Table 1 Main efficacy outcomes of pivotal clinical trials in untreated CLL

CLL8 [18, 20, 127]

Phase III, fit patients (aged 30–81)

FCR vs. FC—intended six cycles each

90%/44% (FCR) vs. 80%/22% (FC)

Final re-staging:

[PB] 63% (FCR) vs. 35% (FC), (p < 0.0001)

Median follow-up 5.9 years; median PFS 56.8 m (FCR) vs. 32.9 m (FC), HR 0.59 (95% CI 0.50–0.69), (p < 0.001)

Median follow-up 5.9 years; OS rates 87% vs. 83% (FC), (p = 0.012)

CLL10 [18, 21]

Phase III, fit patients without del(17p)

BR vs. FCR—intended six cycles each

97.8%/31.5% (BR) vs. 97.8%/40.7% (FCR)

Final re-staging:

[PB] 62.9% (BR) vs. 74.1% (FCR)

[BM] 31.6% (BR) vs. 58.1% (FCR)

Median follow-up 58.2 months; median PFS 42.3 m (BR) vs. 57.6 m (FCR), HR 1.593 (95% CI 1.271–1.996), (p < 0.0001)

Median follow-up 58.2 months; OS rates 80.1% (BR) vs. 80.9% (FCR), HR 1.108 (95% CI 0.755–1.627), (p = 0.599)

RESONATE-2 [45, 128]

Phase III, patients ≥ 65y without del(17p)

Ib vs. Chl, cross-over allowed upon PD

Ib—until PD or intolerance, Chl—up to 12 cycles

Initial report: 86%/4% (Ib) vs. 35%/2% (Chl)

Ext. f/up: 92%/34% (Ib) vs. 37%/UK (Chl)

N/R

Median follow-up 82.7 months; median PFS NR (Ib) vs. 15 m (Chl), HR 0.154 (95% CI, 0.108–0.220)

7-year PFS rates: 59% (Ib) vs. 9% (Chl)

Median follow-up 82.7 months; median OS NR (Ib) vs 89 m (Chl), HR 0.453 (0.276–0.743)

ALLIANCE 202 [5, 53]

Phase III, Patients ≥ 65y

1:1:1 Ib:IbR:BR

Ib—until PD or intolerance, IbR: as per Ib, plus RTX C2-6, BR—intended six cycles

93%/7% (Ib)

94%/12% (IbR)

81%/26% (BR)

N/R

Median follow-up 55 months;

median PFS 44 m (BR), NR (Ib), NR (IbR). IbR vs Ib, HR 0.99 (95% CI 0.66–1.48), (p = 0.96)

48-month PFS rates: 47% (BR), 76% (Ib), 76% (IbR)

48-month OS rates: 84% (BR), 85% (Ib), 86% (IbR)

ILLUMINATE [3, 35]

Phase III, patients ≥ 65y or < 65 with pre-existing conditions

IbO vs. ChlO, cross-over allowed upon PD

IbO—Ib until PD or intolerance plus O C1-6, ChlO—intended six cycles

91%/42% (IbO)

81%/17% (ChlO)

Median follow-up 45 months;

[PB or BM] 38% (IbO) vs. 25% (ChlO), (p = 0.033)

Median follow-up 45 months; median PFS NR (IbO) vs 22 m (ChlO), HR 0.25 (95% CI 0.16–0.38), (p < 0.0001)

42-month PFS rates: 74% (IbO) vs 33% (ChlO)

Median follow-up 45 months; NR vs NR, HR 1.08 (95% CI 0.60–1.97), (p = 0.793)

ELEVATE-TN [6, 57, 58]

Phase III, patients ≥ 65y or < 65 with comorbidities (CrCl 30-69 ml/min or CIRS > 6)

1:1:1 AO:A:ChlO, A—until PD or intolerance, AO: as per A, plus O C1-6, ChlO—intended six cycles

Initial report: 94%/14% (AO), 86%/1% (A), 79%/5% (ChlO)

5-year f/up:

96%/32% (AO), 90/14% (A), 82%/14% (ChlO)

Patients achieving CR/CRi only;

[PB] 49% (AO), 7% (A), 61% (ChlO) (lancet)

Median follow-up 58.2 months; median PFS NR (AO), NR (A), 27.8 m (ChlO). AO vs ChlO, HR 0.11, (p < 0.0001), A vs. ChlO HR 0.21, (p < 0.0001)

60-month PFS rates: 84% (AO), 72% (A), 21% (ChlO)

Median follow-up 58.2 months; median OS NR (all arms), AO vs ChlO, HR 0.55, (p = 0.0499)

60-month OS rates: 90% (AO), 84% (A), 82% (ChlO)

SEQUOIA [4, 129]

Phase III, patients ≥ 65y or < 65 with comorbidities, without del(17p)

1:1 Z:BR, Z—until PD or intolerance, BR—intended six cycles

94.6%/6.6% (Z) vs

85.3%/15.1% (BR)—ash 2021

N/R

Median follow-up 26.2 months; NR vs. NR, HR 0.42 (95% CI 0.28–0.63), (p < 0.0001)

24-month OS rates: 94.3% (Z) vs. 94.6% (BR)

FLAIR [2]

Phase III, patients < 75, no del(17p) > 20% cancer cell fraction

1:1 FCR:IbR (Parallel group trial), IbR—up to 6 years plus RTX × 6 (C1-6), FCR—intended six cycles

