Preclinical assessment of targeted drug combinations against CTCL patient–derived samples. CTCL patient cells were incubated with each of 5 targeted agents (ruxolitinib, venetoclax, vorinostat, mivebresib, and bortezomib) individually to calculate single-agent IC₅₀ values. Cells were then incubated with combinations of each drug at 3 concentrations, and the combination index (CI) was calculated by using the Chou-Talalay method. Resulting CIs were plotted as heatmaps. (A) Representative heat map of a high-responder to ruxolitinib (i) and a low-responder to ruxolitinib (ii). (Bi) The CI at 1% to 30% viability for patient-derived samples exposed to combinations of ruxolitinib, venetoclax, vorinostat, and mivebresib. Strongest synergy was seen with venetoclax plus ruxolitinib and venetoclax plus mivebresib across patient samples. (Bii) The fold improvement in cytotoxicity for the same concentrations was calculated and plotted for these CTCL patient–derived samples exposed to combinations of ruxolitinib, venetoclax, vorinostat, and mivebresib. The highest fold potentiation was seen with the combination of ruxolitinib and venetoclax. Very strong synergy, CI < 0.1; strong synergy, CI < 0.3; synergy, CI < 0.7; slight to moderate synergy, CI < 0.9; additive effect, 0.9 < CI < 1.1; slight to moderate antagonism, CI < 1.45; antagonism, CI < 3.3; strong antagonism, CI < 10; and very strong antagonism, CI > 10. Adapted from Chou.²¹  Very strong potentiation, >10-fold; strong potentiation, two- to 10-fold; potentiation, 1.5- to twofold; moderate antagonism, 0.6- to 0.8-fold; antagonism, 0.3- to 0.6-fold; strong antagonism, <0.3-fold.