## BCR-ABL Tyrosine Kinase Inhibition in CML **Key Point:** Imatinib mesylate is the gold-standard first-line tyrosine kinase inhibitor (TKI) for Philadelphia chromosome-positive CML in all phases. ### Mechanism of Action Imatinib selectively inhibits the constitutively active BCR-ABL tyrosine kinase, which results from the t(9;22) translocation. This fusion protein drives uncontrolled proliferation in CML. ### Clinical Evidence - Induces complete hematologic response in >95% of chronic phase CML patients - Achieves major molecular response in ~80% of patients - Significantly improved overall survival compared to historical interferon-based regimens - Standard starting dose: 400 mg daily for chronic phase **High-Yield:** Imatinib revolutionized CML treatment and is the prototype of targeted cancer therapy against a specific oncogenic driver. ### Comparison with Alternatives | Agent | Role in CML | Limitation | |-------|-------------|------------| | Imatinib | First-line TKI | Resistance in ~20% (BCR-ABL mutations) | | Daunorubicin | Chemotherapy (pre-TKI era) | Non-selective; inferior outcomes | | Hydroxyurea | Cytoreductive agent | Temporary control; not curative | | Interferon-alpha | Historical first-line | Poorly tolerated; inferior to TKIs | **Clinical Pearl:** Resistance to imatinib may develop through BCR-ABL point mutations (especially T315I) or gene amplification, necessitating second-generation TKIs (dasatinib, nilotinib, ponatinib).
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