Sequential acquisition of tyrosine kinase domain mutations in a case of chronic myeloid leukemia: A dormant clone war against TKI

Abstract The tyrosine kinase inhibitor (TKI) therapy has a high response rate in chronic myeloid leukemia (CML). However majority of patients relapse due to high mutation susceptibility of tyrosine kinase domain (TKD) of BCR/ABL fusion gene. We report a case of CML which was diagnosed and monitored for 10 years as per the ELN guidelines. Mutational analysis using Sanger sequencing (SS) and Next generation sequencing (NGS) and In-silico study was performed. The present case describes the acquisition pattern of TKD mutation against the TKIs (Imatinib, Dasatinib and Nilotinib) at different time points. Interestingly, NGS identified a dormant mutant clone with p.G250E mutation in 2019 which was first detected by SS in 2011 along with one novel mutation p. Ala287Thr, which likely explain the dormant nature of these mutant clones. Bioinformatics analysis (Modelling and docking) of novel variant revealed that mutation detected through deep sequencing technique reducing the IM efficacy by increasing inhibition constant and suggests higher concentration of IM to overcome such mutations. The study highlights the importance of NGS in CML, as it can detects clinically relevant low level mutant clones in CML patients.