Redox Associated Gene Expression Predicts For Responses To The Pro-Oxidant Molecule Imexon In Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma: Results Of a Multi-Center Phase II Study
Authors: Barr Paul M. , Briehl Margaret M. , Bernstein Steven H , Friedberg Jonathan W. , Baran Andrea , Peterson Derick R. , Persky Daniel Oscar , Casulo Carla , Herr Megan M. , Littleton Jamie , Cebula Erin , Schwartz Mark , Puvvada Soham D. , Dorr Robert T , Fisher Richard I , Miller Thomas P. 
Published: October 2019

Abstract

Background
Imexon is a 1-carboxamido-2-cyan-aziridine isomer investigated as an anti-cancer agent given its pro-oxidant properties. By binding reduced sulfhydryls leading to the accumulation of reactive oxygen species, imexon interferes with the endoplasmic reticulum and mitochondrial reduction-oxidation (redox) balance, inhibiting protein translation and cell growth and inducing apoptosis. Pre-clinical studies demonstrated activity across an array of tumor cells in vitro and increased activity amongst B-cell non-Hodgkin lymphomas (NHL). A partial response in a follicular lymphoma (FL) patient was observed in a previous phase I study. This phase II trial was initiated to further investigate the clinical activity of imexon in patients with relapsed or refractory NHL.

Methods
Histologically confirmed NHL, > 1 prior therapy, age≥18, ECOG performance status 0–2, measurable disease, signed informed consent, creatinine and bilirubin < 2.0 x IULN as well as G6PD > IULN were required. Patients were treated with imexon 1000 mg/m2 IV daily on days 1-5 of a 21 day cycle for up to 1 year. Messenger RNA analysis was performed on pre-treatment tumor specimens, evaluating 22 genes important for antioxidant enzyme expression, 16 genes previously associated with outcome in NHL as well as 4 immune cell surface markers. Included were 13 genes used to generate a redox signature score, previously demonstrated to correlate with NHL prognosis (Tome, Blood 2005).

Results
Twenty-two NHL patients [9 FL, 5 diffuse large B cell (DLBCL), 3 mantle cell, 2 transformed follicular, 2 chronic lymphocytic leukemia and 1 Burkitt] with a median age of 64 (range 43-92) completed a median of 2.5 (range 1-13) cycles of therapy. With a median number of 4 prior therapies, 9 patients had undergone a prior stem cell transplant, 10 had stage IV disease and 6 were refractory to prior therapy. Twenty patients were evaluable for response, 2 pts discontinued therapy during cycle 1 due to progressive disease and grade 5 sepsis respectively. Of the 20 evaluable patients, the overall response rate was 30% (6/20) with another 35% achieving stable disease. Responses were observed in 4 FL and 2 DLBCL pts. After a median follow-up of 7 months, the median progression free survival (PFS) was 2.4 mos (range, 0.6 to 19.1 mos) with a median PFS of 6.7 mos (range, 1.2 to 9.0 mos) in FL patients. The median overall survival has not been reached. Grade 3 and 4 toxicities consisted of anemia (7 pts), thrombocytopenia (2 pts), neutropenia (2 pts), sepsis (2 pts), vomiting (2 pts), pneumonia (2 pts), fatigue (2 pts), dehydration (2 pts) as well as hypokalemia, hyperuricemia, transient ischemic attack, increased creatinine, rash and urinary tract infection in 1 pt each. 13 pts had available pre-treatment tumor biopsies, 2 of which attained a partial response with therapy. Patients with a higher redox score were more likely to achieve an objective response (p=0.03). Further, individual genes most predictive of response included CD68, GPX1 and SOD2.

Conclusions
This is the first trial to demonstrate that targeting the cellular redox environment is a viable therapeutic strategy in NHL and may be particularly effective in FL. The side effect profile may lend imexon to rational combination studies. Lymphomas reliant on antioxidant defense enzymes for proliferation and survival may be more susceptible to redox directed therapy. Evaluation of antioxidant related gene expression as a predictive biomarker is warranted in future investigations of imexon and similar targeted agents. (NCT01314014)

Disclosures:
Barr: Seattle Genetics: Consultancy; Celgene: Consultancy. Off Label Use: Imexon; being investigated for use in Non-Hodgkin lymphoma. Schwartz:HTG Molecular Diagnostics: Employment. Dorr:Amplimed Corporation: Employment.