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1897 MRD-Guided Zanubrutinib, Venetoclax and Obinutuzumab after an Optional Debulking with Bendamustine in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Primary Endpoint Analysis of the Phase 2 CLL2-Bzag Study

Program: Oral and Poster Abstracts
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, clinical trials, Lymphoid Leukemias, CLL, Clinical Research, Diseases, Lymphoid Malignancies, Minimal Residual Disease
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Moritz Furstenau, MD1*, Adam Giza2*, Christof Schneider, MD3*, Eugen Tausch, MD4*, Sandra Robrecht, PhD2*, Matthias Ritgen5*, Jörg Bittenbring, MD6*, Holger F. Hebart, MD7, Björn Schöttker8*, Anna Lena Illert9*, Ullrich Graeven, MD10*, Andrea Stoltefuss, MD11*, Bernhard Heinrich12*, Robert Eckert, MD13, Anna-Maria Fink, MD2*, Janina Stumpf2*, Florian Simon, MD14*, Kirsten Fischer, MD2*, Othman Al-Sawaf, MD2, Petra Langerbeins15*, Fanni Kleinert16*, Jonathan Weiss16*, Karl-Anton Kreuzer14*, Anke Schilhabel17*, Monika Brüggemann, MD18*, Barbara F. Eichhorst, MD19, Stephan Stilgenbauer, MD4, Michael Hallek, MD20* and Paula Cramer, MD2*

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, Koeln, Germany
2Faculty 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
3Division of CLL, Department of Internal Medicine III, University of Ulm, Ulm, Germany
4Department of Internal Medicine III, Division of CLL, Ulm University, Ulm, Germany
5Department II of Internal Medicine, University of Schleswig-Holstein, Kiel, Germany
64Department of Internal Medicine 1 (Oncology, Hematology, Clinical Immunology, and Rheumatology), Saarland University Medical School, Homburg, Homburg, DEU
7Stauferklinikum, Mutlangen, Mutlangen, DEU
8Hämatologisch-onkologische Schwerpunktpraxis Würzburg, Würzburg, Germany
97Department of Medicine III, Technical University of Munich, School of Medicine, Munich, Germany
10Department of Hematology, Oncology and Gastroenterology, Medical Clinic I, Hospital Maria Hilf GmbH, Mönchengladbach, Germany, Mönchengladbach, DEU
11Evangelisches Krankenhaus, Hamm, DEU
12Hämatologisch-onkologische Praxis Heinrich/Bangerter, Augsburg, Augsburg, Germany
13Onkologische Schwerpunktpraxis, Esslingen, DEU
14Faculty 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, Cologne, DEU
15Department I of Internal Medicine and Center of Integrated Oncology Aachen, Bonn, Cologne, Duesseldorf; Cologne, University of Cologne, Cologne, Germany
16Faculty 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, Cologne, Germany
172nd Department of Internal Medicine, University of Schleswig-Holstein, Campus Ki, Kiel, DEU
18Clinic for Internal Medicine II - Haematology, Oncology, University Clinic Schleswig-Holstein, Kiel, Germany
19University of Cologne, Cologne, Germany
20Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany, Cologne, Germany

Background

In chronic lymphocytic leukemia (CLL) triple combinations of BTK inhibitors (BTKi), venetoclax (ven) and CD20 antibodies have been tested mostly as first-line treatments and so far sparse data is available on their efficacy in the relapsed/refractory (r/r) setting. In this phase 2 trial, we evaluate the combination of zanubrutinib (zanu), ven and obinutuzumab (obi) in r/r CLL. In order to tailor therapy to the different needs of differently pretreated patients (pts), treatment duration was based on detection of measurable residual disease (MRD). Furthermore, a ctDNA-based MRD monitoring and a ctDNA-based real-time screen of resistance and driver mutations were performed throughout the study.

Methods

The CLL2-BZAG study evaluated a combination of obi, zanu and ven after an optional debulking with bendamustine in r/r CLL. In the induction, obi was administered 3 times in cycle 1 (days 1/2, 8 & 15) and monthly in cycles 2-6. Zanu was added in cycle 2 and ven in cycle 3 with a dose ramp-up over 5 weeks. Maintenance with continuous zanu and ven and 3-monthly obi was administered either until achievement of a deep remission with undetectable MRD <10-4 (uMRD) in peripheral blood (PB) or for up to 24 months.

The primary endpoint was the uMRD rate by flow cytometry (FCM) in PB at the final restaging (RE, after 6 months of triple therapy). MRD was measured by FCM from PB and by digital droplet PCR (ddPCR) of patient-specific VDJ rearrangements from blood plasma. uMRD was defined as <1 CLL cell/10,000 leukocytes (<10-4) and no detectable patient-specific VDJ ctDNA.

Results

Between 11/2020 and 10/2022, 42 pts were enrolled, 2 pts with ≤2 induction cycles were excluded from the analysis population as predefined by the protocol. Median age was 64 years (range 40-82), 32.5% of pts were female. All 40 pts had r/r CLL with a median of 1 prior therapy (range 1-5), 18 pts (45%) had already received a BTKi, 7 pts ven (17.5%), of these 5 pts (12.5%) had received both. Fifteen pts (37.5%) had a del(17p)/TP53 mutation, 31 (77.5%) had unmutated IGHV and 19 of 38 pts with available information (50%) a complex karyotype.

