T315I

T315I refers to a specific point mutation in the BCR-ABL1 tyrosine kinase domain, where threonine at residue 315 is replaced by isoleucine. This position is known as a gatekeeper residue that helps regulate access to the kinase pocket, and the substitution alters drug binding while preserving kinase activity.

The mutation is most notably associated with Philadelphia chromosome–positive leukemias, including chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL). It commonly arises as a mechanism of resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, and nilotinib. T315I can be present at diagnosis in a minority of cases or emerge during therapy as selective pressure favors resistant clones.

Diagnosis of T315I typically involves molecular methods such as sequencing of the BCR-ABL1 kinase domain, with newer techniques like next-generation sequencing providing greater sensitivity for low-level mutations.

Management of T315I-associated resistance centers on therapies active against the mutation. Ponatinib, a third-generation TKI, retains activity against T315I and is commonly used, though it carries a risk of vascular thrombotic events that requires careful patient selection and monitoring. Other approaches include allosteric inhibitors targeting alternative sites on BCR-ABL1, such as asciminib, which can be effective in some T315I cases. Allogeneic stem cell transplantation remains a potential curative option for eligible patients, typically considered in resistant or advanced disease. Clinical decisions are individualized based on disease phase, prior therapy, and patient factors.

Ongoing research continues to refine strategies to overcome T315I-mediated resistance and improve outcomes for affected patients.