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Venetoclax enhances FLT3-ITD inhibition in AML
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Figure 4. BCL-2, BCL-XL and MCL-1 contribute to sur- vival of FLT3-ITD+ cells in vivo. NOD/SCID/IL-2RĪ³null (NSG) mice were engrafted with luciferase expressing MV4;11 cells and leukemic engraftment was con- firmed by BLI and treatment began 14 days post inoc- ulation. Mice were treated orally with 5 mg/kg quizar- tinib, 100 mg/kg venetoclax, 100 mg/kg navitoclax or 10 mg/kg AMG 176 as single agents or in combina- tions as indicated once daily for 21 days. All treat- ment groups were run concurrently, however for clar- ity survival data has been split between panels A and B and vehicle, quizartinib, venetoclax, navitoclax and AMG 176 single agent groups have been plotted in both panels for reference. (A) Kaplan-Meier survival curves for quizartinib in combination with AMG 176, venetoclax or navitoclax. N=8-10 animals/group. Median survival and statistics were determined by log-rank test: *P=0.0059 for quizartinib + venetoclax vs. quizartinib + AMG 176; and **P=0.0095 for quizartinib + navitoclax vs. quizartinib + AMG 176. (B) Kaplan-Meier survival curves for AMG 176 in combi- nation with venetoclax or navitoclax. N=8-10 ani- mals/group. Median survival and statistics were determined by log-rank test: *P=0.0008 for veneto- clax + AMG 176 vs. quizartinib; and **P=0.0002 for navitoclax + AMG 176 vs. quizartinib. (C) Quantitation of the bioluminescence imaging (BLI) signal from MV4;11-engrafted mice in each group at indicated time post-inoculation: *P<0.005 for quizartinib single agent and all combinations vs. venetoclax, AMG 176 or navitoclax single agents at week 5 by one-way ANOVA with Tukey post-test; **P<0.05 for quizartinib + venetoclax, quizartinib + navitoclax, quizartinib + AMG 176 and navitoclax + AMG 176 vs. quizartinib single agent on week 7 by one-way ANOVA with Dunnett post-test; ***P=0.0001 for quizartinib + venetoclax, quizartinib + navitoclax, quizartinib + AMG 176, venetoclax + AMG 176 and navitoclax + AMG 176 vs. single agent quizartinib at week 9 by one-way ANOVA with Dunnett post-test.
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