Frontline Venetoclax for Chronic Lymphocytic Leukemia

Treatment with the BCL-2 inhibitor venetoclax combined with an anti-CD20 monoclonal antibody has shown high response rates in patients with relapsed or refractory chronic lymphocytic leukemia (CLL; e.g., NEJM JW Oncol Hematol Mar 21 2018 and N Engl J Med 2018; 378:1107). However, analysis of this regimen in the frontline setting has been limited.

To address this issue, investigators conducted an industry-funded, multicenter, prospective, open-label, randomized, phase 3 trial (GAIA–CLL13) of treatment with venetoclax in 926 previously untreated, medically fit adults with advanced-stage CLL; those with del(17p) or TP53 mutations were ineligible. Patients were randomized to one of four treatment groups:

• Chemo-immunotherapy with fludarabine, cyclophosphamide, and rituximab if ≤65 years of age or bendamustine and rituximab if >65 (Chemo)
• Venetoclax plus rituximab (VR)
• Venetoclax plus obinutuzumab (VO)
• Venetoclax plus obinutuzumab and ibrutinib (VOI)

Treatment duration in the chemo-immunotherapy group was 6 monthly cycles and in the venetoclax groups was based in part on results of minimal residual disease (MRD) testing by multicolor flow cytometry of blood and bone marrow.

At 15 months, undetectable MRD (<1 CLL cell/10,000 white blood cells; a coprimary endpoint) was achieved by more patients receiving VO or VOI than by those receiving Chemo (86% and 92% vs. 52%; P<0.001 for both comparisons); undetectable MRD was achieved by a similar percentage of those receiving VR or Chemo (57% and 52%). Clinical complete response rates were higher with VO and VOI (57% and 62%) than with Chemo and VR (31% and 49%). At a median follow-up of 38.8 months, progression-free survival (a coprimary endpoint) was improved with VO or VOI versus Chemo or VR. Treatment discontinuation rates due to adverse events were higher with Chemo (15%) or VOI (13%) than with VO (6%) or VR (6%).