Background
Is there still a role for chemoimmunotherapy as first therapy?
Pivotal frontline CLL studies | ORR/CR + CRi | Best uMRD/timepoint otherwise stated | PFS | OS |
---|---|---|---|---|
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) |
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) |
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) |
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) |
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) |
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) |
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) |
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) |
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’ |
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) |
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 |
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) |
When using a BTKi, which is the preferred agent?
Pivotal studies | All any-grade/grade ≥ 3 adverse events | Any-grade/grade ≥ 3 neutropenia; any-grade/grade ≥ 3 infection | Any-grade/grade ≥ 3 thrombocytopenia; any-grade/grade ≥ 3 bleeding | Any-grade/grade ≥ 3 diarrhoea | Any-grade/grade ≥ 3 atrial fibrillation | Any-grade/grade ≥ 3 hypertension | Treatment discontinuation due to AE Treatment related deaths |
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UK/63% (FC) vs. UK/73% (FCR)) | Neutropenia: UK/21% (FC) vs. UK/34% (FCR) Infection: UK/21% (FC) vs. UK/25% (FCR) | Thrombocytopenia: UK/11% (FC) vs. UK/7% (FCR) Bleeding: N/R | N/R | N/R | N/R | Discontinuation: UK/17% overall Death: 3% (FC) vs. 2% (FCR) | |
CLL10 [18] | 92%/UK (BR) vs. 98%/UK (FCR) | Neutropenia: 60%/59% (BR) vs. 76%/75%% (FCR) Infection: 67%/26% (BR) vs. 77%/40% (FCR) | Thrombocytopenia:18%/14% (BR) vs. 24%/21% (FCR) Bleeding: N/R | N/R | N/R | N/R | Discontinuation: 13% (BR) vs. 23% (FCR) Death: 2% (BR) vs. 5% (FCR |
N/R | Neutropenia: 16%/10% (Ib) vs. 23%/18% (Chl) Infection: N/R | Thrombocytopenia: UK/2% (Ib) vs. UK/2% (Ib) Bleeding: UK/4% (Ib) vs. UK/2% (Chl) Ext. f/up UK/7% (Ib) | 42%/4% (Ib) vs. 17%/0% (Chl) | 6%/1.5% (Ib) vs. 1%/UK (Chl) Ext. f/up—UK/6% (Ib) | 14%/4% (Ib) vs. UK/0% (Chl) Ext. f/up—UK/12% (Ib) | Discontinuation: 9% (Ib) vs. 23% (Chl) Ext. f/up—24% (Ib) Death: N/R 3% fatal cardiac events (Ib) | |
ALLIANCE 202 [53] | Haematologic: UK/41% (Ib), UK/39% (IbR), UK/61% (BR) Non-haematologic: UK/74% (Ib), UK/74% (Ib), UK/63% (BR) | Neutropenia: UK/15% (Ib), UK/21% (IbR), UK/40% (BR) Infection: UK/18% (Ib), UK/20% (IbR), UK/15% (BR) | Thrombocytopenia: UK/7% (Ib), UK/5% (IbR), UK/15% (BR) Bleeding: UK/2% (Ib), UK/4% (IbR), UK/0% (BR) | N/R | 17%/9% (Ib), 14%/6% (IbR), 3%/3% (BR) | UK/29% (Ib), UK/33% (IbR), UK/15% (BR) | Discontinuation: N/R Death: Sudden deaths 4% (Ib), 2% (IbR), 1% (BR) |
90%/68% (IbO) vs. 95%/70% (ChlO) | Neutropenia: 44%/37% (IbO) vs 63%/46% (ChlO) Infection: N/R | Thrombocytopenia: 35%/19% (IbO) vs. 25%/10% (ChlO) Bleeding: IbO: 4%/UK (IbO) vs. UK/UK (ChlO) | 34%/3% (IbO) vs 10%/0% (ChlO) Ext. f/up—35%/3% (IbO) | 7%/5% (IbO) vs. 0%/0% (ChlO) Ext. f/up—15%/6% (IbO) | 13%/4% (IbO) vs. 4%/3% (ChlO) Ext. f/up—19%/4% (IbO) | Discontinuation: 16% (IbO) vs. 9% (ChlO) Ext. f/up—22% (IbO) Death: 12.4% (IbO) vs. 2.6% (ChlO) | |
