A 48-year-old woman with chronic myeloid leukemia treated with imatinib for two years loses complete hematologic response. Kinase domain sequencing reveals a threonine-to-isoleucine substitution at position 315 (T315I). Which agent is the most appropriate next-line therapy?
- A Dasatinib
- B Nilotinib
- C Ponatinib ✓
- D Escalated-dose imatinib
Correct answer: C. Ponatinib
Explanation
T315I is the classic gatekeeper mutation: the bulkier isoleucine removes a critical hydrogen bond required for binding of imatinib, dasatinib, and nilotinib, rendering all three second-generation agents ineffective. Ponatinib retains activity against T315I because its structure does not depend on the same hydrogen bonding interaction, making it the drug of choice for this resistant clone. Dose escalation of imatinib cannot overcome this specific mutation.
Reference: Katzung's Basic and Clinical Pharmacology, 16th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.