Bcr-Abl Kinase Domain Mutations and Other Mutations on the Response to Nilotinib in Bcr Abl –Positive Chronic Myeloid Leukemia - a Study from Eastern India

Abstract

ABSTRACT Aim: The emergence of ABL point mutations is the most frequent cause for imatinib resistance in CML patients and can occur during any phase of the disease. The treatment of CML has changed with the introduction of tyrosine kinase inhibitors (TKI).The aim of the study is to investigate two potential resistance mechanisms i.e., mutations of the BCR-ABL tyrosine kinase domain (TKI) and additional chromosomal abnormalities (ACA), during 1st and 2nd generation TKI treatment in CML. Methods: Between September 2002 and February 2012, 66 patients with Ph-positive CML and imatinib resistance or intolerance were treated with nilotinib and were analyzed. Karotyping and BCR-ABL TKD mutation screening are performed in 66 imatinib-resistant CML patients who were on imatinib at the time of loss of hematologic response (HR), cytogenetic (CyR)or molecular response (MR).Imatinib-resistance mutation analysis (Qualitative) were detected by nested RT-PCR and Sanger sequencing. Out of 66 patients, 34 received escalated imatinib, 32 received nilotinib. Results: In 66 BCR-ABL-positive imatinib-resistant patients,11 different BCR-ABL TKD mutations were detected. Lack of HR was noted in 20 patients where CyR was not evaluated. Imatinib resistance mutation analysis was promoted by no HR (n = 12); loss of HR after achieving CyR (n = 27); failure to achieve CyR milestones (n = 19); loss of CyR (n = 6); development of extra medullary BC (n = 2),The analysis revealed no mutations in 33 patients, M351T in10 patients, G250E in 7 patients, F317L in 7 patients, M244V in 4 patients, E355G in 3 patient, and T315I in 2 patients. The seven novel mutations (F317L, G250E, M244V, M351T, F359V, T315I, E355G) were seen in our patient population. T315I was found in 2/66 patients who demonstrate loss of response. Conclusions: Compared with other western studies the incidence of the T315I mutation is very low in our study population. For patients with TKI resistance, mutation and ACA screening may play a role in identifying patients with poorer prognosis.If nilotinib-resistant mutation was detected, we preferred dasatinib .We plan for bosutinib, panotinib omacetaxine (SC route) in third line therapy in nilotinib-resistant, different mutation-positive CML. Disclosure: All authors have declared no conflicts of interest.