# CLL14: one year of venetoclax plus obinutuzumab instead of chemo-immunotherapy in older, less fit CLL patients

Source: https://onco.cc/key-papers/paper-cll14-venetoclax-obinutuzumab-nejm-2019/  
OnCo record `paper-cll14-venetoclax-obinutuzumab-nejm-2019` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A fixed one-year course of two targeted drugs kept CLL under control far longer than chemo-immunotherapy, and most patients had no detectable disease when treatment stopped.

## Summary

CLL14 randomised 432 previously untreated patients with CLL and coexisting conditions (CIRS score above 6 or creatinine clearance under 70 mL/min) to 12 cycles of venetoclax plus obinutuzumab or chlorambucil plus obinutuzumab. The primary endpoint was investigator-assessed progression-free survival. At 24 months PFS was 88.2% versus 64.1% (hazard ratio 0.35), and undetectable MRD in peripheral blood three months after treatment ended was 75.5% versus 35.2%. Grade 3-4 neutropenia and infections were similar between arms. With six years of follow-up more than half of venetoclax-obinutuzumab patients remained progression-free against roughly a fifth on chemo-immunotherapy, though overall survival was not significantly different.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: New England Journal of Medicine
- Year: 2019
- DOI: 10.1056/NEJMoa1815281
- Authors: Fischer K, Al-Sawaf O, Bahlo J, et al.
- Findings: 432 patients with untreated CLL and comorbidities; 12 cycles of venetoclax-obinutuzumab vs chlorambucil-obinutuzumab.; 24-month PFS 88.2% vs 64.1%; hazard ratio 0.35.; Undetectable MRD (below 10^-4) in blood 3 months after treatment end: 75.5% vs 35.2%.; Grade 3-4 neutropenia 52.8% vs 48.1%; grade 3-4 infections 17.5% vs 15.0%.; Benefit held across IGHV-unmutated and TP53-aberrant subgroups, though del(17p)/TP53 patients relapsed earlier.
- What it means: CLL14 established the first chemotherapy-free, fixed-duration regimen for front-line CLL and made MRD-guided thinking mainstream in the disease. Patients get a year of treatment and then a treatment-free period rather than indefinite therapy. The choice today is between fixed-duration venetoclax combinations and continuous BTK inhibitors, with no proven survival difference.
- Caveats: Overall survival has not differed significantly, partly because effective salvage therapies exist.; Patients were older and less fit; CLL13/GAIA later confirmed benefit in fit patients.; Venetoclax requires a 5-week ramp-up and tumour-lysis monitoring, which is a practical burden.; Retreatment strategy after relapse was not defined by the trial.

## Sources

- Full text (DOI): https://doi.org/10.1056/NEJMoa1815281
- ClinicalTrials.gov NCT02242942: https://clinicaltrials.gov/study/NCT02242942

## Connected records

- pairings: [Venetoclax + obinutuzumab (12 months)](https://onco.cc/pairings/venetoclax-plus-obinutuzumab/)
- cancers: [Chronic lymphocytic leukaemia](https://onco.cc/cancers/cll/), [Chronic lymphocytic leukaemia, first treatment](https://onco.cc/cancers/cll-treatment-naive/)
- targets: [BCL-2](https://onco.cc/targets/bcl2/), [CD20](https://onco.cc/targets/cd20/)
- drugs: [Obinutuzumab](https://onco.cc/drugs/obinutuzumab/), [Venetoclax](https://onco.cc/drugs/venetoclax/)
- companies: [AbbVie (incl. ImmunoGen, Capstan)](https://onco.cc/companies/abbvie/), [Roche / Genentech](https://onco.cc/companies/roche-genentech/)
- terms: [del(17p) / TP53 aberration in CLL](https://onco.cc/terms/del17p-tp53/), [IGHV mutational status](https://onco.cc/terms/ighv-status/), [Minimal / molecular residual disease (MRD)](https://onco.cc/terms/mrd/), [Progression-free survival (PFS)](https://onco.cc/terms/pfs/)
- trials: [CLL13 / GAIA](https://onco.cc/trials/cll13-gaia/), [CLL14](https://onco.cc/trials/cll14/)
- people: [Kirsten Fischer](https://onco.cc/people/kirsten-fischer/), [Michael Hallek](https://onco.cc/people/michael-hallek/)
- bottlenecks: [Dormant cells and minimal residual disease](https://onco.cc/bottlenecks/b-dormancy-mrd/), [Older and multimorbid patients are excluded and undertreated](https://onco.cc/bottlenecks/b-aging-comorbidity/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)
- key papers: [MURANO: two years of venetoclax plus rituximab versus chemo-immunotherapy in relapsed CLL](https://onco.cc/key-papers/paper-murano-venetoclax-rituximab-nejm-2018/)

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