## Tyrosine Kinase Inhibitors in CML **Key Point:** Imatinib mesylate is the gold-standard first-line TKI for chronic myeloid leukemia, specifically targeting the BCR-ABL fusion tyrosine kinase that arises from the Philadelphia chromosome t(9;22). ### Mechanism of Action Imatinib competitively binds to the ATP-binding pocket of the BCR-ABL kinase domain, preventing autophosphorylation and downstream signaling through the RAS/MAPK and PI3K/AKT pathways. This leads to cell cycle arrest and apoptosis of leukemic cells. ### Clinical Significance - Dramatically improved survival in CML patients compared to interferon-α and cytarabine - Typical dose: 400 mg daily for chronic phase; 600 mg for accelerated phase or blast crisis - Achieves complete hematologic response in >95% of chronic phase patients - Second-generation TKIs (dasatinib, nilotinib, bosutinib) are reserved for imatinib resistance or intolerance **High-Yield:** Imatinib is also effective in gastrointestinal stromal tumors (GIST) expressing KIT mutations and in dermatofibrosarcoma protuberans (DFSP) with PDGFRA mutations—a classic exam pattern. **Clinical Pearl:** Monitor for BCR-ABL transcript levels (RT-PCR) to assess treatment response; major molecular response (MMR) is defined as BCR-ABL/ABL ratio ≤0.1% on the International Scale. [cite:Harrison 21e Ch 104]
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