AFFILIATIONS
1 Department of Oncology, Hematology, Clinical Immunology and Rheumatology, Saarland University Medical Center, Homburg/Saar, Germany, Department of Oncology, Hematology, Pneumonology and Stem Cell Transplantation, Frankfurt Oder Klinikum, Frankfurt (Oder), Germany
2 Department of Oncology, Hematology, Clinical Immunology and Rheumatology, Saarland University Medical Center, Homburg/Saar, Germany
3 Institute for Medical Informatics, Statistics, and Epidemiology, University of Leipzig, Leipzig, Germany
4 Department of Hematology and Oncology, Brüderkrankehaus St Josef, Paderborn, Germany
5 Department of Internal Medicine II, Augsburg University Medical Center and Comprehensive Cancer Center Augsburg, CCC Alliance WERA and Bavarian Cancer Research Center (BZKF), Augsburg, Germany
6 Onkologische Gemeinschaftspraxis Dresden, Dresden, Germany
7 Department of Hematology and Stem Cell Transplantation, West German Cancer Center and German Cancer consortium (DKTK partner site Essen), University Hospital Essen, Essen, Germany
8 University Clinic for Hematology, Oncology, Hemostaseology and Palliative Care, Johannes Wesling Medical Center Minden, University of Bochum, Minden, Germany
9 Department of Hematology and Oncology, Bundeswehr Krankenhaus Ulm, Ulm, Germany
10 Department of Hematology and Oncology, Bundeswehr Krankenhaus Ulm, Ulm, Germany
11 Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
12 Department of Internal Medicine A, Münster University, Münster, Germany
13 Department of Hematology and Oncology, Helios Klinikum Emil von Behring, Berlin, Germany
14 Department Internal Medicine III, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany
15 Department of Hematology and Oncology, Diakonie Klinikum Jung-Stilling, Siegen, Germany
16 Department of Hematology, Oncology and Palliative Care, SLK-Kliniken Heilbronn, Heilbronn, Germany
17 Department of Hematology and Oncology, Caritas Klinikum Saarbrücken, Saarbrücken, Germany
18 Medizinische Klinik II, DIAKO Ev. Diakonie-Krankenhaus, Bremen, Bremen, Germany
19 Department of Hematology, Oncology, Stem cell Transplantation and Palliative Care, Klinikum Stuttgart, Stuttgart, Germany
20 Department of Medicine III, Ludwig-Maximilians-Universitaet, Muenchen, Muenchen, Germany
21 Department of Oncology, Hematology, Immunology, and Palliative Care, Vincentius Hospital,ViDia Christliche Kliniken Karlsruhe, Karlsruhe, Germany
22 Department Internal Medicine I, Krankenhaus der Barmherzigen Brüder, Trier, Trier, Germany
23 Department of Medicine IV, Klinikum Bayreuth GmbH, Bayreuth, and Comprehensive Cancer Center Erlangen EMN, Bayreuth, Germany
24 Department of Internal Medicine III, Ulm University Hospital, Ulm, Ulm, Germany
25 Center for Hematology and Oncology Bethanien, Frankfurt, Germany
26 Department of Haematology, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
27 Second Department of Internal Medicine, University of Athens, Attikon University General Hospital, Athens, Greece
28 Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, Greece
29 Department of Hematology and Oncology, Klinikum Rheine, Rheine, Germany
30 Department of Hematology and Oncology, UKSH Campus Lübeck, Lübeck, Germany
31 Department of Internal Medicine IV, University Hospital of Giessen and Marburg, Giessen, Germany
32 Department of Internal Medicine IV, Universitätsmedizin Halle (Saale), Halle (Saale), Germany
33 Onkologische Schwerpunktpraxis Kurfürstendamm, Berlin, Germany
34 Department of Internal Medicine III, Petrus Hospital Wuppertal, Wuppertal, Germany
35 Department of Internal Medicine 1, Westpfalz-Klinikum, Kaiserslautern, Kaiserslautern, Germany
36 Department of Internal Medicine V, Klinikum Nürnberg-Nord, Nürnberg, Germany
37 Department of Hematology, Immunology and medical Oncology, St. Bernward Krankenhaus, Hildesheim, Germany
38 Department of Internal Medicine I, Werner Forßmann Hospital, Eberswalde, Germany
39 Department of Oncology, Hematology, Clinical Immunology and Rheumatology, Saarland University Medical Center, Homburg/Saar, Germany
40 Institute of Pathology, Julius-Maximilians-Universität Würzburg, Würzburg, Germany
41 Department of Nuclear Medicine, University Hospital Regensburg, Regensburg, Germany
42 Center for Hematology and Oncology Bethanien, Frankfurt, Germany
43 Department of Oncology, Hematology, Clinical Immunology and Rheumatology, Saarland University Medical Center, Homburg/Saar, Germany
44 Department of Oncology, Hematology, Clinical Immunology and Rheumatology, Saarland University Medical Center, Homburg/Saar, Germany
45 Department of Oncology, Hematology, Clinical Immunology and Rheumatology, Saarland University Medical Center, Homburg/Saar, Germany
46 Department of Oncology, Hematology, Clinical Immunology and Rheumatology, Saarland University Medical Center, Homburg/Saar, Germany
47 Institute for Medical Informatics, Statistics, and Epidemiology, University of Leipzig, Leipzig, Germany
48 Department of Oncology, Hematology, Clinical Immunology and Rheumatology, Saarland University Medical Center, Homburg/Saar, Germany
49 Department of Oncology, Hematology, Clinical Immunology and Rheumatology, Saarland University Medical Center, Homburg/Saar, Germany, Medical University Vienna, Vienna, Austria
50 Institute for Medical Informatics, Statistics, and Epidemiology, University of Leipzig, Leipzig, Germany
ABSTRACT
Introduction
Large B-cell lymphoma (LBCL) is the most common lymphoma entity in older adults. In the PHOENIX trial, R-CHOP + ibrutinib improved survival in pts <60 yrs old, but not in older pts due to increased toxicity (Younes 2019). Ibrutinib led to significantly lower R-CHOP completion rates in pts ≥60 years (73.7% vs 88.8%). Acalabrutinib is a 2nd generation BTK inhibitor with a more favorable safety profile (Seymore 2023). We hypothesized that acalabrutinib combined with reduced dose R-CHOP (R-miniCHOP-Acala) is better tolerable and therefore may improve survival in older adults with LBCL.
