MRD-guided zanubrutinib, venetoclax, and obinutuzumab in relapsed CLL: primary end point analysis from the CLL2-BZAG trial
Abstract
Abstract The phase 2 CLL2-BZAG trial tested a measurable residual disease (MRD)–guided combination treatment of zanubrutinib, venetoclax, and obinutuzumab after an optional bendamustine debulking in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). In total, 42 patients were enrolled and 2 patients with ≤2 induction cycles were excluded from the analysis population per protocol. Patients had a median of 1 prior therapy (range, 1-5); 18 patients (45%) had already received a Bruton tyrosine kinase (BTK) inhibitor (BTKi); 7 patients (17.5%) venetoclax; and, of these, 5 (12.5%) had received both. Fifteen patients (37.5%) had a TP53 mutation/deletion, and 31 (77.5%) had unmutated immunoglobulin heavy chain variable region gene. With a median observation time of 21.5 months (range, 8.0-35.3) the most common adverse events were COVID-19 (n = 26 patients), diarrhea (n = 15), infusion-related reactions (n = 15), thrombocytopenia (n = 14), nausea (n = 12), fatigue (n = 12), and neutropenia (n = 12). Two patients had fatal adverse events (COVID-19, and fungal pneumonia secondary to COVID-19). After 6 months of the triple combination, all patients responded, and 21 (52.5%; 95% confidence interval, 36.1-68.5) showed undetectable MRD (uMRD) in the peripheral blood. In many patients, remissions deepened over time, with a best uMRD rate of 85%. The estimated progression-free and overall survival rates at 18 months were 96% and 96.8%, respectively. No patient has yet required a subsequent treatment. In summary, the MRD-guided triple combination of zanubrutinib, venetoclax, and obinutuzumab induced deep remissions in a relapsed CLL population enriched for patients previously treated with a BTKi/venetoclax. This trial was registered at www.clinicaltrials.gov as #NCT04515238.
Article Details
Authors (29)
Moritz Fürstenau
1Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German CLL Study Group, University of Cologne, Cologne, Germany
Sandra Robrecht
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Christof Schneider
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Eugen Tausch
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Adam Giza
1Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German CLL Study Group, University of Cologne, Cologne, Germany
Matthias Ritgen
Universitaetsklinikum Schleswig-Holstein, Medizinische Klinik II, Kiel, Germany
Jörg Bittenbring
1José Carreras Center for Immuno- and Gene Therapy and Department of Internal Medicine I, Saarland University Medical School, Homburg, Germany
Holger Hebart
2Kliniken Ostalb, Mutlangen, Germany
Björn Schöttker
32Hämatologisch-Onkologische Schwerpunktpraxis Würzburg, Würzburg, Germany
Anna Lena Illert
Ullrich Graeven
Andrea Stoltefuß
9Department of Hematology and Oncology, Evangelisches Krankenhaus Hamm, Hamm, Germany
Bernhard Heinrich
10Hämatologisch-Onkologische Praxis Heinrich/Bangerter, Augsburg, Germany
Robert Eckert
11Department of Hematology, Oncology, Stem Cell Transplantation, and Palliative Care, Klinikum Stuttgart, Katharinenhospital, Stuttgart, Germany
Anna Fink
Janina Stumpf
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Kirsten Fischer
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Othman Al-Sawaf
Florian Simon
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Fanni Kleinert
1Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German Chronic Lymphocytic Leukemia Study Group, University of Cologne, Cologne, Germany
Jonathan Weiss
1Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German Chronic Lymphocytic Leukemia Study Group, University of Cologne, Cologne, Germany
Karl-Anton Kreuzer
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Anke Schilhabel
2University Hospital Schleswig-Holstein (UKSH) – Campus Kiel, Department of Hematology and Oncology, Kiel, Germany
Monika Brüggemann
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Petra Langerbeins
University Hospital, Cologne, Germany
Stephan Stilgenbauer
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Barbara Eichhorst
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Michael Hallek
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Paula Cramer
18Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German Chronic Lymphocytic Leukemia Study Group, University of Cologne, Cologne, Germany