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
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%
Stilgenbauer et al.[51, 52] 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
MURANO [32, 62–64] 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%
CLL14 [28, 31, 65] 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%

CIRS = Cumulative Illness Rating Scale, CrCl = creatinine clearance, *continuous therapy until progression, death or other reason to withdraw from trial, ^continuous venetoclax therapy, cessation permitted in good response at clinician discretion, & = continuous venetoclax for patients with relapse and refractory disease, fixed-duration therapy for 12 months in treatment-naïve patients with optional additional 12 months of therapy if not in CR or BM MRD-neg response, #continuous therapy until progression, unacceptable toxicity or two years total therapy. Patients in countries without commercial access to venetoclax could continue for a further two years if ongoing clinical benefit. QoL = quality of life. EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30