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Major trial evidence: strong for progression-free survival, thinner and less mature for survival

What the trials show. Every modern targeted first-line regimen has beaten chemoimmunotherapy on progression-free survival. Overall-survival benefit has been shown only in some comparisons:

  • E1912 and ELEVATE-TN: established.
  • GLOW: nominal, not controlled for type-1 error.
  • FLAIR: OS was a secondary endpoint.
  • AMPLIFY: significant at the primary analysis, not after adjusting for multiplicity.

Only one randomised trial pits a licensed fixed-duration strategy against continuous treatment: CLL17, so far reported as a 3-year interim analysis. FLAIR and A041702 also randomised venetoclax combinations against ibrutinib-based treatment (ibrutinib alone in FLAIR; ibrutinib-obinutuzumab in A041702), but their venetoclax arms were MRD-guided, which is not a licensed way to give these drugs (E1912; ELEVATE-TN; GLOW; FLAIR; AMPLIFY in the Calquence SmPC; CLL17) [E].

Trial Design and population Comparison Latest results Source status
CLL14 Phase 3; unfit (CIRS >6 and/or CrCl <70); median age 72; TP53 aberration in 11.8% VenO 12 cycles vs chlorambucil-obinutuzumab 6-year: median PFS 76.2 vs 36.4 months (HR 0.40); OS 78.7% vs 69.2% (p=.052); undetectable MRD 76% vs 35%; second cancers 14.2% vs 8.4%. 9-year: median PFS 76.6 vs 37.9 months; OS 59.3% vs 51.1% (HR 0.80, p=.161); median time to next treatment 91.9 vs 52.5 months; 39.6% treatment-free at 9 years. Within VenO: median PFS 104.9 months (mutated IGHV) vs 64.7 months (unmutated) 6-year: peer-reviewed full text. 9-year: conference only (EHA 2026, via OncLive and an AbbVie press release)
CLL13/GAIA Phase 3; fit; TP53 excluded; n=926 Chemoimmunotherapy (CIT) vs venetoclax-rituximab (VR) vs VenO vs VenO + ibrutinib (GIV), each 12 cycles 5-year PFS 50.7% (CIT), 57.4% (VR), 69.8% (VenO), 81.3% (GIV). GIV beat VenO (p=.0046). No OS differences (90.7–94.7%). Cardiac events most frequent with GIV. Caution: EHA 2026 labels the 4-year figures as "five-year" Blood 2026 (abstract only)
CLL17 Phase 3; fit and unfit; median age 66; TP53 aberration in 7.6%; n=909 Continuous ibrutinib vs VenO (12 cycles) vs IV (15 cycles) 3-year PFS 81.0% / 81.1% / 79.4%; both fixed-duration arms non-inferior. Undetectable MRD 0% / 73.3% / 47.2%. 3-year OS 95.7% / 91.5% / 96.0% (not formally tested). TP53 subgroup favoured ibrutinib (HR 1.20 for VenO, 0.40–3.59). Cardiac disorders 34.6% / 13.9% / 23.8% NEJM 2026 (abstract only) + ASH 2025 abstract; some safety data secondary/promotional; interim; the investigator calls it "not fully powered at this point"
AMPLIFY Phase 3; fit; TP53 excluded; median age 61; n=867 AV vs AVO vs FCR/BR 36-month PFS 76.5% / 83.1% / 66.5%. OS 94.1% / 87.7% / 85.9%. COVID-19 deaths 10 / 25 / 21. EU-label later cut: AV OS HR 0.42, not significant after multiplicity adjustment NEJM 2025 (abstract only); SmPC. No public 48-month numbers
CRISTALLO Phase 3; fit (CIRS ≤6, CrCl ≥70); TP53 excluded; n=166 VenO vs FCR/BR Undetectable MRD at month 15: 81.3% vs 54.7%. PFS still immature (HR 0.49, not significant) Blood 2026
ELEVATE-TN Phase 3; ≥65 or comorbid; TP53 aberration in 13.6% Acalabrutinib ± obinutuzumab (continuous) vs chlorambucil-obinutuzumab 72-month PFS 78.0% / 61.5% / 17.2%. OS HR 0.62 for acalabrutinib-obinutuzumab vs control Blood 2025
SEQUOIA Phase 3; ≥65 or comorbid; no del(17p) in randomised arms Zanubrutinib vs BR. Arm C: del(17p). Arm D: zanubrutinib + venetoclax 60-month PFS 75.8% vs 40.1%; OS 85.8% vs 85.0%. At 72 months: 74% vs 32%. Arm C 72-month PFS 64%. Arm D 36-month PFS 87% (combination unlicensed in the EU) JCO 2025; 6-year data conference/secondary
ALPINE Phase 3; relapsed/refractory; n=652 Zanubrutinib vs ibrutinib PFS HR 0.68 (TP53 subgroup 0.51); OS HR 0.77, not significant; AF 7.1% vs 17.0% Blood 2024
ELEVATE-RR Phase 3; relapsed with del(17p) or del(11q); n=533 Acalabrutinib vs ibrutinib Median PFS 38.4 months in both (HR 1.00); AF 9.4% vs 16.0% JCO 2021
FLAIR Phase 3; fit for FCR; ≤75; >20% del(17p) excluded; n=786 MRD-guided IV (2–6 years) vs ibrutinib vs FCR 5-year PFS 93.9% / 79.0% / 58.1%. Deaths 4.2% / 9.9% / 14.8%. OS advantage in unmutated IGHV. Sudden deaths 3 / 8 / 4. MRD-guided IV is unlicensed NEJM 2025 (abstract only); NEJM 2024
CAPTIVATE Phase 2; ≤70; TP53 aberrations included IV, 15 cycles 5.5-year PFS 66%, OS 97%. PFS 55% (unmutated) vs 79% (mutated). TP53 subgroup: 36% (news reports) vs 30% (EHA); unresolved Final analysis conference/secondary (Targeted Oncology)
GLOW Phase 3; ≥65 or unfit; TP53 excluded; n=211 IV vs chlorambucil-obinutuzumab 66-month PFS 51.7% vs 18.1% (HR 0.27); OS 79.0% vs 60.8% (HR 0.46). 4 sudden cardiac deaths on IV Leukemia, 2 Oct 2026 (abstract only)
MURANO Phase 3; relapsed/refractory Venetoclax-rituximab (2 years) vs BR Median PFS 54.7 vs 17.0 months; 7-year OS 69.6% vs 51.0%. Retreatment: median PFS 23 months, response 72% Blood 2025 (abstract only)
RESONATE-2 Phase 3; ≥65; del(17p) excluded Ibrutinib vs chlorambucil Median PFS 8.9 vs 1.3 years; 9-year OS 68% Blood 2025
E1912 Phase 3; fit; ≤70 Ibrutinib-rituximab vs FCR PFS HR 0.37; OS HR 0.47 Blood 2022
BRUIN phase 1/2 Single arm; after BTKi Pirtobrutinib Response 73.3%; median PFS 19.6 months NEJM 2023 (abstract only)
BRUIN CLL-321 Phase 3; after covalent BTKi Pirtobrutinib vs idelalisib-rituximab or BR Median PFS 14.0 vs 8.7 months (HR 0.54); OS HR 1.09 (crossover) JCO 2025
BRUIN CLL-313 Phase 3; untreated; no del(17p) Pirtobrutinib vs BR 24-month PFS 93.4% vs 70.7% (HR 0.199); interim OS HR 0.257 (immature) JCO 2026 (ASH 2025 late-breaker)
BRUIN CLL-314 Phase 3; no prior BTKi (untreated and relapsed) Pirtobrutinib vs ibrutinib Response 87.0% vs 78.5%; untreated-subgroup PFS HR 0.24 (immature); AF 2.4% vs 13.5% JCO 2026
BRUIN CLL-322 Phase 3; previously treated Pirtobrutinib + venetoclax-rituximab vs venetoclax-rituximab Published in the Lancet in July 2026 (EHA 2026 late-breaker); results not verified Lancet 2026 (title only)
A041702 Phase 3; ≥65 Ibrutinib-obinutuzumab vs MRD-guided ibrutinib-venetoclax-obinutuzumab 5-year PFS 59% vs 68%, HR 0.89, not significant Registry results only

