Combination indices of AZD6738 (1 or 3 µM) with cytotoxic chemotherapy or BCR signaling inhibitor in ATM- or TP53-defective primary CLL cells cocultured with CD40L/IL-21
| Drug combined with AZD6738 and dose (µM) . | AZD6738 dose (µM) . | ATM-defective CLL (n = 3) . | TP53-defective CLL (n = 3) . | ||||
|---|---|---|---|---|---|---|---|
| Fraction affected . | Combination index (mean ± SEM) . | Synergism* . | Fraction affected . | Combination index (mean ± SEM) . | Synergism* . | ||
| Chlorambucil | |||||||
| 4 | 1 | 0.37 | 0.30 ± 0.05 | ++++ | 0.27 | 0.47 ± 0.20 | +++ |
| 16 | 1 | 0.45 | 0.34 ± 0.04 | +++ | 0.35 | 0.38 ± 0.17 | +++ |
| 16 | 3 | 0.50 | 0.78 ± 0.29 | ++ | 0.59 | 0.34 ± 0.08 | +++ |
| Fludarabine | |||||||
| 1 | 1 | 0.22 | 0.83 ± 0.29 | ++ | 0.18 | 0.81 ± 0.24 | ++ |
| 4 | 1 | 0.29 | 0.77 ± 0.27 | ++ | 0.27 | 0.56 ± 0.16 | +++ |
| 16 | 1 | 0.44 | 0.71 ± 0.21 | ++ | 0.49 | 0.37 ± 0.05 | +++ |
| 4-Hydroperoxycyclophosphamide | |||||||
| 1 | 1 | 0.39 | 0.32 ± 0.11 | +++ | 0.29 | 0.36 ± 0.11 | +++ |
| 4 | 1 | 0.49 | 0.33 ± 0.10 | +++ | 0.40 | 0.34 ± 0.13 | +++ |
| 4 | 3 | 0.60 | 0.12 ± 0.02 | ++++ | 0.71 | 0.22 ± 0.07 | ++++ |
| Ibrutinib | |||||||
| 1 | 1 | 0.37 | 0.36 ± 0.00 | +++ | 0.20 | 0.84 ± 0.27 | ++ |
| 4 | 1 | 0.47 | 0.46 ± 0.04 | +++ | 0.27 | 0.83 ± 0.20 | ++ |
| 16 | 1 | 0.60 | 1.00 ± 0.13 | ± | 0.44 | 1.05 ± 0.17 | ± |
| Drug combined with AZD6738 and dose (µM) . | AZD6738 dose (µM) . | ATM-defective CLL (n = 3) . | TP53-defective CLL (n = 3) . | ||||
|---|---|---|---|---|---|---|---|
| Fraction affected . | Combination index (mean ± SEM) . | Synergism* . | Fraction affected . | Combination index (mean ± SEM) . | Synergism* . | ||
| Chlorambucil | |||||||
| 4 | 1 | 0.37 | 0.30 ± 0.05 | ++++ | 0.27 | 0.47 ± 0.20 | +++ |
| 16 | 1 | 0.45 | 0.34 ± 0.04 | +++ | 0.35 | 0.38 ± 0.17 | +++ |
| 16 | 3 | 0.50 | 0.78 ± 0.29 | ++ | 0.59 | 0.34 ± 0.08 | +++ |
| Fludarabine | |||||||
| 1 | 1 | 0.22 | 0.83 ± 0.29 | ++ | 0.18 | 0.81 ± 0.24 | ++ |
| 4 | 1 | 0.29 | 0.77 ± 0.27 | ++ | 0.27 | 0.56 ± 0.16 | +++ |
| 16 | 1 | 0.44 | 0.71 ± 0.21 | ++ | 0.49 | 0.37 ± 0.05 | +++ |
| 4-Hydroperoxycyclophosphamide | |||||||
| 1 | 1 | 0.39 | 0.32 ± 0.11 | +++ | 0.29 | 0.36 ± 0.11 | +++ |
| 4 | 1 | 0.49 | 0.33 ± 0.10 | +++ | 0.40 | 0.34 ± 0.13 | +++ |
| 4 | 3 | 0.60 | 0.12 ± 0.02 | ++++ | 0.71 | 0.22 ± 0.07 | ++++ |
| Ibrutinib | |||||||
| 1 | 1 | 0.37 | 0.36 ± 0.00 | +++ | 0.20 | 0.84 ± 0.27 | ++ |
| 4 | 1 | 0.47 | 0.46 ± 0.04 | +++ | 0.27 | 0.83 ± 0.20 | ++ |
| 16 | 1 | 0.60 | 1.00 ± 0.13 | ± | 0.44 | 1.05 ± 0.17 | ± |
++++, strong synergism; +++, synergism; ++, moderate synergism; +, slight synergism; ±, additive.