Association of Genetic Polymorphisms of Glutatione-S-Transferase Genes and Overall Response/Clinical Features in Diffuse Large B-Cell Lymphoma Patients Treated with Rituximab.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma. It is a heterogeneous disease. Approximately 40% of the patients respond well to chemotherapy based on rituximab-CHOP (R-CHOP). The prognosis for the other 60% is poor and only half of the patients survives 5 years after the onset of the disease. Glutathione-S-transferase (GST) genes, including GSTM1 (GST mu 1), GSTT1 (GST Tetha 1), and GSTP1 (GST pi 1), are a complex multigene family involved in metabolism and detoxification of chemical agents such as alkylators and steroids. They are involved with cell proliferation and cell survival. Since many of these drugs are regularly used to treat LDGCB we studied the GST gene polymorphisms regarding there involvement in prognosis and clinical features of this disease.

79 patients with DLBCL classified according to WHO criteria were studied for GSTM1 or GSTT1 null deletion polymorphism by multiplex PCR and GSTP1 1578A>G and 2295C>T alleles polymorphism by PCR-RFLP using B-globin gene as an internal control.

The median age of the 79 patients was 54 years (15 to 75); 47(59%) were male. Thirty-five (44.3%) patients were treated with R-CHOP21 and 44 (55.7%) with CHOP-like chemotherapy with no rituximab. Twenty-nine (37%) patients had stage III + IV and more than 2 factors described by the International Prognostic Index. Sixty-eight (86%) patients acquired complete remission (CR) (IC95%: 77-93%), 3(4%) acquired partial remission (PR) and 8(10%) were refractory (RD) to treatment. The overall response (OR) with R-CHOP was 35 (44%), 34 (43%) with CHOP with no Rituximab and 10 (13%) with other therapy (p=0.41). The GSTM null genotype was found in 44 (56%) patients with no correlation with treatment response. The GSTT1 null polymorphism was found in 62 (78%) patients, more often in those with bulky disease (61% versus 29%, p=0.02). Further associations between GSTT1 null polymorphism and disease features were not demonstrated. Regarding the GSTP1 1578 A>G allele, 26(42.0%) patients had AA, 35(44%) had AG and 11(14%) had GG polymorphism. Patients with GG polymorphism had extranodal involvement more often than those with the AA and AG polymorphism (50% vs. 6.7% vs. 5.7%, p<0.001). Unexpectedly, all of those 11 patients with GG polymorphism were male (p=0.01). Seventy-seven patients were studied for GSTP1 2293 C>T allele. The wild type CC was found in the majority of them 73(92%). The remaining patients had CT polymorphism and none of them had mutant TT polymorphism. Association between GSTP1 2293 C>T polymorphism and disease characteristics was not observed. Indeed, none of the studied polymorphisms was associated to treatment outcome with CHOP or R-CHOP.

The knowledge concerning the impact of the genetic GST polymorphism in predicting outcome in DLBCL is scarce. In this trial we demonstrated that GSTT1 was the most common GST polymorphism found in patients with DLBCL, mainly in those with bulky disease. In the other hand, the genotype GSTP1 GG was more often associated to extranodal involvement in DLBCL. Concerning to outcomes, we did not found any association between overall response or survival rate and genetic polymorphism of the GST genes.

No relevant conflicts of interest to declare.