Combination treatment with PRT382 and venetoclax is synergistic in vivo. (A) Schematic showing the setup of in vivo experiments. Mice were engrafted on day 0, and weekly bleeds with flow cytometry were used to assess the circulating disease burden. Once ∼1% of the circulating lymphocytes were MCL cells (huCD5+/huCD19+), treatment began. Mice were treated with each single agent or the combination for 4 days on, 3 days off. (B) Kaplan-Meier curve showing survival of the PDX.AA.MCL model. Median survival was 58 days for vehicle, 63 days for PRT, 73 days for venetoclax, and the combo did not reach a median survival by the experiment’s end of 101 days P < .0001. (C) A graph of circulating disease burden over time in the PDX.AA.MCL model is measured as a percentage of huCD5+/huCd19+ cells in the lymphoid compartment. (D) Kaplan-Meier curve showing the survival of the PDX.IR.96069 model. The median survival was 53 days for vehicle and 77 days for PRT. The venetoclax and combo groups did not reach a median survival by the experiment’s end at 104 days. (E) A graph of circulating disease burden over time in the PDX.IR.96069 model measured as a percentage of huCD5+/huCd19+ cells in the lymphoid compartment. (F) Immunohistochemistry of FOXO1 (brown) of a control and PRT382-treated mouse spleen. Scale bars, 100 μm. (G) Western blot showing BAX expression of cells from vehicle or PRT382-treated mice. Values are adjusted by GAPDH loading control and normalized against lane 1. A log-rank test for trend was performed on the survival data in panels B,D. Generalized estimating equations with an autoregressive correlation structure were used to compare the disease burden over time in panels C,E. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001.