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

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.