Safety of Front-Line R-Mini-CHOP with or without Acalabrutinib in Older Adults with DLBCL - an Interim Analysis of Serious Adverse Events in the Arched / GLA 2022-1 Randomized, Open-Label, Phase 3 Trial

Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma entity and has increased incidence in the elderly. Approximately 40% of pts with DLBCL are >70 yrs old. In older/frail pts with untreated DLBCL, the attenuated chemotherapy regimen R-miniCHOP is the standard of care with a 2-yr overall survival (OS) of approximately 60% (Peyrade 2011). BTK inhibition added to R-CHOP improved OS in pts <60 yrs, but not in older pts where tolerability was limited (Younes 2019). A BTK inhibitor with a more favorable safety profile may improve survival also in elderly pts. Acalabrutinib is a second-generation BTK-inhibitor with promising data in combination with R-CHOP in pts with DLBCL up to 80 yrs (Davies ASH 2022). ARCHED/GLA 2022-1 is an investigator-initiated, randomized, open-label, phase 3 trial to evaluate the addition of acalabrutinib to R-miniCHOP in pts with untreated DLBCL aged >80 yrs or 61-80 yrs old and unfit for full-dose R-CHOP. Patients are randomized to receive either R-miniCHOP (control, C) or R-miniCHOP + Acalabrutinib (A). Stratification is based on age, ADL score and IPI. The primary endpoint is progression free survival. Methods This is a safety analysis based on the per protocol quarterly evaluation of serious adverse events (SAE) of the first year of recruitment. Recruitment started in June 2023. All pts randomized until 01/07/2024 were included. Baseline characteristics, SAE incidence and severity were analyzed. Adverse events of special interest (AESI) were reported as SAE. Results At data cut off 57 pts had been randomized (C: 28, A: 29). Median age was 83 yrs (range 66-94), 68% pts were >80 yrs old and 63% male. ECOG status was 0-1 in 67% and ADL score <6 in 28%. Extranodal disease was present in 77%, and 72% had an IPI score ≥3. Baseline characteristics were balanced between arms. A total of 44 SAE were reported in 29 pts (C: 18 events [13 pts; 46%]; A: 26 events [16 pts; 55%]). Fifteen (34%) of them were grade 1-2 (C: 6 events [5 pts; 18%]; A: 9 events [5 pts; 17%]). Twenty (45%) were grade 3 (C: 7 events [6 pts; 21%]; A: 13 events [9 pts; 31%]). One pt in arm C and one in arm A had one grade 4 SAE each. Four deaths (grade 5 SAE) occurred in arm C (14%, one lymphoma-related, one heart failure and two unknown cause) vs three (10%, one due to vascular causes and two unknown cause) in arm A. The most common SAE were infections. In arm C, 4 pts (14%) had one grade 2 and four grade 3 infections, and 5 pts (17%) in arm A had one grade 2 and five grade 3 infections. Cardiac events accounted for 10 SAE. Specifically, in two pts (7%) in arm C one heart failure grade 5, one grade 2 and one grade 3 hypertensive crisis occurred. Six pts (20%) in arm A had five grade 1-2 (three asymptomatic ventricular extrasystoles [AESI], one asymptomatic non-sustained ventricular tachycardia [AESI], and one angina pectoris) and two grade 3 (one atrial fibrillation and one heart failure). Three pts had bleeding SAE, two in arm C (hemoptysis and melena, both grade 1) and one in arm A (grade 3 rectal bleeding). Conclusion Acalabrutinib with R-miniCHOP resulted in increased but manageable toxicity. Rates of serious infections and bleeding were similar between groups. One third of all SAE reported were grade 1-2. More cardiologic SAE were reported in the experimental arm, mostly asymptomatic grade 1-2 AESI. Importantly, no increased rate of treatment emergent deaths was seen with acalabrutinib + R-miniCHOP in this frail, high-risk population. Thus, acalabrutinib with R-miniCHOP has the potential to improve outcomes in older/frail adults with untreated DLBCL. ARCHED is an academic study of the German Lymphoma Alliance and is funded by AstraZeneca GmbH. The trial is approved in the EU and is recruiting in Germany. (EU-CTN: 2022-501187-18-00, NCT05820841).

