A Retrospective Analysis of BCR-ABL-1 Kinase Domain Mutations in Frontline TKI Resistant Chronic Myeloid Leukemia Patients: A Single Centre Experience

CML is a commonly diagnosed myeloproliferative neoplasm in India. Tyrosine kinase inhibitors (TKIs) are the current standard of care for management of CML. Mutations in Tyrosine kinase Domain (TKD) result in resistance to TKIs. The aim of this study is to evaluate the pattern of TKD mutations in CML patients having inadequate response or resistance to first line TKIs and to analyse the outcome of CML patients with and without mutations. It is a retrospective observational study. Medical records of 1633 CML patients from year 2014 to 2021 were analysed. Out of these 108 patients (6.6%) lost their response or did not achieve it in defined time points. 62 patients (71%) were found to have TKD mutations. On analysing specific mutations T315I was the most common mutation seen in 29 (46%) cases followed by M351T in 10 (16%) cases and G250E in 7 (11%) cases. ATP binding region was found to be the most common site in tyrosine kinase domain (50% cases) followed by P-loop (22%) and A loop (9.6%). 13 (20%) cases had ≥2 TKD mutations. The study showed inferior overall survival (OS) in patients with TKD mutations involving T315I mutations and ATP binding domain. Patients may have have underlying TKD mutations at prestation or may develop during course of disease. In case of TKI resistance, testing for specific mutations must be done and appropriate TKI sensitive to underlying mutation is to be used which translates into improved OS.