Expression Levels of Glutathione Peroxidase 1 (GPx1) and Multi-Drug Resistance 1 (MDR1; ABCB1) Identify Patients with Diffuse Large B-Cell Lymphoma (DLBCL) That Have Superior Clinical Outcomes.

Background: Standard chemotherapy fails in 40–50% of patients with DLBCL. Some patients can be salvaged with high-dose regimens, suggesting a role for drug resistance in this disease. While genes in the glutathione (GSH) pathway and ATP-dependent transporter (ABC) family have been implicated in drug resistance in other malignancies, their role in lymphoma, and DLBCL in particular, remains unclear.

Methods: We examined expression of 21 key members of these families in two tissue-based expression-microarray datasets of DLBCL patients, prior to CHOP chemotherapy. Expression signals derived from Affymetrix MAS 5.0 software (SF/NF=1) were publicly available for the primary dataset (

Results: In univariable analysis, expression of GPx1 had the most significant adverse association with FFP in the primary dataset (n=130), hazard ratio (HR) 1.68 (95% CI: 1.26 – 2.22, p<0.001). This effect remained highly statistically significant after controlling for the Monti biological signature, the LLMPP cell of origin signature, and the IPI score, and was confirmed in the validation dataset (n=39) (HR 1.5, 95% CI: 1.01 – 2.3, p=0.048). None of the ABC transporters examined were associated with FFP in the univariable analysis. Recursive partitioning identified a group of patients (n=34) with low-level expression of GPx1 and ABCB1 that had no early failures (FFP2: 100%, 95% CI: 90% – 100%). Notably, this group was comprised of patients in all IPI and LLMPP signature subgroups and achieved superior long-term FFP compared to the entire cohort (p<0.001).

Conclusions: Overall, our findings suggest an important role for redox-stress defense and drug elimination in the treatment failure of DLBCL and identify GPx1 and ABCB1 as potentially powerful biomarkers of early response and response duration. Coordinate expression of these genes delineates a subgroup of patients with superior clinical outcomes regardless of other clinical and biological risk stratification in current use. Prospective, treatment-based studies with uniform inclusion and response criteria are needed to validate these markers in clinical practice.