Which tyrosine kinase inhibitor is selective for BCR-ABL and is the standard first-line therapy for chronic myeloid leukemia in chronic phase?

Explanation

## BCR-ABL Targeted Therapy **Key Point:** Imatinib mesylate is a selective tyrosine kinase inhibitor that specifically targets the BCR-ABL fusion protein, the hallmark abnormality in chronic myeloid leukemia (CML). ### Mechanism of Action Imatinib binds to the ATP-binding pocket of BCR-ABL kinase, preventing autophosphorylation and downstream signaling that drives uncontrolled myeloid proliferation. This selectivity for BCR-ABL makes it highly effective with minimal off-target effects at therapeutic doses. ### Clinical Use in CML - **Standard first-line agent** for chronic phase CML - Induces complete hematologic remission in >95% of patients - Achieves major molecular response in 80–90% of patients - Dramatically improved survival compared to historical interferon-α therapy **High-Yield:** Imatinib is the prototypical example of rational drug design based on molecular pathology — targeting a specific oncogenic kinase rather than using cytotoxic chemotherapy. ### Resistance Mechanisms - Point mutations in BCR-ABL kinase domain (most common) - BCR-ABL gene amplification - Clonal evolution **Clinical Pearl:** Second and third-generation TKIs (dasatinib, nilotinib, ponatinib) are reserved for imatinib resistance or intolerance, not first-line use. [cite:Harrison 21e Ch 109]