Administering time-limited regimens that were combinations of venetoclax plus obinutuzumab or venetoclax plus obinutuzumab and ibrutinib was superior to chemoimmunotherapy in achieving undetectable measurable residual disease in the peripheral blood at month 15 in fit patients with chronic lymphocytic leukemia (CLL), according to results of the phase III GAIA (CLL13) trial.1 In addition, undetectable MRD rates in the bone marrow and complete response rates were significantly higher with both venetoclax/obinutuzumab and venetoclax/obinutuzumab/ibrutinibcompared with chemoimmunotherapy, but not with a fourth regimen of venetoclax/rituximab, reported Barbara Eichhorst, MD, of University Hospital, Cologne, Bonn, Germany, at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition.
Barbara Eichhorst, MD
“The study showed us that [venetoclax/rituximab] is not superior to [chemoimmunotherapy] for achieving undetectable MRD. There was a low rate of discontinuations in all three experimental arms—under 15%. There were some Bruton’s tyrosine kinase [BTK]-associated severe adverse events, but otherwise there was no significant difference in the safety between treatment arms. All treatments given in the study showed a good safety profile in this fit patient population,” Dr. Eichhorst stated.
For fit CLL patients, the standard of care for front-line therapy in the United States is continuous treatment with a BTK inhibitor or venetoclax plus obinutuzumab, particularly in patients with unfavorable prognostic factors. The time-limited combinations of venetoclax plus obinutuzumab and venetoclax plus rituximab have produced high rates of undetectable MRD, which is strongly associated with extended progression-free survival.
Venetoclax plus obinutuzumab is approved as front-line therapy for unfit patients based on data from the CLL14 trial.2 There are no data for this regimen in fit patients. The GAIA (CLL13) trial evaluated the efficacy and safety of three time-limited venetoclax plus CD20 antibody-based regimens vs chemoimmunotherapy as front-line treatment for fit patients with CLL without TP53 mutations/deletions and del(17p).
Study Details
The study enrolled treatment-naive fit patients with CLL who required therapy. “Fit” was defined as cumulative illness rating scale score ≤ 6 and normal creatinine clearance ≥ 70 mL/min. Patients with TP53 mutations/deletions and del(17p) were excluded, because they are known to have a poor response to chemoimmunotherapy.
Patients were randomly assigned in a 1:1:1:1 ratio to receive:
- Chemoimmunotherapy for six cycles: fludarabine, cyclophosphamide, and rituximab (FCR) for patients ≤ 65 years and bendamustine plus rituximab (BR) for patients older than 65
- Venetoclax (standard ramp-up from cycle 1, day 22; 400 mg/d for cycle 2–12) and rituximab (375/500 mg/m2 on day 1 for cycle 1–6)
- Venetoclax for 12 cycles and obinutuzumab (1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of cycle 2–6)
- Venetoclax for 12 cycles plus obinutuzumab and ibrutinib (420 mg/d of cycle 1–12; if MRD-detectable, continued until cycle 36).
Stratification factors included country, Binet stage, and age (≤ 65 or > 65 years). The co-primary endpoints of the trial were the rate of undetectable MRD (< 10–4) by flow cytometry in peripheral blood at month 15 (venetoclax/obinutuzumab vs chemoimmunotherapy) and progression-free survival (venetoclax/obinutuzumab/ibrutinibvs chemoimmunotherapy). MRD in bone marrow was evaluated 3 months after the end of treatment (month 9) in patients with clinical complete response.
From February 2016 to September 2019, a total of 926 patients were randomly assigned 1:1 to receive chemoimmunotherapy (n = 229; 150 FCR and 79 BR) venetoclax/rituximab (n = 237); venetoclax/obinutuzumab (n = 229), or venetoclax/obinutuzumab/ibrutinib(n = 231). Median age was 61 years. Median cumulative illness rating score was 2. The majority of patients were in advanced Binet stage (stage B: 37.8%, stage C: 35.6%), and unmutated IGHV status was present in 56%.
Fourteen patients did not receive study treatment (13 FCR, 1 venetoclax/obinutuzumab) and were not included in the safety analysis. The cutoff point for the first co-primary endpoint analysis was February 28, 2021. The median follow-up was 27.9 months.
Study Findings
The study met the co-primary endpoint of undetectable MRD in peripheral blood at month 15. In the intent-to-treat population, the rate of undetectable MRD was significantly higher in patients receiving venetoclax plus obinutuzumab compared to chemoimmunotherapy: 86.5% vs 52.0%, respectively (P < .0001). Venetoclax/obinutuzumab/ibrutinibalso showed a superior undetectable MRD rate of 92.2% compared to chemoimmunotherapy (P < .0001), while venetoclax/rituximab (57.0%) did not.
In the intent-to-treat analysis, corresponding bone marrow undetectable MRD rates were 37.1% (chemoimmunotherapy), 43.0% (venetoclax/rituximab), 72.5% (venetoclax/obinutuzumab) and 77.9% (venetoclax/obinutuzumab/ibrutinib ). Month 15 overall response rates and complete response rates for the four regimens followed the numerical pattern for undetectable MRD rates.
Progression-free survival, the co-primary endpoint, will not be analyzed until the first quarter of 2022, because too few events had occurred at data cutoff.
The most common grade 3 to 5 treatment-emergent adverse events were neutropenia (50.5% of all patients), thrombocytopenia (12.2%), tumor lysis syndrome (7.5%), infusion-related reaction (7.2%), febrile neutropenia (6.5%), and pneumonia (5.3%). Grade 3 to 4 infections were more frequent in the chemoimmunotherapy arm (19.9%) and the venetoclax/obinutuzumab/ibrutinib arm (22.1%) than the other two arms. The numbers of second malignancies were 33, 19, 22 and 21 for chemoimmunotherapy, venetoclax/rituximab, venetoclax/obinutuzumab, and venetoclax/obinutuzumab/ibrutinib, respectively. Fatal adverse events were reported in 5, 7, 6, and 9 of the patients, respectively.
DISCLOSURE: Dr. Eichhorst has served as a consultant or advisor for AbbVie, BeiGene, AstraZeneca, Novartis, Celgene, ArQule, Oxford Biomedica (UK), MSD, F. Hoffmann-La Roche Ltd, Gilead, and Janssen; has received travel, accommodation, or expenses from AbbVie, Novartis, Celgene, F. Hoffmann-La Roche Ltd, Gilead, and Janssen; has received research funding from AbbVie, BeiGene, AstraZeneca, F. Hoffmann-La Roche Ltd, Gilead, and Janssen; and has served on a speakers’ bureau for AbbVie, BeiGene, AstraZeneca, Novartis, Celgene, Adaptive Biotechnologies, Hexal, F. Hoffmann-La Roche Ltd, Gilead, and Janssen.
REFERENCES
1. Eichhorst B, Niemann C, Kater AP, et al: A randomized phase III study of venetoclax-based time-limited combination treatments (RVE, GVe, GIVe) vs standard chemoimmunotherapy (CIT: FCR/BR) in frontline chronic lymphocytic leukemia (CLL) of fit patients: First co-primary endpoint analysis of the International Intergroup GAIA-CLL13 trial. 2021 ASH Annual Meeting & Exposition. Abstract 71. Presented December 11, 2021.
2. Fischer K, Al-Sawaf O, Bahlo J, et al: Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 380:2225-2236, 2019.
