The first-line treatment of chronic lymphocytic leukemia (CLL) with venetoclax plus obinutuzumab with or without ibrutinib resulted in improved progression-free survival (PFS) compared with chemoimmunotherapy, according to the results of the GAIA-CLL13 trial.
A greater proportion of patients treated with the venetoclax-obinutuzumab combination also achieved undetectable minimal residual disease (MRD). The results of the open-label, phase 3 GAIA-CLL13 trial (ClinicalTrials.gov Identifier: NCT02950051) were published in the New England Journal of Medicine.
The study randomly assigned 926 patients with newly-diagnosed CLL to receive 1 of 4 regimens: venetoclax plus obinutuzumab, venetoclax plus obinutuzumab and ibrutinib, venetoclax plus rituximab, and chemoimmunotherapy (fludarabine, cyclophosphamide, plus rituximab or bendamustine plus rituximab). The venetoclax combinations were administered for 12 cycles and chemoimmunotherapy for 6 cycles. Patients receiving ibrutinib could discontinue the drug after 2 consecutive undetectable MRD measurements.
The primary endpoints were rate of undetectable MRD at 15 months and PFS. Secondary endpoints included undetectable MRD at earlier time points and in bone marrow, complete response (CR), and overall survival (OS).
At baseline, the median age ranged from 60 to 62, with approximately one-third of patients in each group aged older than 65. The majority of patients had an Eastern Cooperative Oncology group performance status of 0. There were 19.0-25.5% of patients with no cytogenetic abnormalities, 41.0-47.7% with a 13q deletion, 13.9-19.2% with an 11q deletion, 14.3-20.5% with trisomy 12, and 39.0-43.7% with mutated IGHV. The majority of patients had an International Prognostic Index risk of intermediate to high.
The combination of venetoclax plus obinutuzumab with or without ibrutinib resulted in undetectable MRD among 92.2% and 86.5% of patients, respectively, compared with 52.0% among patients treated with chemoimmunotherapy (P <.001 for both). There were 57.0% of patients treated with venetoclax plus rituximab who achieved an undetectable MRD level (P =.32).
The 3-year PFS was highest among patients treated with venetoclax plus obinutuzumab and ibrutinib at 90.5% compared with 75.5% in the chemoimmunotherapy group (hazard ratio [HR], 0.32; 97.5% CI, 0.19-0.54; P <.001). The PFS was also higher among patients treated with venetoclax plus obinutuzumab, with a 3-year rate of 87.7% (HR, 0.42; 97.5% CI, 0.26-0.68; P <.001).
There was no significant difference in the 3-year PFS between the chemoimmunotherapy group and the venetoclax plus rituximab group (80.8%; HR, 0.79; 97.5% CI, 0.53-1.18; P =.18).
The 3-year OS was similar between all treatment groups at 95.3% and 96.3% with venetoclax plus obinutuzumab with or without ibrutinib, respectively, 96.5% with venetoclax plus rituximab, and 95.0% with chemoimmunotherapy.
The CR rate was 61.9% and 56.8% with venetoclax plus obinutuzumab with or without ibrutinib, respectively, and 49.4% with venetoclax plus rituximab, and 31.0% with chemoimmunotherapy.
The rate of serious adverse events (AEs) was 50.2% and 44.7% in the venetoclax plus obinutuzumab with or without ibrutinib groups, respectively, 40.1% in the venetoclax plus rituximab group, and 47.7% in the chemoimmunotherapy group. The most common grade 3-4 AEs were infections and cytopenia. Grade 3-4 infections occurred most frequently in the venetoclax triplet arm at 21.2%, followed by 18.5% with chemoimmunotherapy, 13.2% with venetoclax plus obinutuzumab, and 10.5% with venetoclax plus rituximab.
“Time-limited combinations of targeted agents such as venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib led to longer and deeper responses than the current first-line chemoimmunotherapy standard,” the authors concluded in their report.
Disclosures: This research was supported by AbbVie, Janssen, and Roche. Please see the original reference for a full list of disclosures.
Eichhorst B, Niemann CU, Kater AP, et al. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388:1739-1754. doi: 10.1056/NEJMoa2213093