Table 3 Clinical trials of venetoclax with or without anti-CD20 antibodies or chemotherapy in CLL/SLL
Study | Cohort | Design | ORR/CRR MRD | PFS/OS | III/IV toxicity (> 10%) | Note |  |
|---|---|---|---|---|---|---|---|
Phase I/II | Â | ||||||
Roberts et al.[11] NCT01328626 | R/R Dose finding: n = 56 Expansion: n = 60 | Phase I 150-1200 mg venetoclax daily* 400 mg venetoclax daily* | ORR 79% CRR20% BM flow cytometry-neg 5% | 15-month PFS 66% 24-month OS 84% | 3 cases clinical TLS, one fatal Neutropenia 41% Anemia 12% Thrombocytopenia 12% |  |  |
NCT01889186 | del(17p) R/R: n = 158 TN: n = 5 | Phase II 400 mg venetoclax daily* | ORR 77% CRR 20% PB uMRD 30% BM uMRD 13% | 24-month PFS 54% 24-month OS 73% | No clinical TLS Neutropenia 40% Anemia 15% Thrombocytopenia 15% Pneumonia 10% |  |  |
Seymour et al.; Ma et al.[25, 58] NCT01682616 | R/R n = 49 | Phase Ib 200-400 mg venetoclax daily^ + rituximab × 6 | ORR 86% CRR 53% BM uMRD 61% | 5-year PFS 56% 5-year OS 86% | 2 cases clinical TLS, one fatal Neutropenia 53% Anemia 14% Thrombocytopenia 16% Febrile neutropenia 12% Infections and infestations 16% | Among 33 patients with deep remission (CR or uMRD), 14 continued venetoclax and 19 ceased with similar PFS |  |
Coutre et al.[55] NCT02141282 | Idelalisib exposed n = 36 | Phase II 400 mg venetoclax daily* | ORR 67% CRR 8% PB uMRD 22% BM uMRD 6% | 12-month PFS 79% 12-month OS 94% | No clinical TLS Neutropenia 50% Thrombocytopenia 25% Anemia 17% |  |  |
Jones et al.[56] NCT02141282 | Ibrutinib exposed n = 91 | Phase II 400 mg venetoclax daily* | ORR 65% CRR 9% PM uMRD 26% BM uMRD 5% | Median PFS 25 months 12-month OS 92% | 2 cases laboratory TLS Neutropenia 51% Anemia 29% Thrombocytopenia 29% Lymphopenia 1% Febrile neutropenia 11% |  |  |
Flinn et al.[30] NCT01685892 | R/R: n = 50 TN: n = 32 | Phase Ib 100-400 mg venetoclax daily & + obinutuzumab × 6 | R/R ORR 95% CRR 37% PM uMRD 64% BM uMRD 62% TN ORR 100% CRR 78% PM uMRD 91% BM uMRD 78% | R/R 24-month PFS 85% OS NA TN 24-month PFS 91% OS NA | Neutropenia 53–58% Thrombocytopenia 22% Infection 13–29% |  |  |
Cochrane et al.[57] NCT02980731 | R/R n = 210 | Phase IIIb 400 mg venetoclax daily# | ORR 77% CRR 19% QoL + 9.3 points by EORTC QLQ-C30 | 12-month PFS 83% 12-month OS 88% | Neutropenia 32% Thrombocytopenia 17% Anemia 11% |  |  |
Phase III | Â | ||||||
NCT02005471 | R/R Venetoclax + rituximab n = 194 | 400 mg venetoclax daily 24 months + rituximab × 6+ | ORR 93% CRR 27% PB uMRD 62% BM uMRD 27% | Median PFS 54 months 5-year OS 82% | TLS 3%, 1 case clinical TLS Neutropenia 58% Infection 18% |  |  |
|  | Bendamustine + rituximab n = 195 | 70 mg/m2 bendamustine D1-2 Q28D × 6 + rituximab × 6 |  | ORR 68% CRR 8% PB uMRD 13% BM uMRD 2% | Median PFS 17 months 5-year OS 62% | TLS 1%, 1 case clinical TLS Neutropenia 39% Infection 22% |  |
