Concurrent BCL-2 and BCL-X_L inhibition induces synergistic killing in most ALL xenografts. (A) The predicted additive effect of combined BH3-mimetics was calculated using the Bliss model of fractional independence and subtracted from the actual measured combinatorial effect to generate Bliss scores for each combination of drug concentrations. The sum of Bliss scores across the combination concentration matrix for each xenograft was calculated and summarized by ALL subtype. Red symbols represent the Bliss sum for xenografts, which demonstrated objective in vivo responses to navitoclax, but not venetoclax therapy. Bliss sums >300 were considered to indicate substantial synergy in our studies (where 7 × 7 concentration matrices were used; this is consistent with the threshold used in other studies, where, for example, a threshold of >150 was used for 9 × 3 or 5 × 5 matrices, corresponding to a similar average difference between observed and predicted killing per combination of drug concentrations).⁴⁰  (B) Bliss scores across the combination concentration matrix for each xenograft are presented as a heatmap, with red squares representing drug synergy where there was observed absolute difference in killing of at least 20% in excess of that predicted by the Bliss model of fractional independence.