First-line venetoclax combinations in chronic lymphocytic leukemia

The phase III GAIA/CLL13 trial compared venetoclax-based regimens in the frontline therapy of CLL vs. historical chemoimmunotherapy regimens. Importantly, venetoclax-based regimens that contained obinutuzumab outperformed both venetoclax plus rituximab and the historical chemoimmunotherapy 

comparator arm with respect to both PFS and undetectable MRD at 15 months of therapy. Grade 3 or 4 infections were more common in the triplet therapy regimen of venetoclax plus ibrutinib plus obinutuzumab and in the historical chemoimmunotherapy comparator arm compared to venetoclax + anti-CD20 monoclonal antibody (either rituximab or obinutuzumab). At 15 months after start of treatment, uMRD was highest in the triplet regimen (venetoclax, ibrutinib, obinutuzumab) at 92.2% (97.5% CI: 87.3%–95.7%), followed closely by venetoclax plus obinutuzumab at 86.5% (97.5% CI: 80.6%–91.1%). Both venetoclax plus rituximab and traditional chemoimmunotherapy demonstrated significantly lower rates of uMRD by peripheral blood at this time point. In terms of PFS, with a median follow-up of 38.8 months, estimated 3-year PFS was not significantly different for the triplet regimen (venetoclax, ibrutinib, obinutuzumab; 90.5%; HR = 0.32; 97.5% CI: 0.19–0.54) and venetoclax plus obinutuzumab (87.7%; HR = 0.42; 97.5% CI: 0.26–0.68). The improvement in PFS with both the triplet regimen (venetoclax, ibrutinib, obinutuzumab) and venetoclax plus obinutuzumab compared to historical chemoimmunotherapy was statistically significant, which was not the case for the 3-year PFS with frontline venetoclax plus rituximab. Although longer follow-up data will be helpful, this report raises the question of whether the additional toxicities noted with triplet therapy (venetoclax, ibrutinib, obinutuzumab) in the frontline setting will outweigh any potential benefit in uMRD or PFS compared to venetoclax plus obinutuzumab alone, which has not yet been shown with statistical significance.