Fit patients newly diagnosed with chronic lymphocytic leukemia (CLL) had improved progression-free survival (PFS) when treated with venetoclax plus obinutuzumab compared to patients treated with either chemoimmunotherapy or venetoclax plus rituximab (hazard ratio [HR] = 0.47, p<0.0001; and HR=0.57, p=0.0011, respectively). These four-year follow-up results from the phase III GAIA/CLL13 clinical trial were published in Lancet Oncology.
The open-label trial randomized 926 patients from countries in Europe and the Middle East between December 2016 and October 2019. The mean patient age was 60.8 years, and 28% of the patients were female. These patients were deemed fit, which was defined as having a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower and a creatinine clearance of at least 70 mL/min. Patients in the control arm received chemoimmunotherapy (rituximab plus bendamustine or fludarabine/cyclophosphamide, n=229). The other patients received one of three experimental combinations: venetoclax plus rituximab (n=237); venetoclax plus obinutuzumab (n=229); or a triple combination of venetoclax, obinutuzumab, and ibrutinib (n=231). The co-primary endpoints were investigator-assessed PFS and undetectable measurable residual disease (MRD) rate in peripheral blood at month 15. The planned time-limited treatment duration was six cycles in the chemoimmunotherapy arm, 12 cycles in the rituximab-venetoclax arm and the venetoclax-obinutuzumab arm, and between 12 and 36 cycles — depending on MRD status — in the triple-combination arm.
“The idea behind the triple combination in the first line was to induce deeper remissions and potentially increase the fraction of ‘functionally cured’ patients with very long-term remissions that may never need a second-line therapy, a phenomenon we have so far only reliably observed with fludarabine, cyclophosphamide, and rituximab,” said Moritz Fürstenau, MD, of the University of Cologne in Germany and the German CLL Study Group. “We also compared this triple combination to our current standard of care for patients with non-high-risk disease in large parts of Europe, of venetoclax plus obinutuzumab.”
Like the venetoclax-obinutuzumab combination, the triple combination arm also had a significantly longer PFS compared to the chemoimmunotherapy group (HR=0.30, p<0.0001) and the venetoclax–rituximab group (HR=0.38, p<0.0001). There was no difference in the PFS between the venetoclax-obinutuzumab combination and the triple combination (HR=0.63, p=0.031).
The estimated four-year PFS rate was 85.5% (97.5% CI 79.9-91.1; 37 [16%] events) in the triple-combination group; 81.8% (97.5% CI 75.8-87.8; 55 [24%] events) in the venetoclax-obinutuzumab group; 70.1% (97.5% CI 63.0-77.3; 84 [35%] events) in the venetoclax-rituximab group; and 62.0% (97.5% CI 54.4-69.7; 90 [39%] events) in the chemoimmunotherapy arm.
The overall survival (OS) did not differ significantly between the treatment groups, and the median OS was not reached in any of the treatment groups.
“Patients with an unmutated IGHV gene, which was the majority of patients, seemed to particularly benefit from the triple combination, as they had significantly longer PFS when treated with all three drugs compared to venetoclax-obinutuzumab only,” Dr. Fürstenau said.
However, “the triple combination was associated with more infections and more cardiac adverse events (AEs) compared to venetoclax plus obinutuzumab,” he added.
The most common grade 3 or worse treatment-related AE was neutropenia in 53% of the chemoimmunotherapy arm, 46% of the rituximab-venetoclax arm, 56% of the venetoclax-obinutuzumab arm, and 48% of the triple-combination arm.
Deaths determined to be associated with study treatment occurred in three (1%) patients in the chemoimmunotherapy group and four (2%) in the triple-combination arm.
According to Dr. Fürstenau, venetoclax-obinutuzumab is the standard of care in the frontline CLL setting in many parts of Europe.
“I believe that these results will further underscore the potential of time-limited combinations in the first-line CLL setting, as we have also seen excellent outcomes of those patients retreated with venetoclax combinations after having already received venetoclax combinations in the first line,” Dr. Fürstenau said.
Obinutuzumab-venetoclax is approved by the U.S. Food and Drug Administration (FDA) as a treatment for patients with newly diagnosed CLL. Ibrutinib monotherapy is also FDA approved in this patient population. Currently, the triple combination is not approved in the U.S. “Given the excellent efficacy of venetoclax plus obinutuzumab with a more favorable toxicity profile, we currently don’t recommend the addition of ibrutinib in the first-line setting,” he added.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Fürstenau M, Kater AP, Robrecht S, et al. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2024;25(6):744-59.
