Time-limited venetoclax-based regimens prolong PFS vs. chemoimmunotherapy in CLL
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Time-limited venetoclax, obinutuzumab and ibrutinib or venetoclax plus obinutuzumab prolonged PFS compared with chemoimmunotherapy among fit, previously untreated patients with chronic lymphocytic leukemia, according to study results.
The preplanned interim analysis of the international, randomized phase 3 GAIA/CLL13 trial, presented during European Hematology Association Hybrid 2022 Congress, also showed patients with unmutated immunoglobulin heavy-chain variable (IGHV) status appeared to benefit most from targeted therapy.
Rationale and methods
In Europe, EHA guidelines inform decisions on front-line treatment of CLL based on genetic risk factors, such as TP53 mutational status, as well as age and fitness of the patient, Barbara Eichhorst, MD, associate professor and attending physician at University Hospital Cologne in Germany, said during her presentation.
“For unfit patients, we have the option between targeted treatments, including long-term treatment with [Bruton tyrosine kinase] inhibitors, as well as time-limited treatment with the BCL2 inhibitor venetoclax [Venclexta; AbbVie, Genentech] in combination with obinutuzumab [Gazyva, Genentech], based for the latter one on data from the CLL14 trial,” Eichhorst said. “We do not yet have data in a randomized phase 3 trial for the fit patients on venetoclax plus obinutuzumab. ... Therefore, we as a research consortium in Europe wanted to address the question within this four-arm randomized trial.”
The CLL13 trial enrolled 926 fit patients (median age, 61 years) with treatment-naive chronic lymphocytic leukemia without the presence of TP53 aberrations.
Researchers randomly assigned patients in a 1:1:1:1 ratio to chemoimmunotherapy, venetoclax plus rituximab (Rituxan; Genentech, Biogen), venetoclax plus obinutuzumab, or venetoclax, obinutuzumab and ibrutinib (Imbruvica; Janssen, Pharmacyclics). If minimal residual disease (MRD) was detected, treatment continued until cycle 36.
The undetectable MRD rate (<10-4) by flow in peripheral blood at 15 months (venetoclax plus obinutuzumab vs. chemoimmunotherapy) and PFS (obinutuzumab, ibrutinib and venetoclax vs. chemoimmunotherapy), each with a significance level of 2.5%, served as the co-primary endpoints.
Results of the MRD co-primary endpoint, presented in December during ASH Annual Meeting and previously reported by Healio, showed a significantly higher rate of MRD in peripheral blood at 15 months among the intent-to-treat population with the venetoclax-obinutuzumab regimen vs. (86.5%; 97.5% CI, 80.6-91.1) compared with chemoimmunotherapy (52%; 97.5% CI, 44.4-59.5). Ibrutinib plus venetoclax also conferred a significantly higher undetectable MRD rate (92.2%; 97.5% CI, 87.3-95.7) compared with chemoimmunotherapy; however, venetoclax plus rituximab did not (57%; 97.5% CI, 49.5-64.2).
At EHA, Eichhorst presented results of the co-primary endpoint of PFS at interim analysis among 920 patients.
Median follow-up was 38.8 months.
Key findings
Results showed superior PFS with venetoclax, obinutuzumab and ibrutinib (HR = 0.32; 97.5% CI, 0.19-0.54) and venetoclax plus obinutuzumab (HR = 0.42; 97.5% CI, 0.26-0.68). However, PFS did not differ significantly between venetoclax plus rituximab and chemoimmunotherapy (HR = 0.79; 97.5% CI, 0.53-1.18).
“So it depends also on the antibody that you combine with the venetoclax treatment,” Eichhorst said.
Researchers observed 3-year PFS rates of 90.5% with venetoclax, obinutuzumab and ibrutinib, 87.7% with venetoclax plus obinutuzumab, 80.8% with venetoclax plus rituximab, and 75.5% with chemoimmunotherapy.
Moreover, patients with unmutated IGHV had 3-year PFS rates of 86.6% with venetoclax, obinutuzumab and ibrutinib, 82.9% with venetoclax plus obinutuzumab, 76.4% with venetoclax plus rituximab and 65.5% with chemoimmunotherapy. Those with mutated IGHV had 3-year PFS rates of 96% with venetoclax, obinutuzumab and ibrutinib, 93.6% with venetoclax plus obinutuzumab, 87% with venetoclax plus rituximab and 89.9% with chemoimmunotherapy.
“We see a huge difference, particularly with patients with unmutated IGHV status,” Eichhorst said.
Researchers reported similar OS rates across all treatment arms.
Grade 3 or higher infections occurred more commonly with venetoclax, obinutuzumab and ibrutinib (22.1%) and chemoimmunotherapy (20.4%) than with the venetoclax-rituximab (11.4%) and venetoclax-obinutuzumab (14.9%) combinations. Adverse event-associated mortality occurred among nine patients assigned venetoclax, obinutuzumab and ibrutinib, nine assigned venetoclax plus obinutuzumab, eight with venetoclax plus rituximab and 10 with chemoimmunotherapy.
Looking ahead
Future research will include a direct comparison of venetoclax, obinutuzumab and ibrutinib vs. the venetoclax-obinutuzumab regimen in the GAIA trial, and a trial directly comparing venetoclax plus obinutuzumab with ibrutinib is ongoing.
For more information:
Barbara Eichhorst, MD, can be reached at barbara.eichhorst@uk-koeln.de.
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Eichhorst B, et al. Abstract LB2365. Presented at: European Hematology Association Hybrid 2022 Congress; June 9-12, 2022.
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