Cytotoxic response to forodesine, fludarabine, and bendamustine
| . | Previous treatment . | Response . | Forod 2 μM + dGuo 20 μM . | Fludarab 7.5 μM . | Benda 25 μM . | Forod + Fluda 7.5 μM . | Benda 10 μM . | Forod + Benda 10 μM . |
|---|---|---|---|---|---|---|---|---|
| CLL No. | ||||||||
| 1 | No | — | 49.8 ± 3 | 64.7 ± 2 | 69.8 ± 5 | 58.1 ± 4 | 56.3 ± 4 | 78.9 ± 3 |
| 2 | No | — | 36.8 ± 5 | 67.6 ± 5 | 39.9 ± 2 | 55.9 ± 3 | 34.4 ± 3 | 61.2 ± 4 |
| 3 | No | — | 54.8 ± 3 | 33.2 ± 1 | 10.5 ± 2 | 33.5 ± 6 | 5.9 ± 6 | 64.9 ± 4 |
| 5 | No | — | 62.7 ± 4 | 40.2 ± 2 | 13.1 ± 4 | 45.6 ± 7 | 10.2 ± 3 | 69.9 ± 1 |
| 6 | No | — | 59.4 ± 2 | 53.5 ± 6 | 30.6 ± 3 | 50.6 ± 3 | 20.8 ± 3 | 72.5 ± 3 |
| 7 | No | — | 50.1 ± 3 | 68.1 ± 3 | 62.9 ± 3 | 65.1 ± 3 | 53.2 ± 3 | 78.6 ± 1 |
| 8 | No | — | 50.3 ± 6 | 38.3 ± 3 | 22.7 ± 4 | 35.6 ± 5 | 11.6 ± 5 | 62.6 ± 3 |
| 9 | No | — | 49.1 ± 3 | 68.3 ± 4 | 67.1 ± 2 | 55.8 ± 3 | 58.1 ± 3 | 69.9 ± 4 |
| 13 | No | — | 75.1 ± 3 | 44.3 ± 3 | 66.1 ± 3 | 68.7 ± 2 | 50.7 ± 2 | 87.2 ± 1 |
| 15 | No | — | 53.1 ± 2 | 44.4 ± 4 | 34.7 ± 5 | 45.3 ± 5 | 21.1 ± 4 | 62.6 ± 3 |
| 16 | No | — | 65.6 ± 3 | 53.4 ± 6 | 53.9 ± 3 | 49.2 ± 2 | 39.8 ± 2 | 75.3 ± 4 |
| 17 | No | — | 50.8 ± 5 | 48.8 ± 3 | 61.4 ± 5 | 44.9 ± 4 | 44.1 ± 4 | 74.1 ± 1 |
| 18 | No | — | 61.2 ± 3 | 50.4 ± 5 | 41.5 ± 2 | 50.7 ± 3 | 36.6 ± 2 | 85.3 ± 4 |
| 21 | No | — | 62.2 ± 2 | 52.3 ± 3 | 54.1 ± 2 | 58.9 ± 4 | 51.3 ± 3 | 79.6 ± 2 |
| 22 | No | — | 55.6 ± 5 | 43.5 ± 4 | 66.1 ± 3 | 50.6 ± 4 | 43.5 ± 4 | 70.2 ± 4 |
| 27 | No | — | 52.1 ± 2 | 68.3 ± 2 | 48.6 ± 5 | 57.2 ± 3 | 35.9 ± 3 | 68.5 ± 5 |
| 44 | FCM | Yes | 56.8 ± 2 | 42.2 ± 4 | 57.6 ± 4 | 55.1 ± 3 | 33.1 ± 5 | 67.2 ± 3 |
| 45 | No | — | 60.2 ± 1 | 32.2 ± 3 | 39.5 ± 2 | 52.3 ± 2 | 28.3 ± 4 | 77.2 ± 3 |
| 49 | CHOP | Yes | 44.1 ± 4 | 51.1 ± 3 | 47.2 ± 3 | 45.1 ± 4 | 35.2 ± 6 | 70.9 ± 2 |
| 50 | FCM | No | 44.9 ± 3 | 42.1 ± 2 | 46.4 ± 5 | 44.1 ± 3 | 30.9 ± 5 | 68.3 ± 4 |
| Mean | 54.7 ± 9 | 50.1 ± 10 | 44.6 ± 15 | 51.1 ± 8 | 35.1 ± 15 | 72.2 ± 8 | ||
| CLL p53 del | ||||||||
| 30 | CdA/FCM | Yes | 87.2 ± 3 | 5.1 ± 2 | 26.1 ± 4 | 65.3 ± 2 | ND | ND |
| 31 | CLB | No | 67.3 ± 5 | 19.9 ± 3 | 28.6 ± 3 | 38.3 ± 4 | 25.1 ± 3 | 74.5 ± 3 |
| 32 | R-CHOP | No | 33.4 ± 6 | 32.2 ± 5 | 37.3 ± 3 | 36.5 ± 4 | 30.5 ± 5 | 46.2 ± 3 |
