Cytochromes P450 and Glutathione S-Transferases Polymorphisms: Can They Predict Efficacy of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia?

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by over production of cells due to expression of an abnormal BCR/ABL1 kinase gene. Tyrosine kinase inhibitors (TKI) are the treatment option to achieve deep and prolonged molecular response in CML patients. Resistance or sub-optimal response to TKI such as imatinib has been reported in 5-20% of the patients carrying wild type of Cytochromes P450 (CYP) and glutathione S-transferases (GST). This study was planned to evaluate possible association of presence or absence of polymorphic variation in CYP1A1, GSTT1 and GSTM1 with response to nilotinib in CML patients

A total of 33 CML patients receiving nilotinib treatment (ELN 2013 guidelines) at National Institute of blood Diseases and Bone Marrow Transplantation were enrolled. Informed consent was obtained as per declaration of Helsinki. The presence (⁺) or absence (^-) of CYP 1A1 (A2455G), GSTT1 and GSTM1 was determined by RFLP and multiplex PCR respectively. Treatment response was evaluated by quantification of BCR ABL1 transcripts by real time qPCR. The chi square test was used to compare the genotype distribution between patients and control. A p value less than 0.05 was considered as statistically significant. Odds ratio (OR) with 95% confidence interval (CI) calculated using statistical package SPSS version 22.

The male:female ratio for the study group was 1.75:1 with a mean age of 37±12 years. About 25, 5 and 3 patients were diagnosed with CML in chronic, accelerated and blast crisis phase respectively. There were 25 responders, 5 partial responders and 3 non-responders to nilotinib treatment altogether. The GSTT1^- genotype was most frequent in responders (72%) followed by GSTM1⁺ and CYP 1A1^- (p= <0.05). Interestingly, GSTT1^-/GSTM1^- and heterozygous CYP 1A1⁺ were less frequent (8% and 20%) but observed only in responders.

This is the first study on nilotinib response and CYP1A1, GSTT1, GSTM1 polymorphisms in CML from Pakistan. Null or GSTT1^-, GSTM1⁺ and CYP 1A1^- seemed to be frequent in nilotinib responders only and may have influence on drug response.