Triple-therapy improves PFS in fit, previously untreated CLL patients

Phase-3 trial shows improved PFS with venetoclax/obinutuzumab/ibrutinib therapy in fit, untreated patients with chronic lymphocytic leukaemia.

Study aimed at comparing venetoclax-based first-line regimens with CIT

In fit patients with advanced CLL of favourable genetic risk, chemoimmunotherapy with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR) is still standard first-line treatment. In less fit patients, venetoclax/obinutuzumab (VG) is superior to chlorambucil/obinutuzumab concerning PFS1. Triple combinations including BTK inhibitors have shown promising results in phase 2 trials2. Data comparing VG with FCR or BR, nor data comparing VG plus ibrutinib (GIV) with FCR or BR as a first-line treatment in fit patients with CLL is not yet available. Therefore, the 4-arm, phase 3 GAIA/CLL13 study (NCT02950051) evaluated the efficacy and safety of 3 time-limited, venetoclax-based, first-line regimens in comparison with chemoimmunotherapy in fit patients with CLL.

Patients (n=920) were 1:1:1:1 randomised to receive 6 cycles of FCR (for patients <65 years) or BR (>65 years), 12 cycles rituximab/venetoclax (RV), 12 cycles VG, or 12 cycles GIV. The first co-primary endpoint, a superior undetectable minimal residual disease (MRD) rate in both the VG arm and GIV arm over the FCR/BR arm at month 15, was already met in 20213. Now, Prof. Barbara Eichhorst (University Hospital Cologne, Germany) presented results on the second co-primary endpoint of the trial: interim PFS in the GIV arm versus the FCR/BR arm. 

Time-limited treatment with GIV or VG improves undetectable MRD rate compared with standard CIT

Results demonstrated superior PFS for GIV compared with FCR/BR (90.5% vs 75.5% at 3 years; HR 0.32; P<0.000001). Superior PFS was also seen in the VG arm versus FCR/BR (87% vs 75.5% at 3 years; HR 0.42; P<0.0001). PFS was not significantly different between the RV and FCR/BR arms (80.8% vs 75.5% at 3 years; HR 0.79; P=0.183). In all study arms, 3-year PFS rates were higher for patients with mutated IGHV compared with patients with unmutated IGVH. With respect to time to next treatment, GIV was superior to FCR/BR: at 3 years, 98.3% of GIV patients, 94.1% of VG patients, 92.9% of RV patients, and 87.2% of FCR/BR patients were without new treatment. Overall response data are not yet mature. 

“These results demonstrate that time-limited treatment with GIV or VG improves both undetectable MRD rate at 15 months and PFS compared with standard chemoimmunotherapy in fit, previously untreated patients with CLL,” summarised Prof. Eichhorst.

  1. Al Sawaf O, et al. Lancet Oncol. 2020;21:1188–1200.
  2. Huber H, et al. Blood. 2022;139:1318–1329.
  3. Eichhorst B, et al. Abstract 71. ASH 2021 Annual Meeting, Atlanta, GA, USA, 11–14 December.
  4. Eichhorst B, et al. Time-limited venetoclax-obinutuzumab +/- ibrutinib is superior to chemoimmunotherapy in frontline chronic lymphocytic leukemia (CLL): PFS co-primary endpoint of the randomized phase 3 GAIA/CLL13 trial. Abstract LB2365. EHA2022 Hybrid Congress, 09–12 June.