Methods
ARCHED/GLA 2022-1 (EU-CTN 2022-501187-18-00; NCT05820841) is an investigator-initiated, open-label, randomized phase 3 trial comparing six cycles of R-miniCHOP followed by two rituximab doses every three weeks with six cycles of R-miniCHOP plus acalabrutinib followed by two rituximab doses with acalabrutinib. Eligible pts have untreated CD20-positive LBCL, are aged >80 years, or 61–80 years and considered unfit for full-dose R-CHOP according to investigators’ assessment after simplified geriatric assessment (sGA). A preplanned safety interim analysis was performed after the 92nd patient in each arm completed six cycles, discontinued miniCHOP, or died. Prespecified stopping criteria were: a between-arm difference in miniCHOP discontinuation >15%, miniCHOP completion rate <70% in the control arm, or treatment-related mortality >11% in the experimental arm. Baseline characteristics, adverse events (AE), serious AE (SAE), and treatment adherence were assessed overall and by age group. AE were classified according to MedDRA and graded according to CTCAE v5.0.
Results
At data cutoff on 20th May 2026, 230 pts had been enrolled at 46 sites in Germany and Greece, and 184 had completed or discontinued R-miniCHOP. Two pts received no study treatment and were excluded, leaving 182 pts in the analysis set (91 per arm). Median age was 82 years (range, 64–94); 65% were aged >80 years, 61% were male, and 38% had ECOG 2–3. ADL was <6 in 27%, IADL <8 in 55%, and median CIRS-G score was 6. By sGA, were 43% unfit and 45% frail. IPI was 3–5 in 67%, and Elderly Prognostic Index was 6–8 in 67%. Baseline characteristics were balanced between arms.
All six miniCHOP cycles were completed by 73/91 pts (80%) in the R-miniCHOP-Acala arm and 72/91 (79%) in the R-miniCHOP arm. Toxicity-related discontinuation occurred in 9% vs 5%, and discontinuation due to intercurrent illness in 0% vs 2%, respectively. Cycle duration and relative doses of doxorubicin, cyclophosphamide, and vincristine were similar between arms and age groups. In the R-miniCHOP-Acala arm, 70% of pts (64/91) received six and 64% received eight acalabrutinib cycles (55/86, 5 additional pts still ongoing on cycle 6 at data cut-off). Median acalabrutinib relative dose was 93%.
Any-grade AE occurred in 100% of pts receiving R-miniCHOP-Acala and 97% receiving R-miniCHOP; grade ≥3 AE occurred in 56% and 52%, respectively. At least one SAE occurred in 54% in both arms, with grade ≥3 SAE in 41% and 42%, respectively.
Gastrointestinal AE were more frequent in the experimental arm: 48% with R-miniCHOP-Acala and 31% with R-miniCHOP; grade ≥3 GI AE occurred in 7% and 3%, respectively. Peripheral polyneuropathy occurred in 26% with R-miniCHOP-Acala and 14% with R-miniCHOP, grade ≥3 in 3% and 2%, respectively. Bleeding occurred in 22% and 5%, grade ≥3 bleeding in 4% and 1%, respectively. Cardiac AE occurred in 33% with R-miniCHOP-Acala and 25% with R-miniCHOP; grade ≥3 cardiac AE occurred in 11% and 12%, respectively. Importantly, infections were not increased with acalabrutinib: all-grade: 45% with R-miniCHOP-Acala vs 48% with R-miniCHOP; grade ≥3: 15% vs 20%, respectively.
Fatal AE occurred in 8 pts (9%) with R-miniCHOP-Acala (infection: 3, vascular: 1, unknown: 4) and 6 (7%) with R-miniCHOP (infection: 2, cardiac: 1, bleeding: 1, unknown: 2). Treatment-related deaths occurred in 3 pts (3%) and 2 pts (2%), respectively.
Conclusion
Adding acalabrutinib to R-miniCHOP was tolerable and did not impair chemotherapy adherence in older/frail pts with untreated LBCL. No new additional toxicities were seen with the addition of acalabrutinib to R-miniCHOP. Treatment-related mortality was comparable between arms, and in line with previous reports with R-miniCHOP. None of the prespecified stopping criteria was met. These findings support continued evaluation of R-miniCHOP-Acalabrutinib in the ARCHED/GLA 2022-1 trial.