Glutathione S-transferase GSTM1 and GSTT1 polymorphisms in adult acute myeloid leukemia; its impact on toxicity and response to chemotherapy

Abstract

Background and purpose: Heterogeneity in patient' s response to chemotherapy is consistently observed across populations. Pharmacogenomics, the study of inherited differences in drug disposition and effects, is emerging as a tool to predict efficacy and toxicity of drugs. Glutathione S-transferases (GST) are involved in the metabolism and detoxification of environmental carcinogens and some classes of chemotherapeutics. Polymorphism of GSTM1 and GSTT1, in the form of homozygous deletion, is encountered in varying frequencies in normal population. It has been associated with altered response and toxicity from cytotoxic chemotherapy. In this study, we investigated the impact of these polymorphisms on response and side effects of chemotherapy in adult acute myeloid leukaemia (AML) patients. Correlations between these genetic polymorphisms and other prognostic factors were also investigated.

Patients and methods: We genotyped GSTM1 and GSTT1 in 98 adult AML patients using multiplex PCR. Induction therapy included Doxorubicin and Cytosine arabinoside (3+7) regimen. Treatment outcomes were compared in those with or without GSTM1 and GSTT1 genes.

Results: The frequencies of GSTM1 null and GSTT1 null genotypes were 56% and 14%, respectively. Six percent (6%) were double null. The rate of toxic death during induction was 3/7 (43%) and 17/56 (30%) in GSTT1 null and GSTT1 present patients, respectively, p=0.67. This constituted 75% and 42% of total deaths in each group, respectively, p=0.31. Differences were not statistically significant. On the other hand, the rate of complete remission (CR) in patients with GSTM1 present compared to those with GSTM1 null genotype was 12/27 (48%) versus 23/36 (64%), p=0.21. GSTT1 null genotype was significantly associated with lymphoid marker (mainly CD7) expression (p=0.03), known with its adverse effect on prognosis. Overall survival and disease-free survival were similar in patients with and without the genes. No significant associations were encountered between GST genotypes and treatment outcomes.

Conclusion: Our data suggest possible association, though not significant, between GSTT1 null genotype and toxic death during induction and between GSTM1 present genotype and lower rate of CR. Studies on larger numbers are needed focusing on selection of anticancer agents to avoid adverse reactions and therapeutic failure, with special emphasis on drug toxicity and dose adjustment.