Figure 3.
Eftoza in combination with venetoclax reduces tumor burden and improves survival in patient-derived preclinical models of AML. (A) CD45+ cells from patients with naive (n = 45) and R/R (n = 19) primary AML were treated ex vivo with either eftoza (5 nM), venetoclax (1 μM; VEN), or eftoza and venetoclax in combination for 24 hours, and the impact on viability determined from the Annexin V/-7AAD–positive population via flow cytometry compared with the dimethyl sulfoxide-treated control. The resulting data were further segregated to assess treatment responses in samples from patients with AML who were R/R to venetoclax (or collected while on venetoclax-based therapies; n = 7) or harbored TP53 mutations (n = 15). Statistical difference was determined using a Friedman test, in which ∗∗P < .01 and ∗∗∗∗P < .0001 were considered significant. (B) Disseminated AML PDX models were treated with huIgG1 (5 mg/kg, q2d × 5, IP), eftoza (5 mg/kg, q2d × 5, IP), venetoclax (50 mg/kg, qd × 21, po), or eftoza and venetoclax in combination at identical monotherapy doses and schedules, and the impact on tumor burden was determined in the bone marrow a week after the end of treatment (n = 5 mice per treatment). Median response is shown for each treatment (red bar). Flow cytometry histograms depict the percentage of DR4 (red) and DR5 (green) plasma membrane expression of huIgG1-treated AML cells harvested from the bone marrow of inoculated mice at the end of study. Gray represents the isotype negative control. Statistical difference was determined using a one-way analysis of variance with Tukey's post hoc test, for which ∗P < .05, ∗∗P < .01, and ∗∗∗∗P < .0001 were considered significant. (C) Patient-derived AML peripheral blood mononuclear cells were isolated by leukapheresis and injected into whole-body irradiated NOG-F mice. In 8 to 12 weeks, bone marrow engraftment was confirmed, and the mice were treated with vehicle, eftoza (3 mg/kg, q2d × 5, IP), venetoclax (50 mg/kg, qd × 21, po), or eftoza and venetoclax in combination, and the impact on survival (n = 8 mice per group) either after 20- or 28-day treatment was assessed. Statistical difference was determined using the Mantel-Cox test (supplemental Table 6). huIgG1, human immunoglobulin G1; ns, not significant; po, by mouth; qd, daily; q2d, every other day.

Eftoza in combination with venetoclax reduces tumor burden and improves survival in patient-derived preclinical models of AML. (A) CD45+ cells from patients with naive (n = 45) and R/R (n = 19) primary AML were treated ex vivo with either eftoza (5 nM), venetoclax (1 μM; VEN), or eftoza and venetoclax in combination for 24 hours, and the impact on viability determined from the Annexin V/-7AAD–positive population via flow cytometry compared with the dimethyl sulfoxide-treated control. The resulting data were further segregated to assess treatment responses in samples from patients with AML who were R/R to venetoclax (or collected while on venetoclax-based therapies; n = 7) or harbored TP53 mutations (n = 15). Statistical difference was determined using a Friedman test, in which ∗∗P < .01 and ∗∗∗∗P < .0001 were considered significant. (B) Disseminated AML PDX models were treated with huIgG1 (5 mg/kg, q2d × 5, IP), eftoza (5 mg/kg, q2d × 5, IP), venetoclax (50 mg/kg, qd × 21, po), or eftoza and venetoclax in combination at identical monotherapy doses and schedules, and the impact on tumor burden was determined in the bone marrow a week after the end of treatment (n = 5 mice per treatment). Median response is shown for each treatment (red bar). Flow cytometry histograms depict the percentage of DR4 (red) and DR5 (green) plasma membrane expression of huIgG1-treated AML cells harvested from the bone marrow of inoculated mice at the end of study. Gray represents the isotype negative control. Statistical difference was determined using a one-way analysis of variance with Tukey's post hoc test, for which ∗P < .05, ∗∗P < .01, and ∗∗∗∗P < .0001 were considered significant. (C) Patient-derived AML peripheral blood mononuclear cells were isolated by leukapheresis and injected into whole-body irradiated NOG-F mice. In 8 to 12 weeks, bone marrow engraftment was confirmed, and the mice were treated with vehicle, eftoza (3 mg/kg, q2d × 5, IP), venetoclax (50 mg/kg, qd × 21, po), or eftoza and venetoclax in combination, and the impact on survival (n = 8 mice per group) either after 20- or 28-day treatment was assessed. Statistical difference was determined using the Mantel-Cox test (supplemental Table 6). huIgG1, human immunoglobulin G1; ns, not significant; po, by mouth; qd, daily; q2d, every other day.

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