In the phase III GAIA–CLL13 study conducted among the patients with chronic lymphocytic leukaemia (CLL) and a low burden of coexisting conditions, time-limited venetoclax-obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy with respect to inducing undetectable minimal residual disease and longer progression-free survival (PFS). The percentages of patients in the venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib groups with undetectable minimal residual disease in peripheral blood were very high (86.5% and 92.2%); these percentages are among the highest reported in first-line treatment for CLL.
Because the improved incidence of undetectable minimal residual disease translated into superior PFS, the study corroborates the high prognostic value of undetectable minimal residual disease at the end of time-limited treatment. The findings are reported by Dr. Barbara Eichhorst of the Department I of Internal Medicine and Centre of Integrated Oncology Aachen–Bonn–Cologne–Düsseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne in Cologne, Germany, and colleagues on 11 May 2023 in The New England Journal of Medicine.
The authors wrote in the background that approved first-line treatments for fit patients (e.g., those with a low burden of coexisting conditions) with CLL are fixed-duration chemoimmunotherapy, a continuous Bruton’s tyrosine kinase (BTK) inhibitor, the time-limited BCL2 inhibitor venetoclax plus the anti-CD20 antibody obinutuzumab, and a BTK inhibitor plus venetoclax. However, data from prospective, randomised clinical studies evaluating the safety and efficacy of venetoclax-obinutuzumab in fit patients with CLL and normal renal function are lacking.
In the GAIA–CLL13 phase III, open-label study, the investigators randomly assigned, in a 1:1:1:1 ratio, fit patients with CLL who did not have TP53 aberrations to receive 6 cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) or 12 cycles of venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. Ibrutinib was discontinued after 2 consecutive measurements of undetectable minimal residual disease or could be extended. The primary endpoints were undetectable minimal residual disease as assessed by flow cytometry in peripheral blood at month 15 and PFS.
A total of 926 patients were assigned to one of the four treatment regimens (229 to chemoimmunotherapy, 237 to venetoclax-rituximab, 229 to venetoclax-obinutuzumab, and 231 to venetoclax-obinutuzumab-ibrutinib). At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher (86.5%) in the venetoclax-obinutuzumab group (97.5% confidence interval [CI] 80.6 to 91.1) and 92.2% in the venetoclax-obinutuzumab-ibrutinib group (97.5% CI 87.3 to 95.7) than 52.0% in the chemoimmunotherapy group (97.5% CI, 44.4 to 59.5) with p < 0.001 for both comparisons, but it was 57.0% and not different in the venetoclax-rituximab group (97.5% CI 49.5 to 64.2; p = 0.32).
Three-year PFS was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the chemoimmunotherapy group (hazard ratio [HR] for disease progression or death 0.32, 97.5% CI 0.19 to 0.54; p < 0.001). PFS at 3 years was 87.7% and also higher with venetoclax-obinutuzumab (HR for disease progression or death 0.42, 97.5% CI 0.26 to 0.68; p < 0.001), but 80.8% with venetoclax-rituximab (HR 0.79, 97.5% CI 0.53 to 1.18; p = 0.18).
Grade 3 and grade 4 infections were more common with chemoimmunotherapy (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%). No deaths attributed by the investigators to tumour lysis syndrome occurred in the study. Venetoclax-obinutuzumab-ibrutinib was associated with a higher incidence of tumour lysis syndrome than that reported with venetoclax-ibrutinib; this was probably related to simultaneous administration of obinutuzumab with ibrutinib, which led to rapid CLL cell depletion. Atrial fibrillation occurred in 7.8% of the patients who received venetoclax-obinutuzumab-ibrutinib.
The authors commented that reducing the risk of secondary neoplasia might influence the choice of treatment, particularly in patients with CLL that expresses mutated IGHV. Chemoimmunotherapy in IGHV-mutated CLL yields a high level of PFS that will be difficult to improve on. In the GAIA–CLL13 study, among all types of cancer, only non-melanoma skin cancers were less frequent in all 3 experimental groups than in the chemoimmunotherapy group, but further follow-up might show additional benefits with respect to the incidence of secondary neoplasia.
In an accompanied editorial article, Dr. Jennifer A. Woyach of the Ohio State University in Columbus, OH, US and and Dr. John C. Byrd of the University of Cincinnati in Cincinnati, OH, US wrote that although the study was designed to answer the important questions of whether these regimens were superior to standard chemoimmunotherapy, the data also shed light on which anti-CD20 antibody is the most appropriate partner for venetoclax and how outcomes in patients who have received venetoclax-obinutuzumab-ibrutinib compare with those in patients who have received venetoclax-obinutuzumab. Although this was not a prespecified, this study showed obinutuzumab to be a superior antibody for combination with venetoclax when given in the standard manner, even though it was administered at a higher dose than rituximab.
The future use of venetoclax-obinutuzumab-ibrutinib may be limited because the BTK inhibitors acalabrutinib and zanubrutinib, which have improved safety profiles, are now used more often than ibrutinib. Current phase III studies that are designed to compare second-generation BTK inhibitor combinations with venetoclax (with or without obinutuzumab) are therefore of high interest. Until such results are known, the use of triplet therapy should be viewed as investigational.
One important aspect of this study is the use of a new endpoint to measure treatment success. PFS has long been used as the standard endpoint for studies of first-line treatments for CLL. However, with median remissions lasting far in excess of 5 years, designing studies that take 8 to 10 years to produce results is not feasible. Surrogates such as minimal residual disease are of interest, but the lack of data showing outcomes dichotomized according to minimal residual disease status in BTK inhibitor-BCL2 inhibitor combinations makes this a currently unvalidated endpoint.
Regulatory authorities may consider adopting strategies in which a short-term efficacy threshold combined with safety or quality-of-life data can lead to approval of new agents while longer-term results are awaited. According to the editorialists, the GAIA–CLL13 study is a remarkable demonstration of the quality of fixed-duration treatments for younger, fit patients, and it challenges to continue to develop therapeutic strategies that will ultimately cure patients with CLL.
The study was previously presented in part at ASH 2021 Annual Meeting and at the EHA 2022 Congress.
The study was supported by grants from AbbVie, Janssen, and Roche.
- Eichhorst B, Niemann CU, Kater AP, et al. for the GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med 2023;388:1739-1754.
- Woyach JA, Byrd JC. Time-Limited Initial Therapy for Young, Fit Patients with CLL. N Engl J Med 2023;388:1812-1813.