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Blood
Published
2024-11-05
DOI
https://doi.org/10.1182/blood-2024-199685
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Chronic Lymphocytic Leukemia Research
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article

Safety of Front-Line R-Mini-CHOP with or without Acalabrutinib in Older Adults with DLBCL - an Interim Analysis of Serious Adverse Events in the Arched / GLA 2022-1 Randomized, Open-Label, Phase 3 Trial

Hanno Maximilian Witte, Norbert Schmitz, Igor Age Kos, Kai Wille et al.
Blood
Chronic Lymphocytic Leukemia Research
article

Safety of Front-Line R-Mini-CHOP with or without Acalabrutinib in Older Adults with DLBCL - an Interim Analysis of Serious Adverse Events in the Arched / GLA 2022-1 Randomized, Open-Label, Phase 3 Trial

Hanno Maximilian Witte, Norbert Schmitz, Igor Age Kos, Kai Wille, Swen Weßendorf, Gerald Illerhaus, Matthias Sandmann, D. Hellwig, Niklas Gebauer, Börge Arndt, Bert Hildebrandt, Uwe M. Martens, Stephan Stilgenbauer, Konstantinos Christofyllakis, Christian Buske, Julian Topaly, Viola Poeschel, Alexander Kiani, Octavian Fleser, Lorenz Thurner, Markus Loeffler, Holger Hebart, Boris Kubuschock, Franziska Brünner, Florian Zettl, Sebastian Broeckling, Kristina Lerch, Georg Lenz, Marita Ziepert, Bastian von Tresckow, Pascal Blatt, Manfred Ahlgrimm, Rolf Mahlberg, Martin Dreyling, Heinz Kirchen, Andreas Rosenwald, Bettina Altmann, Volkmar Boehme, Thomas Illmer, Dominic Kaddu‐Mulindwa, Chrysoula Doxani, Vadim Lesan, Florian Scherer, Gabriele Prange‐Krex, Mathias Rummel, Stephanie Maurer, Ralf Ulrich Trappe, Andreas Viardot, Theodoros P. Vassilakopoulos, Moritz Bewarder, Roland Schmitz, Ulrich Kaiser, Annkristin Heine, Bjoern Chapuy, German Ott, Nina Rosa Neuendorff, Alexander Bott, Martin Klump, Maike Nickelsen, Sarah Altmeyer, Reiner Siebert, Bertram Glass, Jörg-Thomas Bittenbring, Gerhard Held, Susanne Schmidt, Zanir Abdi, Martin Bentz, Matthias Müeller, Tobias Gaska, Oguzhan Nakisli, Iordanis Deligiannis
article en

