![The novel dual BCL2/BCL-XL inhibitor AZD0466 outperformed single BCL2 inhibition in a PDX T-ALL model. (A) Schematic study design. Recipient mice were irradiated at 250 cGy 24 hours before injection of cells. All mice were injected with 1 × 106 cells via the tail vein. Mice with established baseline levels of leukemic burden with 0.5% to 5% of circulating leukemia cells in the peripheral blood were randomized into 6 groups. Treatment was started with vehicle, AZD0466 inhibitor (34 mg/kg; administered IV weekly for 4 weeks), low-dose VXL therapy (intraperitoneally once weekly for 4 weeks; dexamethasone [5 mg/kg], vincristine [0.15 mg/kg]; and L-asparagine [1000 IU/kg, ∼25 IU per mouse]) were used. (B) Bone marrow engraftment in mice inoculated with the PDX T-ALL model D115 evaluated 4 weeks after treatment initiation. Mean ± SD indicated in the figure (number of mice analyzed n = 3 per treatment arm). The statistical differences between 2 separate treatments were evaluated by an unpaired Student t test, ∗∗∗∗P < .0001. (C) Reduction of platelets upon AZD0466 shows no statistically significant reduction as monotherapy or combination therapy with VXL. The statistical differences between 2 separate treatments were evaluated by an unpaired Student t test, ∗P = 0.02. (D) Body weight monitoring over time. Average body weight of PDX T-ALL D115 mice were derived from the experiments illustrated in above panel A. Mice were weighed as individuals 24 hours before weekly treatments. The statistical differences between 2 separate treatments were evaluated by an unpaired Student t test; week 3: vehicle vs combo, ∗∗P = 0.002, vehicle vs VXL, ns = 0.07, 0466 vs combo, ∗∗∗P = 0.0006; week 5: vehicle vs combo, ∗∗∗P = 0.0003, vehicle vs VXL, ∗∗∗P = 0.0004, 0466 vs combo, ∗∗P = 0.005. (E) Kaplan-Meier survival curves of mice bearing T PDX -ALL model D115, treated with vehicle, AZD0466, VXL, or combination. Percentages of survival of mice from study cohorts in panel A are shown. The differences in survival between the 2 groups were compared by Gehan-Breslow-Wilcoxon test, (n = 3 mice per group): ∗P = .01, ∗∗P = .0062, ∗∗∗∗P < .0001. All calculations were performed using GraphPad prism statistical software version 9. BM, bone marrow; ns, not significant.](https://ash.silverchair-cdn.com/ash/content_public/journal/bloodadvances/9/3/10.1182_bloodadvances.2024013423/3/blooda_adv-2024-013423-gr6.jpeg?Expires=1743302280&Signature=ewZDD2Erh35sePO55Mr6wJOCLUpgMawKACwjJi9t3G2Api3uczOWzMcNB0qS-IOWXVbAcjAU1gEyWKUbPwq~GQZojb5SPTLzDG14ZvmhUhz6R23r4tuqMWQgspJ2qgSBeqp8B1VQggvpHbYttTA68xNtljV9px94~xQekm62vGpppiAw~bZYXleqNLq1DzZf~ii4q96ti5ojHQgxv12B8sQeE-rqptWURf9Fkm6oGW0siyMSo6-E8EpokBRlB7G4Hk8rsR~qv2mqTpC5aFUloSbxQcFAK60uFBdXbivrgw8wIJyGRYbOv4pmGwEoCPGSIMBy63QC7VDJLFGCArCpbA__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
The novel dual BCL2/BCL-XL inhibitor AZD0466 outperformed single BCL2 inhibition in a PDX T-ALL model. (A) Schematic study design. Recipient mice were irradiated at 250 cGy 24 hours before injection of cells. All mice were injected with 1 × 106 cells via the tail vein. Mice with established baseline levels of leukemic burden with 0.5% to 5% of circulating leukemia cells in the peripheral blood were randomized into 6 groups. Treatment was started with vehicle, AZD0466 inhibitor (34 mg/kg; administered IV weekly for 4 weeks), low-dose VXL therapy (intraperitoneally once weekly for 4 weeks; dexamethasone [5 mg/kg], vincristine [0.15 mg/kg]; and L-asparagine [1000 IU/kg, ∼25 IU per mouse]) were used. (B) Bone marrow engraftment in mice inoculated with the PDX T-ALL model D115 evaluated 4 weeks after treatment initiation. Mean ± SD indicated in the figure (number of mice analyzed n = 3 per treatment arm). The statistical differences between 2 separate treatments were evaluated by an unpaired Student t test, ∗∗∗∗P < .0001. (C) Reduction of platelets upon AZD0466 shows no statistically significant reduction as monotherapy or combination therapy with VXL. The statistical differences between 2 separate treatments were evaluated by an unpaired Student t test, ∗P = 0.02. (D) Body weight monitoring over time. Average body weight of PDX T-ALL D115 mice were derived from the experiments illustrated in above panel A. Mice were weighed as individuals 24 hours before weekly treatments. The statistical differences between 2 separate treatments were evaluated by an unpaired Student t test; week 3: vehicle vs combo, ∗∗P = 0.002, vehicle vs VXL, ns = 0.07, 0466 vs combo, ∗∗∗P = 0.0006; week 5: vehicle vs combo, ∗∗∗P = 0.0003, vehicle vs VXL, ∗∗∗P = 0.0004, 0466 vs combo, ∗∗P = 0.005. (E) Kaplan-Meier survival curves of mice bearing T PDX -ALL model D115, treated with vehicle, AZD0466, VXL, or combination. Percentages of survival of mice from study cohorts in panel A are shown. The differences in survival between the 2 groups were compared by Gehan-Breslow-Wilcoxon test, (n = 3 mice per group): ∗P = .01, ∗∗P = .0062, ∗∗∗∗P < .0001. All calculations were performed using GraphPad prism statistical software version 9. BM, bone marrow; ns, not significant.
