A 45-year-old woman with CML on imatinib 400 mg/day has a complete cytogenetic response but fails to achieve a major molecular response (BCR-ABL > 0.1% IS at 12 months). BCR-ABL kinase domain mutation analysis reveals T315I. What is the most appropriate next step?
- A Switch to dasatinib 100 mg/day
- B Switch to nilotinib 400 mg twice daily
- C Switch to ponatinib (third-generation TKI) ✓
- D Increase imatinib dose to 600 mg/day
Explanation
The T315I 'gatekeeper' mutation in BCR-ABL confers resistance to all first-generation (imatinib) and second-generation (dasatinib, nilotinib, bosutinib) TKIs because the threonine-to-isoleucine substitution eliminates the critical hydrogen bond and creates steric hindrance against these agents. Ponatinib (third-generation TKI) is specifically designed to overcome T315I resistance and is the standard of care in this scenario. Asciminib (STAMP inhibitor) is also active against T315I at higher doses (200 mg BID). Dose escalation of imatinib or switching to dasatinib/nilotinib will not overcome T315I resistance.
Reference: Harrison's Principles of Internal Medicine, 21st ed.
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Written and medically reviewed by the StethoPrep medical team.