Characterization of Genomic Events Other than Ph and Evaluation of Prognostic Influence on Imatinib in Chronic Myeloid Leukemia (CML): A Study on 1449 Patients from India

Abstract

Background: Analysis of Philadelphia (Ph) chromosome, a hallmark of chronic myeloid leukemia (CML) plays an important role in disease monitoring of the targeted drug Imatinib. Apart from Ph, genomic imbalances such as additional chromosomal abnormalities (ACAs) of major route occur during transformation of the disease and show negative impact on prognosis. Objective: The present study was carried out to investigate frequencies of ACAs, genomic deletions, complex Ph variants and their prognostic influences in a large cohort of newly diagnosed CML-CP (chronic phase) and CML-AP/BP (accelerated/blast phase). Material & Methods: Retrospective, single institutional study on 1367 cases of CML-CP and 82 cases of CML-AP/BP between 2009 and 2015, using conventional cytogenetics along with fluorescence in situ hybridization. Results: Of the 1367 patients in CML-CP, 1041 patients who completed 12 - 18 months of Imatinib therapy showed complete cytogenetic remission (CCyR) rates of 76% and 82% at 12 and 18 months respectively. Imatinib induced 81% and 33% CCyR in CML-AP and CML-BP respectively. Frequencies of ACAs in CML-CP, AP and BP were 2%, 27% and 67% respectively. Patients in chronic and AP/BP phase with ACAs showed resistance to Imatinib ( p < 0.0005). The incidence of genomic deletions and complex Ph variants was 21% and 6.3% respectively with no comparable difference of cytogenetic response to Imatinib ( p < 0.732 and p < 0.210 respectively). In a cohort of 112 patients in CCyR, development of new clonal abnormalities, more frequently trisomy 8 was detected in Ph negative clone. Conclusion: Our data demonstrated that Imatinib as a frontline therapy had significantly improved management of CML. However, ACAs play an important role in resistance to Imatinib, both in chronic and acute phase, which may limit sole ABL targeted therapy.