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T315I is the gatekeeper mutation in the ABL1 kinase that defeats imatinib, dasatinib, nilotinib and bosutinib. Ponatinib and asciminib are the two drugs approved for it.
The threonine-to-isoleucine change at the gatekeeper residue removes a hydrogen bond the first- and second-generation inhibitors need and adds steric bulk. It is detected by Sanger or next-generation sequencing of the kinase domain when BCR::ABL1 levels rise. Ponatinib (Iclusig) is labelled for T315I-positive CML in any phase and T315I-positive Ph+ ALL; asciminib (Scemblix), which binds the myristoyl pocket rather than the ATP site, is labelled for Ph+ CML in chronic phase with the T315I mutation at a higher dose. Allosteric plus ATP-site combinations are in trials for compound mutations.
In plain words · The fusion that defines chronic myeloid leukaemia and a quarter of adult acute lymphoblastic leukaemia; the first cancer driver ever switched off by a pill.
If your leukaemia's BCR::ABL1 level has risen and sequencing finds T315I, the usual tablets will no longer work; ponatinib or asciminib are the two approved options and a transplant may be discussed. Testing for the mutation is done from a blood sample whenever response is lost.
Written only from the label or guideline text cited on this page. Not medical advice; your own report and the reading your team gives it come first.
The ABL1 c.944C>T (p.T315I) substitution in the BCR::ABL1 kinase domain by Sanger or next-generation sequencing of blood or marrow RNA.
“Ph+ CML in CP with the T315I mutation.”
SCEMBLIX prescribing information| Threshold | Drug | Cancer | Regulator | Source |
|---|---|---|---|---|
| T315I-positive The Iclusig label also covers chronic, accelerated and blast phase CML with the T315I mutation. | Ponatinib | Chronic myeloid leukaemia (CML) | FDA | label |
| T315I mutation, chronic phase | Asciminib | Chronic myeloid leukaemia, chronic phase | FDA | label |
Matched on the name and aliases of the readout in the title, setting and summary of each trial; a match is a mention, not proof the readout was an entry criterion.
Shares Ponatinib, Asciminib, Chronic myeloid leukaemia, chronic phase, Chronic myeloid leukaemia, accelerated and blast phase.
Shares the tags biomarker, resistance.
Shares the tags biomarker, resistance.
Shares the tags biomarker, resistance.
Shares the tags biomarker, resistance.
Shares the tags biomarker, resistance.
Shares BCR::ABL1 transcript (Philadelphia chromosome, quantitative PCR), BCR::ABL1 kinase domain mutations (T315I and others), Ponatinib, Asciminib.
Shares On-target resistance mutations (gatekeeper, solvent-front, compound) and the tags biomarker, resistance.