Abstract
PI3K-delta (δ) is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib (IDELA) is a potent and selective orally administered inhibitor of PI3Kδ with demonstrated activity in patients with relapsed or refractory (R/R) CLL either as a single agent (Brown, ASCO 2013) or in combination (Barrientos et al, ASCO 2013; Coutre et al, EHA 2013; Barrientos et al, EHA 2013), and in previously untreated patients in combination with rituximab (R) (O'Brien et al, ASCO 2013). This report describes the effect of established high risk prognostic markers on the clinical activity of idelalisib based therapy in CLL patients enrolled in 3 clinical trials.
Subjects were enrolled into one of three trials: 1) phase 1 monotherapy dose escalation, dosing from 50 mg bid to 350 mg bid (N=54, R/R); 2) phase 1 combination with either R, ofatumumab, bendamustine ± R, fludarabine or chlorambucil±R (N= 114, R/R) ; 3) phase 2 combination with R (N=64, age≥ 65 yrs, previously untreated). Response was assessed by investigators per IWCLL 2008. Genetic markers were assessed in a central lab using archived DNA obtained at study enrollment.
ORR and CR results are shown in the table below, with data grouped per either R/R or previously untreated patients.
| . | Relapsed/Refractory Phase 1 monotherapy, N=54 Phase 1 combinations, N=114 . | Previously Untreated Phase 2, IDELA + R, N=64 . | ||
|---|---|---|---|---|
| n* . | %ORR (%CR) . | n* . | %ORR (%CR) . | |
| Del(17p)/TP53mut | ||||
| Either | 46 | 65 (2) | 9 | 100 (33) |
| Neither | 114 | 83 (5) | 52 | 96 (19) |
| IGHV | ||||
| Unmutated | 140 | 78 (4) | 37 | 97 (14) |
| Mutated | 19 | 84 (11) | 23 | 96 (35) |
| Del(11q) | ||||
| Deleted | 33 | 85 (3) | 10 | 100 (10) |
| Not Deleted | 127 | 76 (5) | 51 | 96 (24) |
| NOTCH1 | ||||
| Mutated | 35 | 74 (9) | 8 | 100 (13) |
| Wild Type | 126 | 79 (3) | 51 | 96 (20) |
| . | Relapsed/Refractory Phase 1 monotherapy, N=54 Phase 1 combinations, N=114 . | Previously Untreated Phase 2, IDELA + R, N=64 . | ||
|---|---|---|---|---|
| n* . | %ORR (%CR) . | n* . | %ORR (%CR) . | |
| Del(17p)/TP53mut | ||||
| Either | 46 | 65 (2) | 9 | 100 (33) |
| Neither | 114 | 83 (5) | 52 | 96 (19) |
| IGHV | ||||
| Unmutated | 140 | 78 (4) | 37 | 97 (14) |
| Mutated | 19 | 84 (11) | 23 | 96 (35) |
| Del(11q) | ||||
| Deleted | 33 | 85 (3) | 10 | 100 (10) |
| Not Deleted | 127 | 76 (5) | 51 | 96 (24) |
| NOTCH1 | ||||
| Mutated | 35 | 74 (9) | 8 | 100 (13) |
| Wild Type | 126 | 79 (3) | 51 | 96 (20) |
*some samples missing for each test
IDELA shows robust activity independent of the four genetic markers evaluated. Thus, patients can be considered for idelalisib-based treatment in clinical trials regardless of these high-risk features.
Coutre:Gilead Sciences: Research Funding. Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies. Leonard:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. De Vos:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Furman:Gilead Sciences: Research Funding. Brown:Gilead Sciences: Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Benson:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Spurgeon:Gilead Sciences: Research Funding. Zelenetz:Gilead Sciences: Research Funding. Lamanna:Gilead Sciences: Research Funding. Kipps:Gilead Sciences: Research Funding. Kahl:Gilead Sciences: Research Funding. Bello:Gilead Sciences: Research Funding. Burger:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Dansey:Gilead Sciences: Employment. Kim:Gilead Sciences: Employment. Holes:Gilead Sciences: Employment. Lazarov:Gilead Sciences: Employment. Dubowy:Gilead Sciences: Employment. O'Brien:Gilead Sciences: Research Funding.
Author notes
Asterisk with author names denotes non-ASH members.
