Abstract LB-261: Targeting BET Family Bromodomain with ABBV-075 and BCL-2 with venetoclax (ABT-199) is synergistic in primary acute myeloid leukemia models

Despite advances in understanding of the biology of acute myeloid leukemia (AML), cure remains elusive for the majority of patients. ABBV-075 is a potent and selective BET family bromodomaininhibitor that entered phase I clinical trials. ABT-199 ( Venetoclax) is a small-molecule BH3 mimetic that selectively inhibits BCL-2 causing cell death. ABBV-075 and Venetoclaxwere recently shown to be synergistic in AML cell lines ( Bui MH, Cancer Res 2017 ). In this study, we evaluated the anti-leukemia effects of concomitant BCL-2 blockade by venetoclaxin combination with BET inhibitorABBV-075 in primary AML samples. First, anti-leukemia activity of venetoclaxand ABBV-075 was examined in 12 primary AML samples with diverse genetic alterations. The combination significantly enhanced cell death (71.2 ± 29.3 %), as compared to the single agent treatment (51.4 ± 32.2 % in venetoclax10 nM group and 32.8 ± 21.7% in ABBV-075 20 nM group). ABBV-075 inhibited cell proliferation in the majority of AML cases (51.3 ± 30.9 %) and the cell growth suppression was more profound in the combination group (87.9 ± 18.8 %, p ). Most importantly, three of 12 patients were resistant to venetoclax, but two of 3 were sensitive to ABBV-075 or ABBV-075/ venetoclaxcombination. We next performed the whole genome transcriptome analysis of pre-treatment AML cells by RNA-sequencing (RNA-seq). The samples which were sensitive to venetoclaxand the combination with ABBV-075 were characterized by high level of BCL2 and mid-low level of MCL1expression. In samples with low level of AR, IL1R1expression and high CCND1 expression, the combination of venetoclaxand ABBV-075 was synergistic in inducing AML cell death. To test the efficacy in vivo, we established a patient-derived xenograft (PDX) from an AML patient with FLT3-ITD, DNMT3A, IDH1and NPM1mutation in NSG mice. Upon engraftment, mice were randomized to receive vehicle, single agent venetoclaxat 50 mg/kg for 21 days, ABBV-075 at 0.5 mg/kg for 21 days; or venetoclaxat 50 mg/kg plus ABBV-075 at 0.5 mg/kg for 21 days. After 21 days treatment, flow cytometry data demonstrated significantly reduced leukemia burden in treated groups (7.9 ± 5.9 % in venetoclaxgroup and 12.2 ± 5.1 % in ABBV-075 group) compared to controls (33.0 ± 12.2 %), more prominently in the combination group (1.9 ± 0.8 %). In summary, combinatorial blockade of BET family bromodomainand BCL-2 pathways promotes apoptotic cell death and suppresses proliferation in the majority of primary AML cells. Ongoing studies will evaluate efficacy of this combination therapy in 10 additional primary human AML xenografts and elucidate mechanisms of synergy. Citation Format: Tianyu Cai, Vinitha Mary Kuruvilla, Tamar Uziel, Qi Zhang, Lina Han, Antonio Cavazos, Yu Shen, Marina Konopleva. Targeting BET Family Bromodomainwith ABBV-075 and BCL-2 with venetoclax(ABT-199) is synergistic in primary acute myeloid leukemia models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-261.