The VEN plus SOR and SAV combinations induced deep, long remissions in MOLM14 and MV4;11 AML xenografts. (A) Schedule for drug treatment and BLI. Drugs (50 mg/kg/d ART838, 150 mg/kg/d VEN, and/or 30 mg/kg/d SOR) were administered by mouth (via gavage) on this 5-day on/9-day off schedule for ≥5 identical 5-day treatment cycles. (B-D) NRG mice were transplanted IV with luc/YFP-labeled MOLM14 AML cells or (E-G) luc/YFP-labeled MV4;11 AML cells 10 days prior to initial BLI. Based on Xenogen quantification of baseline luminescence on day 0, mice were placed into experimental groups balanced for luminescence (5 mice per group), and drug treatment initiated. (B,E) BLI of each mouse for the initial 21 days and last imaging day (day 98 in panel B, day 70 in panel E of these 2 experiments involving AML xenograft-bearing mice treated with either vehicle, 2-drug, or SAV combinations). Luminescence intensity color coding was scaled to the same minimum and maximum across all individual experiments. (C,F) Waterfall plots representing fold-change in luminescence on day 7 vs day 0 for each mouse. (D,G) Kaplan-Meier survival curves. Experiments were terminated on day 103 for MOLM14 AML and day 91 for MV4;11 AML (vertical dotted line). One SAV mouse (D) and 1 ART838 plus SOR mouse (G) died unexpectedly with low AML burden and were censored. (D) Comparisons of vehicle vs ART838 plus VEN, vehicle vs ART838 plus SOR, vehicle vs VEN plus SOR, vehicle vs SAV, SAV vs ART838 plus VEN, SAV vs ART838 plus plus SOR all have P < .005. (G) Comparisons of vehicle vs ART838 plus VEN, vehicle vs ART838 plus SOR, vehicle vs VEN plus SOR, vehicle vs SAV, SAV vs ART838 plus VEN have P ≤ .005; SAV vs ART838 plus SOR all have P < .05. P values were calculated by log-rank (Mantel-Cox) test. (H) 3 similar MOLM14 AML and 4 similar MV4;11 AML xenograft treatment experiments were performed, and results summarized. Treatment response outcomes were: Leukemia response quantitation via fold change in AML burden (luminescence) on day 7 vs day 0 for each mouse (geometric means for each treatment group were averaged across all experiments); survival (fold change in median survival vs vehicle; fold changes were averaged for each treatment group across all experiments). In the survival columns, > indicates that groups contained mice with no detectable luminescence (above background, 5.7 × 10⁵ photons per mouse based on intensity values from nonleukemia-bearing mice) on the last BLI done in the experiment. In the aggregated results of all experiments using the MOLM14 AML model, 7 mice (70%) had no detectable luminescence (above background) after treatment with VEN plus SOR and 8 mice (42%) with SAV (at 42-101 days after treatment completion). In the aggregated results of all experiments using the MV4;11 AML model, 9 mice (69%) had no detectable luminescence (above background) after treatment with VEN plus SOR and 10 mice (42%) with SAV (at 9-45 days after treatment completion). Inverse association between the fold-change (day 7/d 0) in AML burden and the fold-change in median survival relative to vehicle for MOLM14 or MV4;11 AML were calculated using the Spearman rank correlation coefficient. nd, not done; “X”, mouse death.