Clinical Results of Gemox-R in Mantle CELL Lymphoma: The Role of Oxaliplatin

Introduction: Mantle cell lymphoma (MCL) is mostly incurable. The current standard therapy achieves a high rate of complete remission (CR), but the pattern of continuous relapses still marks this disease as a challenge. We previously reported the efficacy of GemOx-R, a combination regimen of gemcitabine, oxaliplatin and rituximab, in patients with refractory and relapsing MCL. Our aim is to confirm our previous results in a larger retrospective series and evaluate the efficacy of each component of GemOx-R in a panel of MCL cell lines and in patient-derived primary cells.

Methods: Between 2003 and 2015, 30 patients with MCL were included in a retrospective study of treatment with GemOx-R from the University Hospital Son Espases: 10 cases frontline and 20 in the salvage setting. Frontline cohort was consolidated with radioimmunotherapy and received maintenance therapy with rituximab. The translational study was performed in established cell lines as well as primary MCL lines from patients by cell viability, cell cycle, apoptosis and western blot analysis. Drug synergy was determined by the isobologram and combination index methods.

Results: This is a high risk series of patients: median age 70 years, 87% stage IV and 86% intermediate or high risk MIPI. Overall response rate and CRR was 80% and 60% in the frontline cohort as well as 85 % and 60% for salvage patients, respectively. Median progression-free survival was 28 months in the entire series: 66 and 22 months, respectively, for the two cohorts. Median overall survival was 34 months in the entire series: not reached and 20 months, respectively, for the two cohorts. Grade 3 and 4 toxicity was as follows: neutropenia (63%), anemia (34%) and thrombocytopenia (30%) as well as 24% of grade 1 and 2 neurotoxicity. Cell viability and apoptosis analysis showed that oxaliplatin is the most effective drug in this regimen in contrast to the poor responses induced by gemcitabine and rituximab. Oxaliplatin had a profound effect on cellular viability, consistent with the induction of caspase activityand the downregulation of pro-survival proteins. We further present synergistic efficacy of oxaliplatin combined with cytarabine in MCL cells.

Conclusions: (1) GemOx-R shows excellent results in MCL both in the frontline and salvage settings considering the high risk patients included. (2) Oxaliplatin is the most effective drug in GemOx-R; (3) oxaliplatin has a robust in vitro activity comparable to that of cytarabine, and the combination of both oxaliplatin and cytarabine shows a significant synergism; (4) taken together, our findings suggest that oxaliplatin alone or combined with cytarabine could constitute a new or alternative backbone for promising new regimens in MCL.