Spectrum of BCR-ABL1 kinase domain mutations: A cohort study from Saudi Arabia

Abstract

Background: The BCR-ABL1 tyrosine kinase domain mutation constitutes a major cause of resistance to the tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML). In this retrospective study, we assessed the ABL kinase domain mutation in 123 patients (61 females and 62 males) aged 10–79 years (median age of 50 years). These patients were referred to our clinics at King Faisal Specialist Hospital and Research Center (General Organization), Riyadh, Kingdom of Saudi Arabia during period (2011–2014). These patients had Philadelphia-positive CML displaying either failure to tyrosine kinase inhibitor (TKI) or suboptimal response with increased BCR-ABL1 levels through serial monitoring by using quantitative Real time PCR. Methods: The mutation analysis was performed on RNA extracted from Peripheral blood samples after the amplification of the BCR-ABL1 transcript by nested PCR followed by direct sequencing of the BCR-ABL1 kinase domain including the residues (243–487). Results: Of 123 patients, 119 adults and four pediatrics were analyzed. From the total, 25 (20%) were tested positive for 11 different mutations in the ABL1 kinase domain (11 patients with T315I, 3 with Y253H, 2 with E255K, 2 F317L, and 1 patient having each of the following mutations: F359I, E355G, V299L, L248V, L298, M244V, and Y326H). The duration from the diagnosis to mutation detection ranged between 3 and 144 months with a median duration of four years. Conclusion: Despite the retrospective nature of the study and relatively small sample size of a single center analysis, the mutation frequency is in line with similar reported studies from other parts of the world.

Keywords

• BCR-ABL1
• chronic myeloid leukemia
• philadelphia
• sequencing
• tyrosine kinase
• tyrosine kinase inhibitor