T315Ipositive

T315Ipositive describes leukemias in which leukemic cells carry the BCR-ABL1 kinase domain mutation T315I (threonine to isoleucine at residue 315). This substitution occurs in the ATP-binding pocket of BCR-ABL1 and causes a conformational change that reduces or abolishes the binding of most ATP-competitive tyrosine kinase inhibitors (TKIs). As a result, T315Ipositive disease is typically resistant to imatinib and to several second- and third-generation TKIs, complicating therapy.

Detection is by molecular methods applied to peripheral blood or bone marrow samples, such as sequencing of BCR-ABL1 or mutation-specific assays. Monitoring of BCR-ABL1 transcript levels helps track response, and mutation testing is performed at suspected resistance or relapse.

Clinically, the T315I mutation identifies a resistant clone and is associated with a poorer initial response to many TKIs. Treatment options include ponatinib, a TKI with activity against T315I, though dosing and toxicity risks require careful management. Other strategies include allosteric inhibitors like asciminib, which can bypass the ATP-binding site, and allogeneic stem cell transplantation for eligible patients. Clinical trials continue to define sequencing and combinations to improve outcomes for T315Ipositive patients.

Epidemiology in CML and ALL shows T315I arises in a subset of patients who develop resistance to TKIs; among resistant cases, it is one of the more common mutations. Overall prognosis depends on disease phase, prior therapy, comorbidities, and access to effective agents and transplantation.