Combination of AZD5991 and CHOP. (A) Dynamic BH3 profiling indicating changes in apoptotic priming and MCL1 dependence induced by doxorubicin (250 nM) or vincristine (100 nM). Peptide concentrations were 0.3 µM for BIM and 1 µM for MS1. Bar graphs indicate ≥2 replicates of a representative experiment. Statistics was performed with 2-way analysis of variance and Bonferroni test. (B) Tumor volume of mice engrafted with WCTL-91953 and treated with either vehicle, CHOP, AZD5991, or CHOP+AZD5991. (C) Survival of mice engrafted with WCTL-91953 and treated with either vehicle, CHOP, AZD5991. or CHOP+AZD5991. CHOP: 1 cycle, d1-d5; AZD5991: d1 and d2 weekly for 3 weeks; n = 6 per arm. The green line indicates a calculated additive model, with 95% confidence intervals indicated as a green shaded range. P value of synergy of AZD5991+CHOP over additivity: 0.024. (D) BH3 profile of the hepatosplenic TCL PDX CBTL-81777. BIM concentrations as indicated, BAD, 80 μM; MS1, 10 μM. (E) Peripheral blood disease burden of mice engrafted with CBTL-81777 as assessed by hCD45/hCD2⁺ cells on days 0 and 6 after treatment with vehicle, CHOP, AZD5991, or CHOP+AZD5991. (F) BH3 profiles of mice engrafted with CBTL-81777, treated with either vehicle or CHOP (n = 3 per arm), and euthanized 48 hours after initiation of treatment. MS1 peptide, 1 µM; AZD5991, 1 µM. Bar graphs indicate ≥2 biological replicates (1 CHOP-treated sample was censored because of low quality). Statistics were performed with 2-way analysis of variance and Bonferroni test. (G) Survival of mice engrafted with CBTL-81777 and treated with either vehicle, CHOP, AZD5991, or CHOP+AZD5991. CHOP, 1 cycle, d1-d5; AZD5991, d1 and d2 weekly; n = 6 per arm. The green line indicates a calculated additive model, with 95% confidence intervals indicated as a green shaded range. P value of synergy of AZD5991+CHOP over additivity: .0005. All data points indicate mean values; error bars indicate standard error of the mean. *P < .05; **P < .01; ***P < .001; ****P < .0001.