A 48-year-old man with chronic myeloid leukemia initially responds to imatinib but loses hematologic response after two years. Sequencing of his BCR-ABL1 kinase domain reveals the T315I mutation. Which agent is the appropriate next-line therapy?
- A Nilotinib
- B Dasatinib
- C Ponatinib ✓
- D Ruxolitinib
Correct answer: C. Ponatinib
Explanation
Threonine 315 sits at the gatekeeper position of the ABL1 kinase domain; its substitution by isoleucine sterically blocks imatinib, nilotinib, and dasatinib from binding, so these second-generation inhibitors fail against T315I. Ponatinib was designed with an imidazo-pyridazine scaffold that tolerates the bulky isoleucine and retains activity, making it the only approved TKI effective for this mutation. Ruxolitinib is a JAK inhibitor with no BCR-ABL1 activity.
Reference: Harrison's Principles of Internal Medicine, 21st ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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