Paired combinations of idasanutlin, cladribine, venetoclax, and romidepsin demonstrate marked efficacy and selectivity against T-PLL, with idasanutlin and cladribine being particularly synergistic. (A-B) Combination screen for efficacy and synergy of combinations of idasanutlin, cladribine, venetoclax, romidepsin, dinaciclib, bendamustine, ruxolitinib, and ibrutinib in 20 primary T-PLL samples after 72 hours of treatment. After thawing, 5 × 105 primary T-PLL cells per mL in 25 μL were treated with the substance combinations for 72 hours (see supplemental Table 2 for the respective concentrations). Cell viability was assessed using the CTG assay. 1:1 combinations of 7 doses for each drug were used in pairwise drug combination testing, following predictions with the DECREASE model to fill the full drug combination dose-response matrixes.49 SynToxProfiler50 was used to calculate combination efficacies, using the normalized volume under the dose-response area. SynergyFinder51 and the Zero Interaction Potency (ZIP) model52 were used to score the combination synergies. Only those drug concentrations that killed a maximum of 50% of the healthy-donor-derived control PBMCs (n = 2) were included (TC50). Box plots showing the efficacy (A) and synergy (B) across all tested combinations. The 5 most T-PLL–specific combinations are highlighted in blue. (C) Dose-response curves of T-PLL cases (n = 7) as well as age-matched, healthy donor–derived PBMCs (n = 4) and CD3+ T cells (n = 4), treated with increasing concentrations of the 5 most effective combinations (1:1 dose ratios) for 48 hours. Apoptosis was measured using flow cytometry–based AnnV/7AAD analyses (mean of the average of individual responses with SEM; 1-way ANOVA, Bonferroni correction for multiple comparisons; ∗∗P < .01; ∗∗∗P < .001). Supplementing data includes supplemental Figure 5 with heat maps showing patient-specific efficacies and synergies of this combination screening; supplemental Figure 6 with coculture experiments with NKtert cells, testing the most promising combinations; supplemental Figure 7 for a combination screen in selected 14 T-cell leukemia/lymphoma lines, assessing the efficacy of pairwise combinations of cladribine, idasanutlin, venetoclax, and romidepsin. Benda, bendamustine; Cladri, cladribine; Dina, dinaciclib; Ibru, ibrutinib; Ida, idasanutlin; Romi, romidepsin; Ruxo, ruxolitinib; Veneto, venetoclax.
Figure 4.

Paired combinations of idasanutlin, cladribine, venetoclax, and romidepsin demonstrate marked efficacy and selectivity against T-PLL, with idasanutlin and cladribine being particularly synergistic. (A-B) Combination screen for efficacy and synergy of combinations of idasanutlin, cladribine, venetoclax, romidepsin, dinaciclib, bendamustine, ruxolitinib, and ibrutinib in 20 primary T-PLL samples after 72 hours of treatment. After thawing, 5 × 105 primary T-PLL cells per mL in 25 μL were treated with the substance combinations for 72 hours (see supplemental Table 2 for the respective concentrations). Cell viability was assessed using the CTG assay. 1:1 combinations of 7 doses for each drug were used in pairwise drug combination testing, following predictions with the DECREASE model to fill the full drug combination dose-response matrixes.49 SynToxProfiler50 was used to calculate combination efficacies, using the normalized volume under the dose-response area. SynergyFinder51 and the Zero Interaction Potency (ZIP) model52 were used to score the combination synergies. Only those drug concentrations that killed a maximum of 50% of the healthy-donor-derived control PBMCs (n = 2) were included (TC50). Box plots showing the efficacy (A) and synergy (B) across all tested combinations. The 5 most T-PLL–specific combinations are highlighted in blue. (C) Dose-response curves of T-PLL cases (n = 7) as well as age-matched, healthy donor–derived PBMCs (n = 4) and CD3+ T cells (n = 4), treated with increasing concentrations of the 5 most effective combinations (1:1 dose ratios) for 48 hours. Apoptosis was measured using flow cytometry–based AnnV/7AAD analyses (mean of the average of individual responses with SEM; 1-way ANOVA, Bonferroni correction for multiple comparisons; ∗∗P < .01; ∗∗∗P < .001). Supplementing data includes supplemental Figure 5 with heat maps showing patient-specific efficacies and synergies of this combination screening; supplemental Figure 6 with coculture experiments with NKtert cells, testing the most promising combinations; supplemental Figure 7 for a combination screen in selected 14 T-cell leukemia/lymphoma lines, assessing the efficacy of pairwise combinations of cladribine, idasanutlin, venetoclax, and romidepsin. Benda, bendamustine; Cladri, cladribine; Dina, dinaciclib; Ibru, ibrutinib; Ida, idasanutlin; Romi, romidepsin; Ruxo, ruxolitinib; Veneto, venetoclax.

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