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TIME-LIMITED VENETOCLAX-OBINUTUZUMAB +/- IBRUTINIB IS SUPERIOR TO CHEMOIMMUNOTHERAPY IN FRONTLINE CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): PFS CO-PRIMARY ENDPOINT OF THE RANDOMIZED PHASE 3 GAIA/CLL13 TRIAL
Author(s): ,
Barbara Eichhorst
Affiliations:
Internal medicine, German CLL Study Group,University of Cologne,Cologne,Germany
,
Carsten Niemann
Affiliations:
Rigshospitalet,Copenhagen,Denmark
,
Arnon Kater
Affiliations:
Amsterdam UMC,Amsterdam,Netherlands
,
Moritz Fürstenau
Affiliations:
Internal medicine, German CLL Study Group,University of Cologne,Cologne,Germany
,
Julia von Tresckow
Affiliations:
Clinic for Hematology and Stem Cell Transplantation, West German Cancer Center,University Hospital Essen, University of Duisburg-Essen,Essen,Germany
,
Can Zhang
Affiliations:
Internal medicine, German CLL Study Group,University of Cologne,Cologne,Germany
,
Sandra Robrecht
Affiliations:
Internal medicine, German CLL Study Group,University of Cologne,Cologne,Germany
,
Michael Gregor
Affiliations:
Division of Hematology,Cantonal Hospital of Lucerne,Lucerne,Switzerland
,
Gunnar Juliusson
Affiliations:
Department of Hematology,Lund University,Lund,Sweden
,
Patrick Thornton
Affiliations:
Beaumont/Cancer clinical trials Ireland,Dublin,Ireland
,
Philipp Staber
Affiliations:
Department of Medicine I, Division of Hematology & Hemostaseology,Medical University of Vienna,Vienna,Austria
,
Tamar Tadmor
Affiliations:
Hematology Unit,Bnai Zion Medical Center,Haifa,Israel
,
Vesa Lindström
Affiliations:
Department of Hematology,Helsinki University Hospital Comprehensive Cancer Center and University of Helsinki,Helsinki,Finland
,
Caspar da Cunha-Bang
Affiliations:
Department of Hematology,Rigshospitalet, Copenhagen University Hospital,Copenhagen,Denmark
,
Christof Schneider
Affiliations:
Department of Internal Medicine III,Ulm University,Ulm,Germany
,
Christian B. Poulsen
Affiliations:
Department of Haematology,Zealand University Hospital,Roskilde,Denmark
,
Thomas Illmer
Affiliations:
BAG/Onkologische Schwerpunktpraxis,Dresden,Germany
,
Björn Schöttker
Affiliations:
Hämatologisch Onkologische Schwerpunktpraxis,Würzburg,Germany
,
Ann Janssen
Affiliations:
Hematology Department,University of Leuven,Leuven,Belgium
,
Ilse Christiansen
Affiliations:
Department of Hematology,Aalborg University Hospital,Aalborg,Denmark
,
Thomas Nösslinger
Affiliations:
Hanusch Hospital,Vienna,Austria
,
Michael Baumann
Affiliations:
Clinic for Medical Oncology and Hematology,Cantonal Hospital St. Gallen,St. Gallen,Switzerland
,
Marjolein van der Klift
Affiliations:
Department of Internal Medicine,Amphia Hospital,Breda,Netherlands
,
Ulrich Jäger
Affiliations:
Medical University of Vienna,Vienna,Austria
,
Henrik Frederiksen
Affiliations:
Department of Hematology,Odense University Hospital,Odense,Denmark
,
Maria Leys
Affiliations:
Department of Internal Medicine/Hematology,Maasstad Ziekenhuis,Rotterdam,Netherlands
,
Mels Hoogendoorn
Affiliations:
Medical Center Leeuwarden,Leeuwarden,Netherlands
,
Kourosh Lotfi
Affiliations:
Department of Hematology and Department of Clinical and Experimental Medicine,Linköping University,Linköping,Sweden
,
Holger Hebart
Affiliations:
Stauferklinikum,Mutlangen,Germany
,
Tobias Gaska
Affiliations:
Hematology und Oncology,Brüderkrankenhaus St. Josef,Paderborn,Germany
,
Harry Koene
Affiliations:
St. Antonius Hospital,Nieuwegein,Netherlands
,
Florian Simon
Affiliations:
Internal medicine, German CLL Study Group,University of Cologne,Cologne,Germany
,
Nisha De Silva
Affiliations:
Internal medicine, German CLL Study Group,University of Cologne,Cologne,Germany;University College Hospital London NHS Trust,London,United Kingdom
,
Anna Fink
Affiliations:
Internal medicine, German CLL Study Group,University of Cologne,Cologne,Germany
,
Kirsten Fischer
Affiliations:
Internal medicine, German CLL Study Group,University of Cologne,Cologne,Germany
,
Clemens Wendtner
Affiliations:
Munich Clinic Schwabing, Academic Teaching Hospital,Ludwig-Maximilians-University,Munich,Germany
,
Karl-Anton Kreuzer
Affiliations:
Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, LMHO,University of Cologne,Cologne,Germany
,
Matthias Ritgen
Affiliations:
Department of Internal Medicine II,University of Schleswig-Holstein,Kiel,Germany
,
Monika Brüggemann
Affiliations:
Department of Internal Medicine II,University of Schleswig-Holstein,Kiel,Germany
,
Eugen Tausch
Affiliations:
Department of Internal Medicine III,Ulm University,Ulm,Germany
,
Mark-David Levin
Affiliations:
Department of Internal Medicine,Albert Schweitzer Hospital,Dordrecht,Netherlands
,
Marinus van Oers
Affiliations:
Department of Hematology,Academic Medical Center,Amsterdam,Netherlands
,
Christian Geisler
Affiliations:
Department of Hematology,Rigshospitalet, Copenhagen University Hospital,Copenhagen,Denmark
,
Stephan Stilgenbauer
Affiliations:
Department of Internal Medicine III,Ulm University,Ulm,Germany
Michael Hallek
Affiliations:
Internal medicine, German CLL Study Group,University of Cologne,Cologne,Germany
(Abstract release date: 06/02/22) EHA Library. Eichhorst B. 06/12/22; 366209; LB2365
Dr. Barbara Eichhorst
Dr. Barbara Eichhorst
Contributions
Abstract
Presentation during EHA2022: All Oral presentations will be made available as of Saturday, June 11, 2022 and will be accessible for on-demand viewing until August 15, 2022 on the Virtual Congress platform.