| 33 | FC/R-F/CHOP | No | 78.4 ± 5 | 38.3 ± 3 | 41.8 ± 2 | 67.2 ± 1 | 28.7 ± 3 | 87.2 ± 2 |
| 34 | No | — | 46.5 ± 3 | 4.2 ± 3 | 15.8 ± 3 | 33.7 ± 2 | 10.9 ± 3 | 58.9 ± 5 |
| 35 | No | — | 65.1 ± 3 | 34.6 ± 5 | 26.4 ± 5 | 58.1 ± 2 | 24.4 ± 5 | 72.8 ± 4 |
| 36 | FCM/Camp/P | No | 20.1 ± 5 | 25.3 ± 4 | 23.1 ± 2 | 29.3 ± 2 | 19.2 ± 3 | 42.8 ± 2 |
| 37 | No | — | 79.6 ± 3 | 33.1 ± 5 | 40.6 ± 3 | 67.9 ± 3 | ND | ND |
| 38 | FCM/CHOP | No | 48.2 ± 4 | 42.1 ± 4 | 50.9 ± 4 | 47.7 ± 5 | 39.6 ± 4 | 59.6 ± 4 |
| 39 | FCM | Yes | 72.2 ± 4 | 40.2 ± 4 | 75.3 ± 2 | 56.1 ± 3 | ND | ND |
| 41 | R-CHOP | No | 63.1 ± 6 | 32.3 ± 3 | 41.4 ± 4 | 43.8 ± 5 | 30.5 ± 4 | 70.8 ± 5 |
| Mean | 60.1 ± 21 | 27.9 ± 12 | 37.1 ± 15 | 49.4 ± 14 | 26.1 ± 8 | 64.1 ± 11 |
| . | Previous treatment . | Response . | Forod 2 μM + dGuo 20 μM . | Fludarab 7.5 μM . | Benda 25 μM . | Forod + Fluda 7.5 μM . | Benda 10 μM . | Forod + Benda 10 μM . |
|---|---|---|---|---|---|---|---|---|
| CLL No. | ||||||||
| 1 | No | — | 49.8 ± 3 | 64.7 ± 2 | 69.8 ± 5 | 58.1 ± 4 | 56.3 ± 4 | 78.9 ± 3 |
| 2 | No | — | 36.8 ± 5 | 67.6 ± 5 | 39.9 ± 2 | 55.9 ± 3 | 34.4 ± 3 | 61.2 ± 4 |
| 3 | No | — | 54.8 ± 3 | 33.2 ± 1 | 10.5 ± 2 | 33.5 ± 6 | 5.9 ± 6 | 64.9 ± 4 |
| 5 | No | — | 62.7 ± 4 | 40.2 ± 2 | 13.1 ± 4 | 45.6 ± 7 | 10.2 ± 3 | 69.9 ± 1 |
| 6 | No | — | 59.4 ± 2 | 53.5 ± 6 | 30.6 ± 3 | 50.6 ± 3 | 20.8 ± 3 | 72.5 ± 3 |
| 7 | No | — | 50.1 ± 3 | 68.1 ± 3 | 62.9 ± 3 | 65.1 ± 3 | 53.2 ± 3 | 78.6 ± 1 |
| 8 | No | — | 50.3 ± 6 | 38.3 ± 3 | 22.7 ± 4 | 35.6 ± 5 | 11.6 ± 5 | 62.6 ± 3 |
| 9 | No | — | 49.1 ± 3 | 68.3 ± 4 | 67.1 ± 2 | 55.8 ± 3 | 58.1 ± 3 | 69.9 ± 4 |
| 13 | No | — | 75.1 ± 3 | 44.3 ± 3 | 66.1 ± 3 | 68.7 ± 2 | 50.7 ± 2 | 87.2 ± 1 |
| 15 | No | — | 53.1 ± 2 | 44.4 ± 4 | 34.7 ± 5 | 45.3 ± 5 | 21.1 ± 4 | 62.6 ± 3 |
| 16 | No | — | 65.6 ± 3 | 53.4 ± 6 | 53.9 ± 3 | 49.2 ± 2 | 39.8 ± 2 | 75.3 ± 4 |
| 17 | No | — | 50.8 ± 5 | 48.8 ± 3 | 61.4 ± 5 | 44.9 ± 4 | 44.1 ± 4 | 74.1 ± 1 |
| 18 | No | — | 61.2 ± 3 | 50.4 ± 5 | 41.5 ± 2 | 50.7 ± 3 | 36.6 ± 2 | 85.3 ± 4 |
| 21 | No | — | 62.2 ± 2 | 52.3 ± 3 | 54.1 ± 2 | 58.9 ± 4 | 51.3 ± 3 | 79.6 ± 2 |
| 22 | No | — | 55.6 ± 5 | 43.5 ± 4 | 66.1 ± 3 | 50.6 ± 4 | 43.5 ± 4 | 70.2 ± 4 |
