A 58-year-old man with newly diagnosed chronic myeloid leukaemia (CML) in chronic phase is started on imatinib mesylate 400 mg daily. After 3 months, BCR-ABL transcript levels have decreased by 90%, and he is tolerating the drug well. However, at 18 months, his BCR-ABL transcript levels begin to rise again despite adherence. Mutation analysis reveals a T315I point mutation in the ABL kinase domain. Which of the following tyrosine kinase inhibitors would be the most appropriate next-line therapy?

Explanation

## BCR-ABL Mutations and Resistance to Tyrosine Kinase Inhibitors ### The T315I Gatekeeper Mutation **Key Point:** The T315I mutation in the ABL kinase domain is a 'gatekeeper' mutation that confers resistance to first- and second-generation TKIs (imatinib, dasatinib, nilotinib, bosutinib) by preventing proper drug binding within the ATP-binding pocket. **Mnemonic:** **DINK** = Dasatinib, Imatinib, Nilotinib, Kinase inhibitors (all fail against T315I). **PON** = **Ponatinib** = Only one that works. ### Mechanism of T315I Resistance | TKI Generation | Examples | Mechanism of Action | T315I Sensitivity | |---|---|---|---| | **1st generation** | Imatinib | Binds inactive conformation of ABL kinase | Resistant | | **2nd generation** | Dasatinib, nilotinib, bosutinib | Bind active conformation; more potent | **Resistant** | | **3rd generation** | Ponatinib | DFG-out binding mode; unique scaffold | **Sensitive** | **Clinical Pearl:** Ponatinib was specifically designed to overcome T315I resistance by adopting a novel binding conformation that does not require the threonine residue at position 315. It binds to the DFG-out (aspartate-phenylalanine-glycine) inactive conformation of the kinase. ### Treatment Algorithm for TKI Resistance ```mermaid flowchart TD A[CML on imatinib]:::outcome --> B{BCR-ABL rising?}:::decision B -->|Yes| C[Mutation analysis]:::action C --> D{T315I present?}:::decision D -->|No| E[Switch to 2nd-gen TKI<br/>dasatinib/nilotinib]:::action D -->|Yes| F[Switch to ponatinib<br/>3rd-generation TKI]:::action E --> G[Monitor BCR-ABL<br/>at 3 months]:::outcome F --> G G --> H{Response?}:::decision H -->|Yes| I[Continue therapy]:::action H -->|No| J[Consider allogeneic<br/>stem cell transplant]:::urgent ``` ### Ponatinib Specifics **High-Yield:** - **Binding mode:** DFG-out conformation allows binding even when threonine is mutated to isoleucine. - **Spectrum:** Active against all known BCR-ABL mutations, including T315I, E255K, Y253H, and others. - **Potency:** ~500-fold more potent than imatinib against wild-type BCR-ABL. - **Toxicity:** Increased risk of arterial thrombosis (MI, stroke), hepatotoxicity, and pancreatitis; requires careful monitoring and patient selection. **Warning:** Ponatinib is reserved for T315I-mutant CML or Ph+ ALL because of its toxicity profile. It should not be used as first-line therapy. [cite:Harrison 21e Ch 397; KD Tripathi 8e Ch 65]