Nineteen pts (47.5%) received bendamustine debulking, 37 pts (92.5%) completed 6 induction cycles and 19 pts (47.5%) have already stopped MRD-guided maintenance treatment with 2 pts who discontinued maintenance early due to adverse events (AEs).

With a median observation time of 21.5 months (range 8.0-35.3), 445 AEs were reported, including 90 AEs of CTC grades 3-4. Two pts had fatal AEs (COVID-19, fungal pneumonia secondary to COVID-19). The most common AEs were COVID-19 (n=26 pts), diarrhea (n=15), infusion-related reactions (n=15), thrombocytopenia (n=14), nausea (n=12), fatigue (n=12) and neutropenia (n=12). The most frequent grade ≥3 AEs were neutropenia (n=10 pts), COVID-19 (n=9), thrombocytopenia (n=7) and pneumonia (n=5, Table 1). Two pts had grade ≥3 cardiac AEs (1 pt with grade 3 non-ST-elevation myocardial infarction, 1 pt with 2 AEs of grade 3 atrial fibrillation and a history of atrial fibrillation).

At RE all pts responded and 21 (52.5%) showed uMRD in PB (Figure 1A). In many pts remissions deepened over time, with 34 (85%) achieving uMRD in PB in the course of the study. The proportion of pts with uMRD was similar in pts with TP53 aberrations (80%) and in pts previously exposed to venetoclax and/or BTKi (80%). The estimated PFS and OS rates at 18 months were 96% and 96.8% (Figure 1B). PFS rates at 18 months were similar for pts with TP53 aberrations (100%) and pts pretreated with BTKi/ven (90%). Two pts had a disease progression per iwCLL criteria, however no pt has yet required a subsequent treatment. Of 22 pts who achieved uMRD and are now off-treatment, only 1 had MRD recurrence (≥10-4) during follow-up.

Serial MRD (FCM) and ctDNA (ddPCR) assessments were done on 281 paired blood/plasma samples throughout the study. At RE, 8 pts who achieved uMRD by FCM still had detectable VDJ ctDNA in blood plasma. Four pts without ctDNA were still MRD positive by FCM at RE. Apart from one PLCG2_S707F mutation that occurred 11 months after the end of treatment, no acquisition of known resistance mutations – in particular in BTK, BCL2 – was observed using ddPCR.

Conclusions

The time-limited MRD-guided triple combination of zanu, ven and obi induced deep remissions in a r/r CLL population enriched for pts previously treated with BTKi and/or ven. Apart from COVID-19, low rates of infectious AEs were observed and cardiac toxicities were rare.

Disclosures: Furstenau: Abbvie: Honoraria, Research Funding; Roche: Research Funding; Janssen: Research Funding; AstraZeneca: Research Funding; BeiGene: Research Funding. Schneider: Abbvie: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; BeiGene: Other: travel support; Jannsen Cilag: Consultancy. Tausch: BeiGene: Consultancy, Other: Travel support, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Other: travel support, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau. Ritgen: Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support; Abbvie: Consultancy, Research Funding. Hebart: AbbVie, AstraZeneca, Celgene, Janssen, Roche, and Beigene: Honoraria. Illert: Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Graeven: Ipsen: Research Funding; Celltrion: Honoraria; GSK: Other: travel support; Novartis: Honoraria; Fujifilm: Honoraria; Sanofi: Honoraria; MSD: Consultancy, Honoraria; BMS: Honoraria; AstraZeneca: Honoraria; Amgen: Consultancy, Honoraria; Boehringer Ingelheim: Honoraria, Other: travel support; BioNTech: Current holder of stock options in a privately-held company; MacroGenics: Honoraria, Research Funding. Fink: Abbvie: Other: travel support; AstraZeneca: Consultancy, Honoraria, Research Funding. Simon: AstraZeneca: Research Funding; Lilly Pharma: Other: Travel support. Fischer: Roche: Honoraria, Other: Travel Support; AstraZeneca: Consultancy; Abbvie: Honoraria, Other: TRavel support. Al-Sawaf: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eli Lilly: Speakers Bureau; BeiGene: Research Funding, Speakers Bureau; Adaptive: Speakers Bureau; Ascentage: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Langerbeins: Abbvie: Honoraria, Other: travel support; Janssen: Honoraria, Other: travel support, Research Funding; Beigene: Honoraria, Other: travel support; AstraZeneca: Honoraria, Other: travel support. Weiss: Qiagen: Current Employment. Kreuzer: Abbvie: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau. Brüggemann: Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Affimed: Research Funding; Regeneron: Research Funding; Janssen: Speakers Bureau; BD: Speakers Bureau; Pfizer: Speakers Bureau. Eichhorst: Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau; BeiGene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding, Speakers Bureau; Lilly: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau. Stilgenbauer: Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; GSK: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Sunesis: Consultancy, Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding. Hallek: Abbvie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding. Cramer: Novartis: Research Funding; Gilead: Research Funding; BeiGene: Consultancy, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Honoraria, Research Funding; Acerta: Research Funding; Roche: Honoraria, Other: travel support, Research Funding; Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; BMS: Honoraria.

OffLabel Disclosure: Zanubrutinib, Venetoclax, Obinutuzumab is a combination that is not approved for the treatment of CLL

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