Cancer Treatment and Research Communications (Jan 2022)
Deep sequencing reveals the spectrum of BCR-ABL1 mutations upon front-line therapy resistance in chronic myeloid leukemia: An Eastern-Indian cohort study
Abstract
The course of clinical management in chronic myeloid leukemia (CML) often faces a road-block in the form of front-line (imatinib) therapy resistance. Subsequently, several hotspot mutations were clinically validated in the kinase domain (KD) of BCR-ABL1, in deterring imatinib sensitivity and further, made targeted by next-generation tyrosine-kinase-inhibitor (TKI) drugs. Identifying KD mutations, occurring even at low frequencies, became pertinent here. Globally, cohorts from different origins were tested and the mutational spectra were mapped to categorize clinical management as well as related pathological features of CML. Moreover, targeted deep sequencing could reveal the mutational landscape more efficiently than the less sensitive Sanger sequencing method. However, no such efforts were reported from Eastern Indian cohorts of imatinib-resistant CML-sufferers. This study assessed a prospective study cohort of imatinib-resistant CML cases from Eastern India. Following dissecting the molecular and clinical parameters, the mutational spectrum was comparatively examined using conventional Sanger and next-generation deep sequencing method. This cohort showed a prevalence of e14a2-p210 variant of BCR-ABL1 and acquired resistance against imatinib, while the disease was mostly confined in its chronic phase. Together with a few common hotspot mutations identified in this cohort, deep sequencing revealed cases with a candidate mutation, otherwise undetermined by Sanger method. Also, cases with a second low frequency mutation were identified upon applying deep sequencing. Along with highlighting a few aspects of CML biology employing an Eastern-Indian cohort, this data could mark the immense importance of deep sequencing to contribute in the clinical management of CML upon front-line therapy resistance.
