T315I - a gatekeeper point mutation and its impact on the prognosis of chronic myeloid leukemia

Abstract

Objectives: BCR-ABL kinase domain mutations are an important cause of resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukaemia (CML) of which T315I is the most treatment-resilient. This study aimed to observe the frequency of T315I and its impact on disease prognosis in terms of progression and survival.

Methods: Patients with a response which categorized them into warning zone/or who failed to respond to their TKI treatment completely as per the European LeukemiaNet (ELN) were labeled as non-responders. They were assessed for T315I mutation using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and validated via sequencing. Patients were then longitudinally followed for 96 months for the prognostic impact of the mutation.

Results: Of the 102 non-responders, T315I mutation was detected in 21.6 % of patients with a female preponderance. Almost 59 % of mutation-harbouring patients were labelled as low Sokal risk at baseline. The disease progression into the blastic phase was reported in 58.8 % of mutation-harbouring patients. Overall survival (study period: 96 months) was 81.8 % in patients harbouring T315I mutation. Patients in the blastic phase had significant odds of harbouring T315I mutation.

Conclusions: Sub-optimal response or failure to TKI treatment indicates the development of resistance due to the presence of T315I mutation or other mutation(s). Early identification will help redirect the patient's treatment.

Keywords: BCR-ABL; T315I mutation; chronic myeloid leukaemia (CML); disease progression; overall survival; resistance.

Figure 1:

Kaplan–Meier survival analysis of patients based on the presence of T315I mutation.