A Randomized Phase III Study of Venetoclax-Based Time-Limited Combination Treatments Versus Standard Therapy in Frontline CLL

A study aimed to assess the efficacy and safety of three venetoclax (V) plus CD20 antibody-based regimens in comparison to chemoimmunotherapy (CIT) as a frontline treatment for fit patients with chronic lymphocytic leukemia (CLL) and without TP53 mutation/deletion. The findings were presented by Barbara Eichhorst, MD, and colleagues at the 2021 American Society of Hematology Annual Meeting.

In this trial, called GAIA, researchers analyzed a total of 926 treatment naïve fit CLL patients (median age = 61 years) requiring therapy. Patients with TP53 aberrations were excluded from analysis.

The population of interest were randomized 1:1:1:1 to receive:

• six courses of CIT (FCR for patients ≤65 years: fludarabine 25 mg/m² days 1-3, cyclophosphamide 250 mg/m² days 1-3, rituximab 375 mg/m² day 1 cycle 1 and 500 mg/m² day 1 cycle 2-6; bendamustine-rituximab for patients >65 years [bendamustine 90mg/m² days 1-2])
• one of three V-based combinations
  • RVe: V and rituximab (375/500 mg/m² day 1 cycle 1-6)
  • GVe: V and obinutuzumab (1,000 mg day 1, 8, 15 cycle 1 and day 1 cycle 2-6)
  • GIVe: V, obinutuzumab, and ibrutinib (420 mg/day cycle 1-12, if measurable residual disease [MRD]-detectable continued until cycle 36)

The key outcomes of interest were defined as the rate of undetectable MRD by flow cytometry in peripheral blood (PB) at month 15, and progression-free survival (PFS), each with a significance level of 2.5%.

According to the results, the endpoint of undetectable MRD in PB at 15 months was met, and the researchers noted that the rate of undetectable MRD in the intent-to-treat population was significantly higher in GVe compared to CIT: 86.5% versus 52.0% (p < 0.0001), respectively. Moreover, the researchers observed that GIVe demonstrated a superior undetectable MRD rate (92.2%) compared to CIT (p < 0.0001), while RVe (57.0%) did not (p = 0.317).

“The time-limited therapies of GVe and GIVe provided superior undetectable MRD rates in PB at month 15 compared to CIT. In addition, undetectable MRD rates in BM were higher in GVe and GIVe in particular than in CIT,” the researchers concluded. They added that all study arms displayed a favorable safety profile.