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

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 :
  • Myeloid blast crisis → AML (⅔ of cases)
  • Lymphoid blast crisis → ALL (⅓ of cases)

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
• Adverse effects
  • Fluid retention and edema
  • Myelosuppression
  • Hepatotoxicity (e.g., ↑ LFTs)
  • Myalgia