Abstract: LB2365

Type: Late breaking oral

Session title: Late breaking abstract session

Background

Chemoimmunotherapy (CIT) is still standard in frontline of fit patients (pts) with CLL of lower risk. Fixed-duration venetoclax plus obinutzumab (GV) in frontline of unfit pts has become one of the standard treatments. In addition, triple combinations including BTK inhibitors have shown promising results within phase II trials. Data comparing GV to GV plus ibrutinib (GIV) in fit, previously untreated pts with CLL are not yet available. The GAIA/CLL13 trial evaluated the efficacy and safety of three time-limited venetoclax-based first-line regimens in comparison to CIT in fit pts with CLL. The MRD analysis as one of two co-primary endpoints of the GAIA/CLL13 trial being presented at ASH 2021 showed high rates of undetectable MRD (uMRD) in peripheral blood (PB) for pts treated with GV (86.5%) or GIV (92.2%) in comparison to CIT (52.0%; p<0.0001 for both comparisons).

Aims

A pre-planned interim analysis of progression-free survival (PFS) was conducted at fixed time point of month 61. On data review, an independent data monitoring committee recommended full analysis.

Methods

Treatment-naïve fit (CIRS ≤6, creatinine clearance ≥70ml/min) CLL pts without presence of TP53 aberrations who required therapy were eligible. Pts were randomized in a 1:1:1:1 ratio to receive six courses of CIT (FCR for pts ≤65 years; BR for pts >65 years) or one of three venetoclax (V) combinations (standard ramp-up from cycle 1 d22, 400 mg/d cycle 2-12): V and rituximab (375/500mg/m² d1 cycle 1-6) [RV], V and obinutuzumab (1000 mg d1, 8, 15 cycle 1 and d1 cycle 2-6) [GV], or V, obinutuzumab and ibrutinib (420 mg/d cycle 1-12, if MRD-detectable continued until cycle 36) [GIV].Co-primary endpoints were (1) the rate of uMRD (<10-4) by flow cytometry in PB at month 15 (GV versus (vs) CIT) and (2) PFS (GIV vs CIT), each with a significance level of 2.5%. Key secondary endpoints were PFS and uMRD comparisons between other treatment arms using a pre-specified hierarchical test sequence, overall survival (OS) and safety.

Results

In total, 926 pts (CIT: 229 (150 FCR, 79 BR), RV: 237, GV: 229, GIV: 231) were enrolled. The median age was 61 years (range 27-84), the majority of pts were in advanced Binet stage (B: 37.9%, C: 35.6%) and unmutated IGHV status was present in 56.0%. At the data cut (January 20, 2022) the median observation time was 38.8 months. The second co-primary endpoint was met as GIV showed superior PFS compared to CIT (hazard ratio [HR] 0.32, 97.5% confidence interval [CI] 0.19-0.54, p<0.0001). While superior PFS was also observed for GV vs CIT (HR 0.42, 97.5% CI 0.26-0.68, p<0.0001), PFS was not significantly different between RV and CIT (HR 0.79, 97.5% CI 0.53-1.18, p=0.183) (Figure 1A). Three-year PFS rates were 90.5%, 87.7%, 80.8% and 75.5% for GIVe, GV, RV and CIT. Three-year PFS rates for pts with unmutated IGHV were 86.6% (GIV), 82.9% (GV), 76.4% (RV) and 65.5% (CIT) vs 96.0% (GIV), 93.6% (GV), 87.0% (RV) and 89.9% (CIT) for pts with mutated IGHV (Figure 1B). Similar OS rates were observed across all treatment arms. No major differences in haematological side effects between all four arms were observed, but CTC grade 3-4 infections were more common with GIV (21.2%) or CIT (18.5%) vs GV (13.2%) or RV (10.5%). Secondary neoplasia occurred more frequently with CIT (36 pts) than with the arms GV, GIV, RV (23, 24, 21 pts). Fatal AEs occurred in 9 pts with GV and GIV each, 10 with CIT and 8 with RV.