| 27 | No | — | 52.1 ± 2 | 68.3 ± 2 | 48.6 ± 5 | 57.2 ± 3 | 35.9 ± 3 | 68.5 ± 5 |
| 44 | FCM | Yes | 56.8 ± 2 | 42.2 ± 4 | 57.6 ± 4 | 55.1 ± 3 | 33.1 ± 5 | 67.2 ± 3 |
| 45 | No | — | 60.2 ± 1 | 32.2 ± 3 | 39.5 ± 2 | 52.3 ± 2 | 28.3 ± 4 | 77.2 ± 3 |
| 49 | CHOP | Yes | 44.1 ± 4 | 51.1 ± 3 | 47.2 ± 3 | 45.1 ± 4 | 35.2 ± 6 | 70.9 ± 2 |
| 50 | FCM | No | 44.9 ± 3 | 42.1 ± 2 | 46.4 ± 5 | 44.1 ± 3 | 30.9 ± 5 | 68.3 ± 4 |
| Mean | 54.7 ± 9 | 50.1 ± 10 | 44.6 ± 15 | 51.1 ± 8 | 35.1 ± 15 | 72.2 ± 8 | ||
| CLL p53 del | ||||||||
| 30 | CdA/FCM | Yes | 87.2 ± 3 | 5.1 ± 2 | 26.1 ± 4 | 65.3 ± 2 | ND | ND |
| 31 | CLB | No | 67.3 ± 5 | 19.9 ± 3 | 28.6 ± 3 | 38.3 ± 4 | 25.1 ± 3 | 74.5 ± 3 |
| 32 | R-CHOP | No | 33.4 ± 6 | 32.2 ± 5 | 37.3 ± 3 | 36.5 ± 4 | 30.5 ± 5 | 46.2 ± 3 |
| 33 | FC/R-F/CHOP | No | 78.4 ± 5 | 38.3 ± 3 | 41.8 ± 2 | 67.2 ± 1 | 28.7 ± 3 | 87.2 ± 2 |
| 34 | No | — | 46.5 ± 3 | 4.2 ± 3 | 15.8 ± 3 | 33.7 ± 2 | 10.9 ± 3 | 58.9 ± 5 |
| 35 | No | — | 65.1 ± 3 | 34.6 ± 5 | 26.4 ± 5 | 58.1 ± 2 | 24.4 ± 5 | 72.8 ± 4 |
| 36 | FCM/Camp/P | No | 20.1 ± 5 | 25.3 ± 4 | 23.1 ± 2 | 29.3 ± 2 | 19.2 ± 3 | 42.8 ± 2 |
| 37 | No | — | 79.6 ± 3 | 33.1 ± 5 | 40.6 ± 3 | 67.9 ± 3 | ND | ND |
| 38 | FCM/CHOP | No | 48.2 ± 4 | 42.1 ± 4 | 50.9 ± 4 | 47.7 ± 5 | 39.6 ± 4 | 59.6 ± 4 |
| 39 | FCM | Yes | 72.2 ± 4 | 40.2 ± 4 | 75.3 ± 2 | 56.1 ± 3 | ND | ND |
| 41 | R-CHOP | No | 63.1 ± 6 | 32.3 ± 3 | 41.4 ± 4 | 43.8 ± 5 | 30.5 ± 4 | 70.8 ± 5 |
| Mean | 60.1 ± 21 | 27.9 ± 12 | 37.1 ± 15 | 49.4 ± 14 | 26.1 ± 8 | 64.1 ± 11 |
Primary cells from 31 patients with CLL, 11 with 17p (p53) deletion were incubated with forodesine (Forod) 2 μM + dGuo 20 μM, fludarabine (Fludarab) 7.5 μM, or bendamustine (Benda) 10 and 25 μM for 48 hours. Cell viability was determined by annexin V–FITC labeling by flow cytometry (expressed as the percentage of cytotoxicity with respect to control cells). Data are shown as the mean ± SD of triplicate points. In vivo response to previous treatment was determined as complete response after treatment.
F indicates fludarabine; C, cyclophosphamide; M, mitoxantrone; CHOP, cyclophosphamide-doxorubicin-vincristine-prednisone; CdA, cladribine; ND, not determined; CLB, chlorambucil; R, rituximab; Camp, campath-1; and P, prednisone.