Abstract 4797: The combination of ACP-196 and ACP-319 leads to increased survival in the TCL1-192 CLL mouse model

Abstract

Abstract INTRODUCTION: Recent advances in the treatment of CLL focus on targeting the B-cell receptor (BCR) pathway, which is strongly upregulated in CLL. The BTK inhibitor ibrutinib and the PI3Kä inhibitor idelalisib, both targeting the BCR pathway, are approved for clinical use based on significant survival benefit in clinical trials. In vitro studies have shown synergy for combined PI3Kä and BTK inhibition (Griner, PNAS, 2014). Since CLL propagation relies on the microenvironment, in vivo models are needed for better testing of new drug combinations. We tested two new inhibitors of the BCR pathway, the BTK inhibitor ACP-196 and the PI3Kä inhibitor ACP-319 as single agents and in combination using the murine TCL1-192 allograft model of aggressive, BCR driven CLL. METHODS: TCL1-192 cells were injected into SCID mice and drug was given through the drinking water with vehicle, ACP-196, ACP-319 or a combination of the two drugs at a concentration of 0.15 mg/mL of each drug. Blood was analyzed weekly by flow cytometry and at the end of the study spleens were weighed and analyzed by flow cytometry. RESULTS: Tumor burden in the blood significantly decreased with both single agent and combination treatment compared to vehicle, and with single agent compared to combination, P < 0.05, P < 0.0001 and P < 0.0075, respectively. Combination treatment also resulted in significantly lower spleen weights when compared to spleens from mice treated with single agents or vehicle. Both single agent and combination treatment led to decreased phosphorylation of PLCã2, NFêB and ERK, molecules downstream in the BCR pathway, P < 0.05 compared to vehicle treated mice. Phosphorylation of PLCã2 and NFêB was further decreased with combination treatment compared to single agent treatment. Both single agent and combination treatment greatly enhanced survival of the mice compared to vehicle treatment with a median survival from treatment start of 17 days (vehicle), 23 days (single agent) and 40 days (combination), P < 0.0001 for single agent vs to combination treatment. CONCLUSION: We here show that a combination of ACP-196 (BTK inhibitor) and ACP-319 (PI3Kä inhibitor) is superior to single agent treatment in the murine TCL1-192 model of aggressive, BCR-driven CLL. Survival was significantly increased by combination treatment and the tumor burden was significantly reduced compared to both single agent mice and vehicle treated mice. The on-target effects were validated by reduced phosphorylation of PLCã2 and NFêB. Thus, evaluation of combination treatment with ACP-196 and ACP-319 in clinical trials is warranted. Citation Format: Helena I. Mora-Jensen, Carsten U. Niemann, Michael Gulrajani, Fanny Krantz, Todd Covey, Brian J. Lannutti, Adrian Wiestner, Sarah EM Herman. The combination of ACP-196 and ACP-319 leads to increased survival in the TCL1-192 CLL mouse model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4797.