96.1%/70.2% (AO), 95.0%/49.7% (A), 98.8%/69.8% (ChlO) | Neutropenia: 31.5%/29.8% (AO), 10.6%/9.5% (A), 45%/41.4% (ChlO) Infection: UK/21% (AO), UK/14% (A), UK/8% (ChlO) | Thrombocytopenia: 12.9%/8.4% (AO), 7.3%/2.8% (A), 14.2%/11.8% (ChlO) Bleeding: 43%/2% (AO), 39%/2% (A), 12%/0% (ChlO) | 38.8%/4.5% (AO), 34.6%/0.6% (A), 21.3%/1.8% (ChlO) | 3%/UK (AO), 4%/UK (A), 1%/UK (ChlO | UK/3% (AO), UK/2% (A), UK/3% (ChlO) | Discontinuation: 11% (AO), 9% (A), 14% (ChlO) Ext. f/up: 17% (AO), 16% (A), 14% (ChlO) Death: 2.2% (AO), 3.6% (A), 6.5% (ChlO) | |
SEQUOIA [4] | 94%/53% (Z) vs. 96%/80% (BR) | Neutropenia: 16%/12% (Z) vs 57%/51% (BR) Infection: UK/16.3% (Z) vs. UK/18.9% (BR) | Thrombocytopenia: 3–4%/1–2% (Z) vs. 13%/7% (BR) Bleeding: 45%/4% (Z) vs. 11%/1.8% (BR) | 14%/1% (Z) vs. 13%/1% (BR) | 3.3%/0.4% (Z) vs. 2.6%/1.3% (BR) | 14.2%/6.3% (Z) vs. 10.6%/4.8% (BR) | Discontinuation: 8% (Z) vs. 14% (BR) Death: 4.6% (Z) vs.5.3% (BR) |
FLAIR [2] | N/R | Neutropenia: N/R Infection: 27.1%/UK (FCR) vs 33.6%/UK (IbR) | N/R | N/R | All cardiac adverse events; 1.1% (FCR) vs. 8.3% (IbR) | Discontinuation: N/R Death: Sudden deaths—2.1% (IbR) vs. 0.5% (FCR) | |
UK/80.1% (IbR) vs. UK/79.7% (FCR) | Neutropenia: UK/25.6% (IbR) vs. UK/44.9% (FCR) Ext. f/up—UK/28.4% (IbR) Infection: UK/9.1% (IbR) vs. UK/8.9% (FCR) Ext. f/up—UK/11.4% (IbR) | Thrombocytopenia: UK/3.3% (IbR) vs. UK/36.8% (FCR) Bleeding: UK/1.1% (IbR) vs. UK/0% (FCR) | UK/4.3% (IbR) vs. UK/1.3% (FCR) | 7.4%/UK (IbR) vs. 3.2%/UK (FCR) Ext. f/up—UK/4.5% (IbR) vs. UK/0% (FCR) | UK/18.8% (IbR) vs. UK/ 8.2% (FCR) | Discontinuation: N/R Ext. f/up—21.9% (IbR) (2022) Death: 1 sudden death in IbR arm | |
CLL13 [10] | 96.6%/71.3% (VenR), 98.7%/84.7% (VenO), 98.7%/82.2% (IbVenO), 98.1%/78.7% (CIT) | Neutropenia: 53.2%/46.0% (VenR), 58.8%/55.7% (VenO), 56.7%/48.5% (IbVenO), 55.6%/52.3% (CIT) Infection: 59.5%/11.4% (VenR), 68%/14% (VenO), 75.3%/22.1% (IbVenO), 60.6%/19.9% (CIT) | Thrombocytopenia: 10.1%/4.2% (VenR), 23.2%/18.4% (VenO), 29.9%/16.0% (IbVenO), 19.0%/10.2% (CIT) Bleeding: 5.1%/0.4% (VenR), 10.1%/0.4% (VenO), 27.7%/1.7% (IbVenO), 6.0%/0.5% (CIT) | N/R | 0.8%/0.4 (VenR), 0.9%/0.0% (VenO), 7.8%/2.6% (IbVenO), 1.9%/0.5% (CIT) | N/R | Discontinuation: N/R Death: N/R |
CLL14 [7] | VenO: UK/78.8% ChlO: UK/76.6% | Neutropenia: UK/52.8% (VenO) vs UK/48.1% (ChlO) Infection: UK/17.5% (VenO) vs. UK/15.0% (ChlO) | Thrombocytopenia UK/13.7% (VenO) vs. UK/15.0% (ChlO) Bleeding: N/R | UK/4.2% (VenO) vs. UK/0.5% (ChlO) | N/R | N/R | Discontinuation: N/R Death: N/R |
CAPTIVATE (FD cohort) [52] | N/R | Neutropenia: 42%/33% Infection: 67%/8% | Thrombocytopenia: 59%/13% Major bleeding: 2%/1% | 62%/3% | 4%/1% | 16%/6% | Discontinuation: N/R Death: N/R |
GLOW [34] | UK/75.5% vs. UK/69.5% | Neutropenia: 41.5%/34.9% (IbVen) vs. 58.1%/49.5% (ChlO) Infection: UK/17.0% (IbVen) vs. UK/11.5% (ChlO) | Thrombocytopenia: 11.3%/5.7% (IbVen) vs. 26.7%/20.0% (ChlO) Bleeding: N/R | 50.9%/10.4% (IbVen) vs. 12.4%/1.0% (ChlO) | 14.2%/6.6% (IbVen) vs. 1.9%/0.0% (ChlO) | 13.2%/7.5% (IbVen) vs. 4.8%/1.9% (ChlO) | Discontinuation: N/R Death: 6.6% (IbVen) vs. 1.9% (ChlO) |