP) to tyrosine residues on the enzyme's substrates (i.e., cell signaling proteins of the BCR-ABL1 pathway) → inhibits proliferation and induces apoptosis of malignant cells that carry the mutant tyrosine kinase
- Adverse effects include: fluid retention, pulmonary edema, QT prolongation, nausea, vomiting, diarrhea, and pancytopenia
- Lifelong treatment
- Tyrosine kinase inhibitors: e.g., imatinib, dasatinib, nilotinib
- Allogeneic stem cell transplantation: if targeted therapy is not successful or in young patients without any major comorbidities (the only curative option)
- Cell count normalization: supportive therapy if targeted therapy fails
- Blast phase: acute leukemia treatment
|Disease||CBC and peripheral blood smear||LAP score||Genetics/cause|
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|Chronic myeloid leukemia|| || |
|Leukemoid reaction|| |
The differential diagnoses listed here are not exhaustive.
- Survival rate without treatment:
- Chronic phase: 3.5–5 years
- Blast phase: 3–6 months
- In most patients, life expectancy can be markedly improved through targeted therapy with imatinib. In some cases, it even results in molecular remission.