Conclusion

Time-limited treatment with GIV or GV improves PFS compared to standard CIT in fit, previously untreated patients with CLL.

Keyword(s): Targeted therapy, ibrutinib

Presentation during EHA2022: All Oral presentations will be made available as of Saturday, June 11, 2022 and will be accessible for on-demand viewing until August 15, 2022 on the Virtual Congress platform.

Abstract: LB2365

Type: Late breaking oral

Session title: Late breaking abstract session

Background

Chemoimmunotherapy (CIT) is still standard in frontline of fit patients (pts) with CLL of lower risk. Fixed-duration venetoclax plus obinutzumab (GV) in frontline of unfit pts has become one of the standard treatments. In addition, triple combinations including BTK inhibitors have shown promising results within phase II trials. Data comparing GV to GV plus ibrutinib (GIV) in fit, previously untreated pts with CLL are not yet available. The GAIA/CLL13 trial evaluated the efficacy and safety of three time-limited venetoclax-based first-line regimens in comparison to CIT in fit pts with CLL. The MRD analysis as one of two co-primary endpoints of the GAIA/CLL13 trial being presented at ASH 2021 showed high rates of undetectable MRD (uMRD) in peripheral blood (PB) for pts treated with GV (86.5%) or GIV (92.2%) in comparison to CIT (52.0%; p<0.0001 for both comparisons).

Aims

A pre-planned interim analysis of progression-free survival (PFS) was conducted at fixed time point of month 61. On data review, an independent data monitoring committee recommended full analysis.

Methods

Treatment-naïve fit (CIRS ≤6, creatinine clearance ≥70ml/min) CLL pts without presence of TP53 aberrations who required therapy were eligible. Pts were randomized in a 1:1:1:1 ratio to receive six courses of CIT (FCR for pts ≤65 years; BR for pts >65 years) or one of three venetoclax (V) combinations (standard ramp-up from cycle 1 d22, 400 mg/d cycle 2-12): V and rituximab (375/500mg/m² d1 cycle 1-6) [RV], V and obinutuzumab (1000 mg d1, 8, 15 cycle 1 and d1 cycle 2-6) [GV], or V, obinutuzumab and ibrutinib (420 mg/d cycle 1-12, if MRD-detectable continued until cycle 36) [GIV].Co-primary endpoints were (1) the rate of uMRD (<10-4) by flow cytometry in PB at month 15 (GV versus (vs) CIT) and (2) PFS (GIV vs CIT), each with a significance level of 2.5%. Key secondary endpoints were PFS and uMRD comparisons between other treatment arms using a pre-specified hierarchical test sequence, overall survival (OS) and safety.

Results

In total, 926 pts (CIT: 229 (150 FCR, 79 BR), RV: 237, GV: 229, GIV: 231) were enrolled. The median age was 61 years (range 27-84), the majority of pts were in advanced Binet stage (B: 37.9%, C: 35.6%) and unmutated IGHV status was present in 56.0%. At the data cut (January 20, 2022) the median observation time was 38.8 months. The second co-primary endpoint was met as GIV showed superior PFS compared to CIT (hazard ratio [HR] 0.32, 97.5% confidence interval [CI] 0.19-0.54, p<0.0001). While superior PFS was also observed for GV vs CIT (HR 0.42, 97.5% CI 0.26-0.68, p<0.0001), PFS was not significantly different between RV and CIT (HR 0.79, 97.5% CI 0.53-1.18, p=0.183) (Figure 1A). Three-year PFS rates were 90.5%, 87.7%, 80.8% and 75.5% for GIVe, GV, RV and CIT. Three-year PFS rates for pts with unmutated IGHV were 86.6% (GIV), 82.9% (GV), 76.4% (RV) and 65.5% (CIT) vs 96.0% (GIV), 93.6% (GV), 87.0% (RV) and 89.9% (CIT) for pts with mutated IGHV (Figure 1B). Similar OS rates were observed across all treatment arms. No major differences in haematological side effects between all four arms were observed, but CTC grade 3-4 infections were more common with GIV (21.2%) or CIT (18.5%) vs GV (13.2%) or RV (10.5%). Secondary neoplasia occurred more frequently with CIT (36 pts) than with the arms GV, GIV, RV (23, 24, 21 pts). Fatal AEs occurred in 9 pts with GV and GIV each, 10 with CIT and 8 with RV.

Conclusion

Time-limited treatment with GIV or GV improves PFS compared to standard CIT in fit, previously untreated patients with CLL.

Keyword(s): Targeted therapy, ibrutinib

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