The newest data (2025–2026).

  • ASH 2025 (6–9 Dec 2025): CLL17 primary results; the BRUIN CLL-313 late-breaker; SEQUOIA at 6 years; the CRISTALLO update; AMPLIFY genetics (NOTCH1-mutated disease did worse with AV, exploratory); CLL13 second-line data; Richter-transformation trials.
  • EHA 2026 (Stockholm, 11–14 June 2026):
  • CLL14 final results.
  • AMPLIFY quality-of-life and age-safety analyses.
  • An early-phase cohort of sonrotoclax + zanubrutinib, reporting undetectable MRD in more than 90%.
  • A phase 2 of fixed-duration pirtobrutinib + obinutuzumab.
  • BRUIN CLL-322.
  • These items are conference/secondary, per the Lymphoma Hub abstract guide.
  • Since EHA: GLOW at 67 months (2 October 2026), and a new MRD-based model, CIRI2-CLL, for predicting relapse after fixed-duration therapy (C-statistics 0.82–0.98; JCO, October 2026, abstract only).
  • Not yet public: ASH 2026 abstracts appear on 4 November 2026.

MRD-guided and next-generation first-line trials still running [E]:

  • CLL18/MOIRAI, recruiting, including at Lund (section 17).
  • MAJIC: AV vs VenO, both MRD-guided; 607 enrolled; primary completion expected July 2027 (NCT05057494).
  • CLL16: AVO vs VenO in high-risk disease (NCT05197192).
  • CELESTIAL-TNCLL: sonrotoclax + zanubrutinib vs VenO; primary completion 2032.
  • BGB-11417-304: sonrotoclax + zanubrutinib vs AV.
  • BELLWAVE-011: nemtabrutinib vs ibrutinib or acalabrutinib; primary completion 2032.
  • BELLWAVE-008: nemtabrutinib vs chemoimmunotherapy.
  • GLORA-2: lisaftoclax + acalabrutinib vs chemoimmunotherapy.

Cross-trial caveats [E/I]:

  • Populations differ: fit or unfit, TP53 included or excluded, median age from 61 (AMPLIFY) to 72 (CLL14).
  • Comparators differ: chemoimmunotherapy in most trials, ibrutinib in CLL17.
  • COVID-19 inflated infection deaths in anti-CD20 arms enrolled during 2020–2022.
  • MRD assays and timepoints differ.
  • Undetectable MRD does not translate across strategies. Continuous ibrutinib gives 0% undetectable MRD yet about 81% 3-year PFS. MRD-guided IVO gave far more undetectable MRD than IO without a significant PFS gain.
  • MRD-guided FLAIR results should not be credited to the licensed fixed 15-cycle IV.
  • Indirect comparisons depend on who pays for them. A Janssen-funded comparison favoured IV over AV (press release); BeOne-funded analyses favoured zanubrutinib. No network meta-analysis yet includes CLL17 (Wen 2025; Munir 2026).