Influence of Genetic Variability of GSTM1 and GSTT1 Null Alleles Between Donor and Recipient in the Development of Acute Graft Versus Host Disease.

Glutathione-S-transferase (GST) M1 and T1 are multifunctional enzymes involved in the metabolism of environmental carcinogens and chemotherapeutic drugs. The immunogenic activity of these enzymes and their association with graft rejection has been widely proved in solid organ transplantation. In this study we examined whether genetic variability (absence versus presence of the gene in donor/recipient pairs) could be related to acute graft versus host disease (aGvHD) in patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation (alloHSCT) from related donor (RD).

We evaluated 64 patients with acute leukemia (34 AML and 30 ALL) undergoing alloSCT and receiving myeloablative conditioning (MAC), with a minimum follow-up of 100 days. Donors were HLA-identical siblings in all cases, except in 2 presenting only a single HLA disparity. As source of HSCs, bone marrow progenitors were used in 25 patients (40%) and peripheral blood progenitors in 39 (60%). Total body irradiation (TBI) was used for conditioning treatment in 18 cases (28%). GvHD prophylaxis consisted of a short-term combination of Cyclosporine and Methotrexate. Presence in homozygous or heterozygous (positivity) or absence (negativity) of GSTM1/T1 genes were determined by real-time PCR. A Chi-square test was used to evaluate qualitative variables and non-parametric tests for quantitative variables. The Cox proportional-hazard model was applied to multivariate analysis.

GSTT1 and GSTM1 positivity was observed in 73 and 47% of patients, respectively, and in 72 and 46% of donors, respectively. Nineteen of 64 patients (30%) presented grade II-IV aGvHD. The incidence of grade II-IV aGVHD in GSTM1-positive patients was 79% versus 21% in GSTM1-negative patients. In univariate analysis, only GSTM1 positive patients developed grade II-IV aGvHD (p=0.001). In multivariate analysis, GSTM1 positivity was the only variable significantly associated with the appearance of grade II-IV aGvHD (p=0.002). No significant association was detected between GSTT1 genetic variability and the incidence of aGvHD. We found no significant difference in patients overall survival in relation to GSTM1 and GSTT1 genetic variability.

GSTM1-positive recipients develop more likely grade II-IV aGvHD, independently of other known risk factors. GSTM1 gene determination (homozygous or heterozygous) could be used to assess the aGvHD risk in allogeneic hematopoietic stem cell transplantation.

No relevant conflicts of interest to declare.