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

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.

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 nejm.org.