N/R

N/R

Median follow-up 52.7 months; median PFS NR (IbR) vs. 67 m (FCR), HR 0.44, (p < 0.001)

Median follow-up 52.7 months; no difference in median OS, HR 1.01, (p = 0.956)

E1912 [1, 26]

Phase III, patients ≤ 70y without del(17p)

2:1 IbR:FCR, IbR—Ib until PD or intolerance, plus RTX × 6 (C1-6), FCR—intended six cycles

95.8%/17.2% (IbR) vs. 81.1%/30.3% (FCR)

12-month assessment;

[PB] 8.3% (IbR) vs. 59.2% (FCR)

5-year PFS rates: 78% (IbR) vs. 51% (FCR), HR 0.37 (95% CI 0.27–0.51), (p < 0.0001)

5-year OS rates: 95% (IbR) vs. 89% (FCR), HR 0.47 (95% CI 0.25–0.89), (p = 0.018)

CLL13 [9, 10]

Phase III, fit patients (CIRS ≤ 6, CrCl ≥ 70 ml/min) without TP53 aberrancy

1:1:1:1 VenR:VenO:IbVenO:CIT

VenR—12 months Ven plus RTX × 6 (C1-6), VenO—12 months Ven plus O × 8 (C1-6), IbVenO—as per VenO plus Ib C1-12, continued until cycle 36 if MRD + 

Month 15:

VenR: 93.3%/49.4%

VenO: 96.1%/56.8%

IbVenO: 94.4%/61.9%

FCR: 80.8%/31.0%

Month 15:

[PB] 57.0% (VenR), 86.5% (VenO), 92.2% (IbVenO), 52.0% (CIT)

VenO vs CIT, p < 0.0001, IbVenO vs. CIT, p < 0.0001, VenR vs CIT, p = 0.317

Median observation time 38.8 months; IbVenO vs. CIT, HR 0.32, (97.5% CI 0.19–0.54), (p < 0.0001), VenO vs CIT HR 0.42, (97.5% CI 0.26–0.68), (p < 0.0001), VenR vs. CIT HR 0.79 (97.5% CI 0.53–1.18), (p = 0.183)

Three-year PFS rates: 80.8% (VenR), 87.7% (VenO), 90.5% (IbVenO), 75.5% (CIT)

Median observation time 38.8 months; OS rates ‘similar across all treatment arms’

CLL14 [7, 8, 24]

Phase III, patients with comorbidities (CIRS > 6 or CrCL < 70 ml/min)

1:1 VenO:ChlO, VenO and ChlO—12 cycles each, no cross-over allowed

84.7%/49.5% (VenO) vs. 71.3/21.3% (ChlO)

Month 15^#:

[PB] 75.5% (VenO) vs. 35.2% (ChlO), (p < 0.001)

[BM] 56.9% (VenO) vs. 17.1% (ChlO), (p < 0.001)

Median follow-up 65.4 months; median PFS NR vs 36.4 months, HR 0.35 (95% CI 0.26–0.46), (p < 0.0001)

5-years PFS rates: 62.6% (VenO) vs. 27.0% (ChlO)

5-year OS rates: 81.9% (VenO) vs. 77.0% (ChlO), HR 0.72 (95% CI 0.48–1.09), (p = 0.12)

CAPTIVATE [52, 103]

Phase II, patients 18-70y

Intended 3 cycles Ib, 12 cycles of IbVen

FD cohort:

If PD < 24 months—could receive Ib, if PD > 24 months—could be retreated with IbVen

96%/55%

EOT:

[PB] 77%

[BM] 60%

24-month PFS rates: 95% (all-treated), 96% (without del[17p]), 84% (with TP53 aberrancy)

24-month OS rates: 98% (all-treated), 98% (without del[17p]), 96% (with TP53 aberrancy)

MRD-cohort:

One additional cycle of IbVen—MRD status confirmed and response assessed;

uMRD Confirmed: 1:1 placebo:Ib until confirmed MRD relapse

uMRD Not Confirmed: 1:1 to Ib:IbVen (maximum 2 years overall duration for venetoclax) until PD or intolerance

97%/46%

EOT:

[PB] 75%

[BM] 68%I

30-month PFS rates:

‘uMRD confirmed’ = 95% (placebo) vs. 100% (Ib)

‘uMRD Not Confirmed’—95% (Ib) vs. 97% (IbVen)

N/R

GLOW [32, 34]

Phase III, patients ≥ 65y or < 65y with CIRS ≥ 6 or CrCl < 70 ml/min, without known TP53 aberrancy

1:1 IbVen:ChlO, IbVen—intended 12 cycles after three cycles Ib lead-in, ChlO—intended six cycles

86.8%/38.7% (IbVen) vs. 84.8%/11.4% (ChlO) (IRC)

[BM] 55.7% (IbVen) vs. 21.0% (ChlO)^#

Median follow-up 27.7 months; median PFS IbVen vs ChlO, HR 0.216 (95% CI 0.131–0.357), (p < 0.001)

24-month PFS rates: 84.4% (IbVen) vs. 44.1% (ChlO)

Median follow-up 27.7 months; median OS—‘no difference in overall survival between arms’, HR 1.048 (95% CI 0.454–2.419)