Clinical meaning
Chronic myeloid leukemia (CML) is defined by the Philadelphia chromosome t(9;22), which creates the BCR-ABL fusion oncogene encoding a constitutively active tyrosine kinase. This drives unregulated myeloid proliferation and resistance to apoptosis. CML progresses through three phases: chronic (>90% of patients at diagnosis; leukocytosis with left shift, basophilia, splenomegaly), accelerated (10-19% blasts, increasing basophilia, cytogenetic evolution), and blast crisis (≥20% blasts, behaves like acute leukemia with poor prognosis). Tyrosine kinase inhibitors (TKIs) revolutionized treatment: imatinib was the first targeted therapy, binding the ATP-binding site of BCR-ABL and reducing its kinase activity. Second-generation TKIs (dasatinib, nilotinib, bosutinib) have greater potency and overcome many imatinib-resistant mutations, except the T315I gatekeeper mutation (treated with ponatinib).
Diagnosis & workup
Diagnostics & workup: - CBC with differential: leukocytosis (often >100,000/µL) with left shift (myelocytes, metamyelocytes, bands), basophilia, eosinophilia, thrombocytosis - Peripheral blood smear: granulocyte maturation spectrum (myeloblasts through mature neutrophils) - Bone marrow biopsy with cytogenetics: Philadelphia chromosome t(9;22)(q34;q11.2) -- confirms diagnosis - FISH (fluorescence in situ hybridization): detects BCR-ABL fusion; faster than conventional cytogenetics - Quantitative RT-PCR for BCR-ABL transcripts: most sensitive test; used for monitoring treatment response (target: major molecular response = BCR-ABL ≤0.1% IS) - Sokal or Euro risk scores for prognostic stratification at diagnosis - BCR-ABL kinase domain mutation analysis if treatment failure or loss of response