First-Line Venetoclax Combinations vs Chemoimmunotherapy in Fit Patients With CLL

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In the phase III GAIA–CLL13 trial reported in The New England Journal of Medicine, Barbara Eichhorst, MD, and colleagues found better outcomes with venetoclax plus obinutuzumab and veneto­clax, obinutuzumab, and ibrutinib compared with chemoimmunotherapy as first-line treatment in fit patients with advanced chronic lymphocytic leukemia (CLL).

Barbara Eichhorst, MD

Barbara Eichhorst, MD

Study Details

The open-label trial included 926 fit patients—defined as those with a low burden of coexisting conditions—with no TP53 aberrations from sites in nine European countries and Israel. They were randomly assigned 1:1:1:1 between December 2016 and October 2019 to receive either:

  • 6 cycles of chemoimmunotherapy (n = 229) with fludarabine/cyclophosphamide/rituximab (age ≤ 65 years) or bendamustine/ritux­imab (age > 65 years)
  • 12 cycles of venetoclax/rituximab (n = 237)
  • 12 cycles of venetoclax/obinutuzumab (n = 229)
  • 12 cycles of veneto­clax/obinutuzumab/ibrutinib (n = 231).

Ibrutinib treatment was discontinued after two consecutive measurements of undetectable measurable residual disease (MRD), or treatment could be extended. The two primary endpoints were undetectable MRD (sensitivity of <10−4) on flow cytometry in periph­eral blood at month 15 and progression-free survival.

Efficacy Outcomes

At 15 months, the proportions of patients with undetectable MRD were 86.5% (97.5% confidence interval [CI] = 80.6%–91.1%) in the venetoclax/obinutuzumab group (P < .001 vs chemoimmunotherapy group), 92.2% (97.5% CI = 87.3%–95.7%) in the venetoclax/obinutuzumab/ibrutinib group (P < .001 vs chemoimmunotherapy group), and 57.0% (97.5% CI = 49.5%–64.2%) in the venetoclax/rituximab group (P = .32 vs chemoimmunotherapy group) vs 52.0% (97.5% CI = 44.4%–59.5%) in the chemoimmunotherapy group.

At interim analysis of progression-free survival at a median follow-up of 38.8 months (interquartile range = 32.7–46.1 months), 3-year progression-free survival was 90.5% in the venetoclax/obinutuzumab/ibrutinib group (hazard ratio [HR] = 0.32, 97.5% CI = 0.19–0.54,  P < .001 vs chemoimmunotherapy), 87.7% in the venetoclax/obinutuzumab group (HR = 0.42,  97.5% CI = 0.26–0.68, P < .001), and 80.8% in the venetoclax/rituximab group (HR = 0.79, 97.5% CI = 0.53–1.18, P = .18) vs 75.5% in the chemoimmunotherapy group.


  • Rates of undetectable MRD were higher with venetoclax/obinutuzumab and venetoclax/obinutuzumab/ibrutinib vs chemoimmunotherapy.
  • Progression-free survival was significantly improved with venetoclax/obinutuzumab and venetoclax/obinutuzumab/ibrutinib vs chemoimmunotherapy.

Adverse Events

The most common grade 3 and 4 adverse events across all treatment groups were cytopenias and infections; grade 3 or 4 infections were more common with chemoimmunotherapy (18.5%) and venetoclax/obinutuzumab/ibrutinib (21.2%) than with venetoclax/rituximab (10.5%) or venetoclax/obinutuzumab (13.2%). Serious adverse events were reported in 47.7% of patients in the chemoimmunotherapy group, 40.1% of the veneto­clax/rituximab group, 44.7% of the venetoclax/obinutuzumab group, and 50.2% of the venetoclax/obinutuzumab/ibrutinib group. Adverse events led to death in 10 patients (4.6%) in the chemoimmunotherapy group, 8 patients (3.4%) in the venetoclax/rituximab group, 9 patients (3.9%) in the venetoclax/obinu­tuzumab group (3.9%), and 9 patients (3.9%) in the vene­toclax/obinutuzumab/ibrutinib group.

The investigators concluded, “Venetoclax/obinutuzumab with or without ibrutinib was superior to chemoim­munotherapy as first-line treatment in fit patients with CLL.”  

Dr. Eichhorst, of University Hospital Co­logne, University of Cologne, Germany, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by AbbVie and others. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.