In vitro and in vivo effects of pevonedistat on the antitumor activity of chemotherapy agents and B-cell receptor signaling inhibitors. In vitro exposure of a panel of MCL cell lines to pevonedistat potentiated the cytotoxic effects of bortezomib (A), bendamustine (B), or cytarabine (C). (D) Coefficient of synergy demonstrated that the combination of pevonedistat and cytarabine resulted in synergistic activity (green) in several MCL cell lines. (E) Pevonedistat exhibits synergistic activity in combination with cytarabine in a SCID-mouse model of MCL (C.B-Igh-1 b/lcrTac-Prkdcscid/Ros). The combination of pevonedistat (180 mg/kg per dose) and cytarabine (1000 mg/kg per dose) was more effective in controlling lymphoma growth and prolonging survival than pevonedistat or cytarabine as a single agent. Survival differences between groups were compared using log rank analysis. (F) In addition, pevonedistat exhibited synergistic activity when combined with ibrutinib or GS1101.
