A 45-year-old man with chronic myeloid leukaemia in chronic phase relapses on imatinib. Sequencing of the BCR-ABL kinase domain reveals a T315I gatekeeper mutation. Which agent retains activity against this mutant clone?

• A Dasatinib
• B Nilotinib
• C Bosutinib
• D Ponatinib ✓

Explanation

The T315I substitution removes the threonine whose hydrogen bonding anchors second-generation tyrosine kinase inhibitors, conferring resistance to imatinib, dasatinib, nilotinib and bosutinib alike. Ponatinib was designed with an imidazo-pyridazine scaffold that binds without depending on that threonine, so it remains active against T315I-mutant disease. Arterial thrombotic events are its notable class warning. Asciminib is another newer option but was not listed here.

Reference: Katzung's Basic and Clinical Pharmacology, 15th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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