The Novel Bruton'S Tyrosine Kinase Inhibitor Acp-196 Shows In Vivo Efficacy Against Human Chronic Lymphocytic Leukemia Cells Xenografted To The Nsg Mouse Model

Background: Targeting Bruton9s tyrosine kinase (BTK), an essential kinase in the B cell receptor (BCR) pathway in patients with chronic lymphocytic leukemia (CLL) has proven very effective. For the first generation BTK inhibitor ibrutinib, clinical response rates >70% and 75% progression free survival >2 years have been reported for previously treated patients (Byrd, NEJM, 2013). ACP-196 is a novel, second generation, irreversible BTK inhibitor that may show advantages in terms of binding specificity and drug-drug interactions compared to the first generation BTK inhibitor. Survival and proliferation of CLL cells is highly dependent on microenvironment interaction, which must be taken into consideration when testing new drugs for CLL. We have previously shown that human CLL cells engrafted in the spleen of NSG mice have comparable tumor biology to human lymph node resident CLL cells (Herman, Leukemia, 2013). We here demonstrate the in vivo effects of ACP-196 monotherapy against CLL cells in the NSG xenograft model. Methods: Peripheral blood mononuclear cells from previously untreated CLL patients were injected intravenously into NSG mice. Mice received ACP-196 through the drinking water. The effect of ACP-196 on xenografted CLL cells from peripheral blood and spleen was assessed by flow cytometry. Results: At all dose levels tested, ACP-196 significantly inhibited proliferation of human CLL cells in the spleens of NSG mice, as measured by Ki67 expression (P=0.002). The mean Ki67 decrease was 58%, 70% and 73%, respectively for the low, intermediate, and high dose level compared with vehicle. Tumor burden in spleens from mice treated with the high dose of ACP-196 decreased compared with the vehicle treated group (P=0.007). As seen with other BCR inhibitors, ACP-196 transiently increased CLL cell counts in the peripheral blood in a dose dependent manner (p=0.01). ACP-196 inhibited BCR signaling in vivo, as demonstrated by reduced phosphorylation of PLCγ2. Conclusions: Results presented here for ACP-196 are in accordance with the expected profile of an irreversible BTK inhibitor. The NSG CLL xenograft model will be used for comparative testing of different BTK inhibitors and exploration of combination therapies. Citation Format: Carsten U. Niemann, Arnau Montraveta, Sarah E. M. Herman, Tim Ingallinera, Tjeerd Barf, Dolors Colomer, Adrian Wiestner. The novel Bruton9s tyrosine kinase inhibitor ACP-196 shows in vivo efficacy against human chronic lymphocytic leukemia cells xenografted to the NSG mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2624. doi:10.1158/1538-7445.AM2014-2624