Deep sequencing reveals the spectrum of BCR-ABL1 mutations upon front-line therapy resistance in chronic myeloid leukemia: An Eastern-Indian cohort study.

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.

Long-Term Outcome of Philadelphia Chromosome Positive Leukemia From Eastern Indian Subcontinent: An Experience in the Era of Tyrosine Kinase Inhibitor (TKI) Therapy.

INTRODUCTION: Philadelphia chromosome (Ph) marks a group of leukemia with almost all cases of chronic myeloid leukemia (CML), a subset of acute lymphoid leukemia (ALL) and rare cases of acute myeloid leukemia (AML). In the era of precision medicine, such cases are successfully managed with tyrosine kinase inhibitor (TKI) drugs. This study examined the features and long-term outcome of Ph+ve cases from a tertiary cancer care center from Eastern Indian subcontinent. MATERIALS AND METHODS: Reviewing retrospective case-records registered between 2005 and 2015, cases of CML and ALL were documented under Ph+ve category; while no instance of Ph+ve AML was found. RESULTS: In CML cohort, adult and juvenile incidences were 95.2% and 4.8% respectively; in ALL cohort, the same was found for 66.67% and 33.33% cases. Among the CML cases, 10-year overall survival (OS) and progression-free survival (PFS) were significantly affected upon the phase of disease at time of detection. Furthermore, both OS and PFS significantly dropped whenever non-TKI-based treatment was applied prior to TKI-commencement. Long-term (10-year) sensitivity to 1st generation TKI, imatinib, was noted 88.51% and 83.33% for adult and juvenile CML cohorts, respectively. For Ph+ ALL cohort, the OS was benefitted upon combinatorial TKI and chemotherapy. However, large fractions of affected individual from CML as well as ALL cohorts were found to discontinue follow-up. CONCLUSION: Together with differences in outcome on the basis of drug-use from onset, age (juvenile versus adult) and stage at diagnosis, our analyses bring forward the real-world scenario of Ph+ve leukemia managed with precision medicine.