Glutathione-S-Transferase M1 (GSTM1) and T1 (GSTT1) Deletion Polymorphisms Predict Regimen-Related Toxicity after Autologous and Allogeneic Blood and Marrow Transplantation (BMT).

Abstract

Treatment Related Mortality (TRM) due to BMT conditioning regimen-related toxicity (RRT) has decreased over the past decade, but still has a major impact on patient outcome. In addition, morbidity due to non-fatal toxicity has a major impact on increased length of stay, cost and treating toxicity, while decreasing acute quality-of-life. Several reports have associated individual polymorphisms and survival, TRM, hepatic toxicity and stomatitis. We hypothesized that genetic variability affecting metabolic and detoxifying enzyme activity might explain RRT inter-individual variability. The glutathione-S-transferase (GST) isoenzymes respond to oxidative stress by detoxifying the reactive oxygen species produced by many chemotherapeutic drugs and radiation therapy. We updated our previous single center report (Blood 108:19a, 2006) of 496 first auto or allo BMT pts treated at RPCI from 1/1996 to 12/2002 with 203 additional pts meeting the same eligibility criteria and treated at an international center (NHC) from 1/1998 to 6/2007. Moderate to fatal toxicity was examined in association with GSTM1 and GSTT1 deletion genotypes. 290 patients (58%) from RPCI and 66 patients (33%) from NHC had available banked samples for genotyping. 268 RPCI patients and 54 NHC patients had samples yielding amplifiable DNA included in this analysis. 49% patients were homozygous null for GSTM1, 22% were homozygous null for GSTT1, and 7% were homozygous null for both GSTM1 and GSTT1; these genotype rates did not differ by center. 59% developed grade 2-4 RRT in any one or more organ sites (69% at NHC and 57% at RPCI, p>0.1). Comparison of patient characteristics between RPCI vs. NHC revealed significant differences between the 2 centers on age, donor relation, conditioning regimen intensity, diagnosis and KPS, therefore all analyses were adjusted for center effect. However, there were similar effects of genotype on RRT when stratified by center. GSTM1 deletion was associated with a significantly increased risk of overall grade 2-4 RRT (RR=1.6, 95%CI 1.04–2.6; p=0.03), with the same trend seen in both auto and allo BMT subgroups. In multivariate analysis, significant independent predictors of increased risk of grade 2–4 RRT were GSTM1 deletion (RR=1.78, 95%CI, 1.1–2.9, p=0.02) and unrelated allo donor (RR=6.7, 95% CI 1.3–35, p=0.03), with a trend toward a protective effect of improved performance status (KPS≥90 RR=0.6, 95%CI 0.4–1.03, p=0.07) after controlling for center, age, gender, diagnosis, conditioning regimen intensity and stem cell source. GSTM1 has been previously reported to be associated with TRM in unrelated allo BMT pts, however we now demonstrate this after auto and related allo BMT. GSTT1 deletion was not significantly associated with grade 2–4 RRT, confirming previous BMT studies. Individual organ toxicity (cardiac, bladder, pulmonary, hepatic, GI, CNS, stomatitis and renal) was also assessed: GSTM1 deletion was associated with a significantly increased risk of grade 2–4 Stomatitis RRT (RR=1.6, 95%CI 1.04–2.5, p=0.03). Genotype analysis of SNPs in additional metabolic enzyme pathways is ongoing. This is the first study evaluating RRT (overall and organ-specific) post auto, related and unrelated allo BMT. The ability to predict moderate, severe and fatal RRT after auto and/or allo BMT may improve outcomes by allowing for individualized conditioning regimens.