Tyrosine Kinase Inhibitor Resistance in Patients with Chronic Myeloid Leukemia: A 10-Year Study of BCR-ABL Gene Mutation Profile in Russia (2006-2016)

Abstract

Background. Kinase domain mutations of BCR-ABL gene is the most common cause of tyrosine kinase inhibitor resistance. Aim. To present the data on prognostic value of BCR-ABL mutation burden in Russian patients over the last 10 years. Materials & Methods. The study included 1885 chronic myeloid leukemia (CML) patients with tyrosine kinase inhibitor resistance who were followed up from 2006 to 2016. BCR-ABL point mutations in mRNA samples were analyzed by means of polymerase chain reaction and subsequent Sanger sequencing. Results. In 1257 CML patients with signs of tyrosine kinase inhibitor resistance BCR-ABL expression level was > 1 %. BCR-ABL mutations were detected in 31.8 % of patients. Total mutation count was 467 (70 mutation types). Total count of patients with mutation-associated tyrosine kinase inhibitor resistance decreased from 36.6 % (2006-2008) to 24.95 % (2013-2016) and to marked decrease of 23.12 % in 2014. Detection rate of imatinib-resistant mutations and F359V mutation was shown to decrease within the period from 2010-2011 to 2014-2015. F317L level, which is responsible for dasatinib resistance, considerably increased in 2015. T315I frequency was the highest in 2014, afterwards it was gradually decreasing. Mutation-associated resistance rates varied by region of the Russian Federation. Conclusion. The analysis of trends of mutation incidence in patients with CML can be of extreme significance in longterm prognosis of resistance development and in improvement of treatment planning.