Copy Number Variations in Cytochromes and Glutathione-Transferases As Early Predictors of the Efficacy of Tyrosine Kinase Inhibitors in CML

Chronic myeloid leukemia (CML) is characterized by the presence of the chimeric tyrosine kinase BCR-ABL in all leukemic cells. This non-specific enzyme promotes uncontrolled cell proliferation and genome instability. Tyrosine kinase inhibitors (TKI) help most of the people to achieve long standing remission, however up to 20% of patients develop slow response or even primary resistance to the therapy. In this work we focused on copy number variation (CNV) in glutathione transferases (GSTs) and cytochromes (CYPs) as possible predictors of the response rate to TKI. Thirty one CML patient with optimal response and 16 with therapy failure were enrolled in the study. Patient were grouped according to ELN2013 recommendations: BCR-ABL<1% and/or Ph+ 0% for optimal response and BCR-ABL>10% and/or Ph+ >35% at 6 months of TKI therapy for the failures. We found that these two groups of patients had differed frequencies of wild type and mutated genes: CYP1A2, CYP2A6, CYP2C19, CYP2C9, CYP2D6, CYP2E1, CYP3A4, CYP3A5, GSTM1, GSTP1, GSTT1 (p< 0.0013). Validation in the additional group of 15 CML patients showed that the test allows to predict failures and responders (p=0.02) with high accuracy: positive and negative predictive value 83% and 78%; sensitivity and specificity 71% and 88%.