Abstract

Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma entity and has increased incidence in the elderly. Approximately 40% of pts with DLBCL are >70 yrs old. In older/frail pts with untreated DLBCL, the attenuated chemotherapy regimen R-miniCHOP is the standard of care with a 2-yr overall survival (OS) of approximately 60% (Peyrade 2011). BTK inhibition added to R-CHOP improved OS in pts <60 yrs, but not in older pts where tolerability was limited (Younes 2019). A BTK inhibitor with a more favorable safety profile may improve survival also in elderly pts. Acalabrutinib is a second-generation BTK-inhibitor with promising data in combination with R-CHOP in pts with DLBCL up to 80 yrs (Davies ASH 2022). ARCHED/GLA 2022-1 is an investigator-initiated, randomized, open-label, phase 3 trial to evaluate the addition of acalabrutinib to R-miniCHOP in pts with untreated DLBCL aged >80 yrs or 61-80 yrs old and unfit for full-dose R-CHOP. Patients are randomized to receive either R-miniCHOP (control, C) or R-miniCHOP + Acalabrutinib (A). Stratification is based on age, ADL score and IPI. The primary endpoint is progression free survival. Methods This is a safety analysis based on the per protocol quarterly evaluation of serious adverse events (SAE) of the first year of recruitment. Recruitment started in June 2023. All pts randomized until 01/07/2024 were included. Baseline characteristics, SAE incidence and severity were analyzed. Adverse events of special interest (AESI) were reported as SAE. Results At data cut off 57 pts had been randomized (C: 28, A: 29). Median age was 83 yrs (range 66-94), 68% pts were >80 yrs old and 63% male. ECOG status was 0-1 in 67% and ADL score <6 in 28%. Extranodal disease was present in 77%, and 72% had an IPI score ≥3. Baseline characteristics were balanced between arms. A total of 44 SAE were reported in 29 pts (C: 18 events [13 pts; 46%]; A: 26 events [16 pts; 55%]). Fifteen (34%) of them were grade 1-2 (C: 6 events [5 pts; 18%]; A: 9 events [5 pts; 17%]). Twenty (45%) were grade 3 (C: 7 events [6 pts; 21%]; A: 13 events [9 pts; 31%]). One pt in arm C and one in arm A had one grade 4 SAE each. Four deaths (grade 5 SAE) occurred in arm C (14%, one lymphoma-related, one heart failure and two unknown cause) vs three (10%, one due to vascular causes and two unknown cause) in arm A. The most common SAE were infections. In arm C, 4 pts (14%) had one grade 2 and four grade 3 infections, and 5 pts (17%) in arm A had one grade 2 and five grade 3 infections. Cardiac events accounted for 10 SAE. Specifically, in two pts (7%) in arm C one heart failure grade 5, one grade 2 and one grade 3 hypertensive crisis occurred. Six pts (20%) in arm A had five grade 1-2 (three asymptomatic ventricular extrasystoles [AESI], one asymptomatic non-sustained ventricular tachycardia [AESI], and one angina pectoris) and two grade 3 (one atrial fibrillation and one heart failure). Three pts had bleeding SAE, two in arm C (hemoptysis and melena, both grade 1) and one in arm A (grade 3 rectal bleeding). Conclusion Acalabrutinib with R-miniCHOP resulted in increased but manageable toxicity. Rates of serious infections and bleeding were similar between groups. One third of all SAE reported were grade 1-2. More cardiologic SAE were reported in the experimental arm, mostly asymptomatic grade 1-2 AESI. Importantly, no increased rate of treatment emergent deaths was seen with acalabrutinib + R-miniCHOP in this frail, high-risk population. Thus, acalabrutinib with R-miniCHOP has the potential to improve outcomes in older/frail adults with untreated DLBCL. ARCHED is an academic study of the German Lymphoma Alliance and is funded by AstraZeneca GmbH. The trial is approved in the EU and is recruiting in Germany. (EU-CTN: 2022-501187-18-00, NCT05820841).

BloodVol. 144(Supplement 1)
University of Thessaly (GR), University of Freiburg (DE), Universität Ulm (DE), National and Kapodistrian University of Athens (GR), Universitätsmedizin Greifswald (DE), University Hospital Bonn (DE), University Hospitals of the Ruhr-University of Bochum (DE), Bayreuth Medical Center (DE), Robert Bosch Hospital (DE), University Hospital Regensburg (DE), Krankenhaus der Barmherzigen Brüder Trier (DE), Universitätsklinik Marien Hospital Herne (DE), Städtisches Klinikum Karlsruhe (DE), Westpfalz Klinikum (DE), Diakonie Klinikum Jung-Stilling (DE), Helios Klinikum Emil von Behring (DE), Nuremberg Hospital (DE), Comprehensive Cancer Center Mainfranken (DE), University Hospital Münster (DE), St. Bernward Krankenhaus (DE), Bundeswehrkrankenhaus (DE), University Hospital Schleswig-Holstein (DE), Klinikum Esslingen (DE), Essen University Hospital (DE), Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE), Asklepios Klinik St. Georg (DE), Agaplesion Bethesda Krankenhaus (DE), Klinikum Mutterhaus der Borromäerinnen (DE), Universitätsklinikum Würzburg (DE), Klinikum Arnsberg (DE), MVZ - Kurfürstendamm (DE), DIAKO (DE), Klinikum Saarbrücken (DE), University Hospital Ulm (DE), SLK-Kliniken Heilbronn (DE), Klinikum Rheine (DE), Klinikum Stuttgart (DE), West German Heart and Vascular Center Essen (DE), University of Duisburg-Essen (DE), Martin Luther University Halle-Wittenberg (DE), Charité - Universitätsmedizin Berlin (DE), Ludwig-Maximilians-Universität München (DE), Saarland University (DE), Leipzig University (DE), University of Lübeck (DE)
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