Abstract
Glutathione S-transferases (GST) are phase II detoxification enzymes, involved in the metabolism of carcinogens and anti-cancer drugs. Since GSTs have been also shown to interact with kinase complexes during oxidative or chemical stress-induced apoptosis, their polymorphic variants may account for differences in outcome following chemotherapy between individuals. Studying 106 patients (pts) with acute myeloid leukaemia (AML), we have shown that individuals with a GSTM1 and/or GSTT1 deletion were at higher risk of relapse and of shorter overall survival (
Voso et al, Blood 100:2703, 2002
). The aim of the present study was to confirm or previous findings and to better define the role of GSTM1 and GSTT1 deletions in the context of a molecularly well-characterized cohort of AML-patients who were treated within two prospective clinical trials of the German-Austrian Acute Myeloid Leukemia Study Group (AMLSG) In addition to polymorphisms in GSTM1 and GSTT1, we were also interested in the role of the GSTP1(Ile105Val) polymorphism on outcome. Based on our previous work, we intended to show a 20% difference in the 3-year survival rate. Therefore the estimated power for our current study including 350 patients to confirm the previous findings was 98%. We studied 354 patients (pts) with AML, treated according to two AMLSG prospective multicenter clinical trials (HD98-A for pts with age < 60 years, 254 pts; HD98-B for pts > 60 yrs, 100 pts). The Ile105Val polymorphism of the GSTP1 gene (GSTP1*105) was analyzed by PCR-RFLP, while GSTM1 and GSTT1 homozygous deletions (GSTM1*0 and GSTT1*0) were studied using a multiplex PCR technique, including the housekeeping gene BCL-2 as internal control. GST genotypes were not associated to patients’ characteristics, including type of AML, cytogenetic risk group, presence of FLT3-ITD and abnormal laboratory parameters, and response to induction chemotherapy. GSTP1*105Val was associated with a significant better relapse-free survival using age-stratified test (adjusted HR, 0.7; 95% C.I., 0.51–0.98), while GSTT1 and GSTM1 genotypes had no impact on RFS. A Cox proportional hazard model on RFS including GST genotypes, LDH level, cytogenetic risk group, and FLT3-ITD mutation status showed that the GSTP1 genotype was a significant variable associated with a favourable outcome (n= 236 pts, HR, 0.62; 95% C.I., 0.44–0.88). Limiting the analysis to patients with a normal karyotype, the GSTP1 105Val allele was associated in the multivariable model on RFS with a 51% risk reduction (HR, 0.49; 95%C.I., 0.30–0.81). In conclusion, GSTP1*105Val seems to be of prognostic value, whereas the prognostic value of GSTM1 and GSTT1 reported in previously could not be confirmed.Author notes
Disclosure: No relevant conflicts of interest to declare.
2007, The American Society of Hematology
2007