NCT02242942 | TN CIRS > 6 or CrCl < 70 Venetoclax + obinutuzumab n = 216 | 400 mg venetoclax daily 12 months + obinutuzumab × 6 cycles | ORR 85% CRR 50% PB uMRD 76% BM uMRD 57% | 3-year PFS 82% 24-month OS 92% | 3 cases lab TLS Neutropenia 53% Infection 18% |  |  |
|  | Chlorambucil + obinutuzumab n = 216 | 0.5 mg/kg chlorambucil D1 + D15 Q28D × 12 + obinutuzumab × 6 cycles | ORR 71% CRR 23% PB uMRD 35% BM uMRD 17% | 3-year PFS 50% 24-month OS 93% | 5 cases lab TLS Neutropenia 48% Infection 15% |  |  |
CLL13 (GAIA) [68] NCT02950051 | TN CIRS ≤ 6 and CrCl > 70 Fludarabine, cyclophosphamide + rituximab (≤ 65y) or bendamustine + rituximab (> 65y) n = 216 | 25 mg/m2 fludarabine D1-3, 250 mg/m2 cyclophosphamide D1-3 + rituximab Q28Dx6; 90 mg/m2 bendamustine D1-2 Q28D × 6 + rituximab × 6 | Month 15 ORR 81% CRR 31% PB uMRD 52% BM uMRD 37% | NA | Neutropenia 52% Infections 20% Febrile neutropenia 11% Thrombocytopenia 10% |  |  |
|  | Venetoclax + rituximab n = 237 | 400 mg venetoclax daily 12 months + rituximab | Month 15 ORR 93% CRR 49% PB uMRD 57% BM uMRD 43% | NA | Neutropenia 46% Infections 11% TLS 10% |  |  |
|  | Venetoclax + obinutuzumab n = 228 | 400 mg venetoclax daily 12 months + obinutuzumab × 6 cycles | Month 15 ORR 96% CRR 57% PB uMRD 87% BM uMRD 73% | NA | Neutropenia 59% Thrombocytopenia 18% Infections 14% Infusion reaction 11% |  |  |
|  | Venetoclax + ibrutinib + obinutuzumab n = 231 | 400 mg venetoclax daily 12 months + obinutuzumab × 6 cycles + ibrutinib 420 mg daily to 12 months if uMRD, for 36 months if MRD +  | Month 15 ORR 94% CRR 62% PB uMRD 92% BM uMRD 78% | NA | Neutropenia 57% Infections 22% Thrombocytopenia 16% |  |  |
Venetoclax plus chemotherapy | |||||||
CLL2-BAG [59] NCT02401503 | n = 63 TN: n = 34 R/R: n = 29 | De-bulking if tumor bulk (ALC > 25,000/uL or adenopathy ≥ 5 cm): 70 mg/m2 bendamustine D1-2 Q28D × 2 Induction: Venetoclax + obinutuzumab (2 cycles) Maintenance: Venetoclax up to 24 months + obinutuzumab | TN: ORR 100% CRR 50% PB uMRD 91% RR: ORR 90% CRR 28% PB uMRD 83% | TN: 15-month PFS 100% 15-month OS 100% RR: 15-month PFS 92% 15-month OS 95% | Neutropenia 44% Infections 14% Thrombocytopenia 13% Anemia 11% |  |  |
Lipsky et al.[153] NCT03609593 | TN n = 26 | 50-90 mg/m2 bendamustine D1-2 Q28D + rituximab × 3 followed by 400 mg venetoclax daily 12 months + rituximab × 6 | ORR 100% CRR 92% PB uMRD 100% BM uMRD 90% | NA | Neutropenia 11% | 95% of patients with medium–high TLS risk were risk de-escalated after de-bulking chemotherapy |  |
Flinn et al. [60] NCT03406156 | TN, no del(17p), medium–high TLS risk n = 120 | Obinutuzumab ± bendamustine for up to 6 cycles, followed by venetoclax–obinutuzumab if low-risk TLS status achieved | ORR 90% CRR 36% PB uMRD 89% | 18 months PFS 94% | Neutropenia 28–41% |  |  |