Abstract 3831: Selective targeting BET family BDII bromodomain with ABBV-744 and BCL-2 with venetoclax (ABT-199) is synergistic in primary acute myeloid leukemia models
Authors: Cai Tianyu , Kuruvilla Vinitha , Lin Xiaoyu , Uziel Tamar , Lu Xin , Zhang Lu , Zhang Qi , Han Lina , Cavazos Antonio , Shen Yu , Konopleva Marina 
Published: August 2019

Despite advances in understanding of the biology of acute myeloid leukemia (AML), cure remains elusive for the majority of patients. ABT-199 (Venetoclax) is a small-molecule BH3 mimetic that selectively inhibits BCL-2 causing cell death. ABBV-744 is a highly selective inhibitor for the BDII of BET family proteins, exhibiting greater than 300-fold more potent binding affinity to the BDII bromodomain of BRD4 relative to BDI (Warren Kati AACR 2018; Xiaoyu Lin AACR 2018). In this study, we evaluated the anti-leukemia efficacy of the concomitant BCL-2 blockade by venetoclax and of BDII inhibition with ABBV-744 in primary AML samples.

First, anti-leukemia activity of venetoclax and ABBV-744 was examined in 12 primary AML samples with diverse genomic alterations. The combination significantly enhanced cell death (61.4% ± 8.7%), as compared to the single agent treatment (51.4% ± 9.3% in venetoclax 10 nM group and 22.2% ± 3.4% in ABBV-744 50 nM group, p&lt;0.001). ABBV-744 inhibited cell proliferation in the majority of AML cases (31.7% ± 8.2 %), and the cell growth suppression was more profound in the combination group (82.9% ± 6.9%, p&lt;0.001). Most importantly, three of 12 patients were resistant to venetoclax, but two of these were sensitive to ABBV-744 or ABBV-744/venetoclax combination. We next performed the whole genome transcriptome analysis of pre-treatment AML cells by RNA-sequencing (RNA-seq). The samples which were sensitive to venetoclax and to the combination with ABBV-744 were characterized by high levels of BCL2 and mid-low level of MCL1 expression. In addition, low mRNA expression of AR, IL1R1 expression and high CCND1 expression correlated with response of primary AML cells to the combination of venetoclax and ABBV-744.

To test the efficacy of this regimen in vivo, we established a patient-derived xenograft (PDX) from an AML patient in NSG mice. After 21 days of therapy, flow cytometry data demonstrated significantly reduced leukemia burden in venetoclax treated group (9.5% ± 1.7%) but not in ABBV-744 group (22.3% ± 5.8%) compared to controls (30.8% ± 3.9%), with lowest tumor burden in the combination group (5.0% ± 0.8%, p&lt;0.01). No significant impact on mice’ weight was noted, and no clinical signs of toxicity recorded over the course of therapy. The experiment is ongoing, and the survival analysis will be reported.

Next, the anti-leukemia efficacy of ABBV-744 was tested in 7 additional AML PDX models. In all of the 7 models, Combination of ABBV-744 and venetoclax treatment delayed AML progression compared to untreated mice (survival days: 141 vs 105, 275 vs 153, 62 vs 46, 136 vs 119, 138 vs 77, 129 vs 116, 94 vs 86).

In summary, combinatorial blockade of BDII bromodomain and of BCL-2 anti-apoptotic pathway facilitates apoptotic cell death and suppresses proliferation in the majority of primary AML cells and produces anti-AML activity in AML PDX models in vivo.

Citation Format: Tianyu Cai, Vinitha Kuruvilla, Xiaoyu Lin, Tamar Uziel, Xin Lu, Lu Zhang, Qi Zhang, Lina Han, Antonio Cavazos, Yu Shen, Marina Konopleva. Selective targeting BET family BDII bromodomain with ABBV-744 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 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3831.