Abstract

Data on long-term outcomes and biological drivers associated with depth of remission after BCL2 inhibition by venetoclax in the treatment of chronic lymphocytic leukemia (CLL) are limited. In this open-label parallel-group phase-3 study, 432 patients with previously untreated CLL were randomized (1:1) to receive either 1-year venetoclax-obinutuzumab (Ven-Obi, 216 patients) or chlorambucil-Obi (Clb-Obi, 216 patients) therapy (NCT02242942). The primary endpoint was investigator-assessed progression-free survival (PFS); secondary endpoints included minimal residual disease (MRD) and overall survival. RNA sequencing of CD19-enriched blood was conducted for exploratory post-hoc analyses. After a median follow-up of 65.4 months, PFS is significantly superior for Ven-Obi compared to Clb-Obi (Hazard ratio [HR] 0.35 [95% CI 0.26–0.46], p < 0.0001). At 5 years after randomization, the estimated PFS rate is 62.6% after Ven-Obi and 27.0% after Clb-Obi. In both arms, MRD status at the end of therapy is associated with longer PFS. MRD + ( ≥ 10−4) status is associated with increased expression of multi-drug resistance gene ABCB1 (MDR1), whereas MRD6 (< 10−6) is associated with BCL2L11 (BIM) expression. Inflammatory response pathways are enriched in MRD+ patient solely in the Ven-Obi arm. These data indicate sustained long-term efficacy of fixed-duration Ven-Obi in patients with previously untreated CLL. The distinct transcriptomic profile of MRD+ status suggests possible biological vulnerabilities.

The CLL14 study (NCT02242942) explored the activity of obinutuzumab (anti-CD20) plus venetoclax (Bcl2 inhibitor) versus obinutuzumab plus chlorambucil in patients with previously untreated chronic lymphocytic leukemia (CLL). Here the authors report the 5-year long-term results of the clinical trial and transcriptional profiles associated with response to therapies.

Details

Title
Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia
Author
Al-Sawaf, Othman 1   VIAFID ORCID Logo  ; Zhang, Can 2 ; Jin, Hyun Yong 3 ; Robrecht, Sandra 2 ; Choi, Yoonha 3 ; Balasubramanian, Sandhya 3 ; Kotak, Alex 4 ; Chang, Yi Meng 5 ; Fink, Anna Maria 2 ; Tausch, Eugen 6 ; Schneider, Christof 6 ; Ritgen, Matthias 7 ; Kreuzer, Karl-Anton 2 ; Chyla, Brenda 8 ; Paulson, Joseph N. 3 ; Pallasch, Christian P. 2   VIAFID ORCID Logo  ; Frenzel, Lukas P. 2 ; Peifer, Martin 9   VIAFID ORCID Logo  ; Eichhorst, Barbara 2 ; Stilgenbauer, Stephan 6   VIAFID ORCID Logo  ; Jiang, Yanwen 3 ; Hallek, Michael 2   VIAFID ORCID Logo  ; Fischer, Kirsten 2   VIAFID ORCID Logo 

1  University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, Germany (GRID:grid.6190.e) (ISNI:0000 0000 8580 3777); University College London, Cancer Institute, London, UK (GRID:grid.83440.3b) (ISNI:0000 0001 2190 1201); Francis Crick Institute, London, UK (GRID:grid.451388.3) (ISNI:0000 0004 1795 1830) 
2  University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, Germany (GRID:grid.6190.e) (ISNI:0000 0000 8580 3777) 
3  Genentech Inc., South San Francisco, USA (GRID:grid.418158.1) (ISNI:0000 0004 0534 4718) 
4  Roche Products Ltd, Welwyn Garden City, UK (GRID:grid.419227.b) 
5  Hoffmann-la Roche, Mississauga, Canada (GRID:grid.420733.1) (ISNI:0000 0004 0646 4754) 
6  Department III of Internal Medicine, Ulm University, Ulm, Germany (GRID:grid.6582.9) (ISNI:0000 0004 1936 9748) 
7  Department II of Internal Medicine, University of Schleswig Holstein, Kiel, Germany (GRID:grid.412468.d) (ISNI:0000 0004 0646 2097) 
8  AbbVie Inc., North Chicago, USA (GRID:grid.431072.3) (ISNI:0000 0004 0572 4227) 
9  University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany (GRID:grid.6190.e) (ISNI:0000 0000 8580 3777) 
Pages
2147
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-023-37648-w
ProQuest document ID
2802687538
Copyright
© The Author(s) 2023. corrected publication 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.