The Clinical Characteristics and Efficacy of Chronic Myeloid Leukemia Patients with T315I Mutation

Background: The application of tyrosine kinase inhibitor (TKIs) has greatly improved the overall survival (OS) and quality of life of chronic myeloid leukemia (CML) patients.However, in the TKIs era, 10% to 25% of CML patients still develop TKIs resistance, and ABL kinase point mutations are the most common reason.Most of the ABL kinase region mutations resistant to imatinib could be alleviated by second generation TKIs, but the T315I mutation resistance to the first and second generation TKIs. Ponatinib is a multi-target tyrosine kinase inhibitor, which belongs to the third generation of TKI inhibitors,and is sensitive for CML or Ph postitive ALL patients with T315I mutation. But,how to apply ponatinib bridging graft or whether ponatinib preventive therapy is needed after transplantation is uncertainty.

Methods: 18 CML patients with T315I mutation detected by ABL1 kinase region mutation in Southern Hospital from March 2013 to April 2018 were retrospectively analyzed.G-banding method was used for chromosome analysis and real-time quantitative PCR method was used to detect mutations in ABL1 kinase region by BCR-ABL1 fusion gene Sanger sequencer.

Result:18 CML patients with T315I mutation :13 cases chronic phase (CP) ,2 cases in accelerated phase,3 cases in blastcrisis phase(BP); 9 cases in high risk group, 6 cases in middle risk group and 3 cases in low risk grou by Sokal score score system.15 patients by imatinib ,3 patients first-line treatment with dasatinib .In imatinib group, 13 cases conversed to dasatinib because of drug resistance or intolerance, and 5 cases (5 / 13) were converted to ponatinib because of T315I mutation.One case in dasatinib group converted to ponatinib because of T 315 I mutation.A total of 6 patients (6 / 18) were treated with ponatinib. 6 patients (6 / 18) treated by allogeneic hematopoietic stem cell transplantation (Allo-SCT).The median stage of T315I mutation was 12.5 m from the beginning of treatment to the detection of T 315I mutation in 18 patients.At the end of the follow-up, 8 cases died of recurrence and 10 survived: (CMR 2 cases, CHR 1 cases, PR 3 cases, NR 3 cases, 1 cases not regularly followed up, unable to evaluate the disease state), including 6 patients with PO treatment.

Conclusion:The point of T315I mutation was detected in patients with CML resistance after long-term sequential therapy frequently. The recurrence rate was still high even if these patients experience allogeneic hematopoietic stem cell transplantation.However,these patients treatment with ponatinib before and after transplantation maybe reduce the recurrence rate and improve prognosis.

Key words:Chronic myeloid leukemia;BCR-ABL;T315I;ponatinib.