Epidemiology
Etiology
Pathophysiology
Philadelphia chromosome
- 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
Tip
Philadelphia chromosome is in > 90% of CML patients.
Clinical features
Blast crisis
- The blast crisis is the terminal stage of CML.
- Symptoms resemble those of acute leukemia.
- Rapid progression of bone marrow failure → pancytopenia, bone pain
- Severe malaise
- Subtypes :
Diagnostics
Treatment
Targeted therapy: tyrosine kinase inhibitors
TKIs are the primary drug class used to treat CML.
- Agents
- First-generation TKIs (imatinib): indicated in low-risk CP-CML, patients with comorbidities, or older patients
- Second-generation TKIs (e.g., dasatinib, nilotinib): usually indicated in AP-CML
- Mechanism of action
- Selective inhibition of tyrosine kinase (e.g., by blocking its ATP binding site): inhibits tyrosine phosphorylation of downstream signaling proteins (no phosphate transfer from ATP to tyrosine residues)
- Disruption of the BCR-ABL1 pathway: inhibits proliferation and induces apoptosis in BCR-ABL1-positive cells