BCR::ABL1 kinase domain mutations (T315I and others)
When a CML drug stops working, the leukaemia has usually changed the shape of the pocket the drug fits into; sequencing the BCR::ABL1 kinase domain names the mutation, and the name tells the doctor which drug still fits: most mutations respond to another second-generation drug, but T315I responds only to ponatinib or asciminib.
Overview
What is measured: point mutations in the ABL1 kinase domain of the BCR::ABL1 fusion that stop a tyrosine kinase inhibitor binding. How: Sanger or next-generation sequencing of BCR::ABL1 transcripts from peripheral blood, ordered when transcripts rise (loss of major molecular response, failure to meet the European LeukemiaNet milestones), at progression to accelerated or blast phase, and in Ph-positive ALL at relapse; sequencing detects mutations at about 3 percent abundance and shows whether two mutations sit in the same molecule (compound mutations). The common ones: T315I (the gatekeeper, 15 to 20 percent of mutations, resistant to imatinib, dasatinib, nilotinib and bosutinib), E255K/V and Y253H in the P-loop (nilotinib-resistant), F317L and V299L (dasatinib-resistant), F359V/C (nilotinib-resistant); asciminib, which binds the myristoyl pocket rather than the ATP site, has its own resistance mutations (A337T, P465S). What a result changes: the next drug is chosen from the mutation table: T315I means ponatinib (PACE, with dose reduction in OPTIC) or asciminib at 200 mg twice daily, and transplant in advanced phase; other mutations steer between the second-generation drugs; in relapsed Ph-positive ALL with T315I, ponatinib with blinatumomab is a chemotherapy-free option. Where it matters: CML in chronic and advanced phase, and Ph-positive ALL.
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