Phase II frontline chemolight R-pola-glo trial induces high and durable response rates in elderly and medically unfit/frail patients with aggressive B-cell lymphoma
Abstract
Abstract Background Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma in adults, predominantly affecting older patients with a median age of 65 years at diagnosis. State-of-the-art treatment involves anthracycline-based chemo-immune therapy (R-CHOP/Pola-R-CHP), which achieves high cure rates in fit patients. Elderly/frail and medically unfit patients require attenuated regimens that compromise efficacy, highlighting the unmet need for exploring effective therapies that avoid classical chemotherapeutic agents. For this reason, we developed R-Pola-Glo, comprising the CD20 antibody rituximab (R), the antibody-drug conjugate polatuzumab vedotin (anti-CD79B; Pola), and the bispecific antibody glofitamab (CD20×CD3; Glo). Here, we report the first time the planned primary analysis of efficacy and toxicity of R-Pola-Glo.Methods This prospective, multicenter, one-arm phase II trial (AGMT-NHL-16/GLA2022-10/IKF062; EUCT#: 2024-513949-37) enrolled 80 previously untreated elderly/frail or otherwise medically unfit DLBCL patients ineligible for full-dose R-CHOP. Treatment consisted of a steroid pre-phase followed by 12 q3w cycles. Cycle 1 included obinutuzumab, Pola, and step-up Glo (2.5/10 mg); cycles 2-6 combined R, Pola, and Glo at 30 mg; cycles 7-12 consisted of Glo consolidation (30 mg). The first six cycles were administered inpatient; supportive care included G-CSF and anti-infective prophylaxis. Response was assessed by PET/CT per Lugano after cycles 2, 6, and end of treatment (EOT); toxicities were graded per CTCAE/ASTCT. The data cut was on July 2, 2025. The primary endpoint is 1-year progression-free survival (PFS); secondary endpoints include event-free survival (EFS), overall survival (OS), response rates, and duration of responses, along with toxicity analyses.Results The median age was 80 years (range: 66–92), with 19% (15/80) of patients (pts) over 85 years. Most pts had advanced-stage disease (64% [51/80]), elevated LDH (63% [50/80]), and ECOG 2 (28% [22/80]); 64% (51/80) had intermediate/high-risk IPI (IPI 3–5). According to the simplified geriatric assessment (sGA), 91% of patients were classified as unfit or frail; among 6 “fit” pts, 1 had already received anthracyclines for a different cancer, and 5 had relevant cardiovascular comorbidities not captured by the sGA. Overall, the patient profile aligns with the expected real-world profile of medical unfit/frail DLBCL patients with high treatment complexity. Therapy adherence was high, with 80% (64/80) of patients completing treatment as planned. Treatment was generally well tolerated, with 34% (27/80) of patients experiencing no grade 3-5 adverse effects (AE) in any cycle. Common toxicities included infections, grade 3-5 in 22% of pts (grade 3: 15 pts; grade 5: 3 pts), including 3 fatal infections (COVID: 1; COVID+RSV: 1; unknown focus: 1). Cytokine release syndrome occurred in 31% of pts (grade 3: 1 pts; no grade 4/5), and ICANS in 4% of pts (grade 2: 2 pts; grade 3: 1 pts). Notably, CRS usually occurred at early cycles and low grade, and all resolved completely. The overall response rates at cycles 2, 6, and EOT were 96% (95% CI: 89–99), 94% (95% CI: 86-98), and 90% (95% CI: 81–96); corresponding complete metabolic response (CMR) rates were 58%, 75%, and 81%, respectively. Late CMR conversions were frequent, with 52% of early partial responses converting to CMR by cycle 6 and an additional 40% converting during consolidation, highlighting the importance of extended Glo exposure. At data cut, 89% (71/80) were alive. Notably, with a median follow-up time of 15 months, these responses were durable and the one-year PFS, EFS, and OS rates were 85% (95% CI: 77-93), 82% (95% CI: 74-91), and 90% (95% CI: 83-97), respectively. Exploratory subgroup analysis suggested that R-Pola-Glo efficacy was consistent across all sGA risk groups and mitigated the adverse prognostic impact of classical IPI factors, including LDH.Conclusions R-Pola-Glo achieved high and durable CMR rates with an expected and manageable safety profile, translating into favorable 1-year survival rates in elderly/frail and medically unfit patients with aggressive B-cell lymphoma. Compared with other regimens for this population, R-Pola-Glo demonstrated higher response rates and improved survival outcomes at 1 year, strongly supporting its further clinical evaluation as a frontline option for this vulnerable patient population.
Article Details
Authors (49)
Björn Chapuy
Department of Hematology, Oncology and Tumor Immunology, Charité University Medical Center
Rebecca Wurm-Kuczera
Department of Hematology, Oncology and Tumor Immunology, Charité University Medical Center
Ralph Michael
2Institute for Medical Informatics, Statistics, and Epidemiology, University of Leipzig, Leipzig, Leipzig, Germany
Meng Wang
Petra Pichler
16University Hospital of St. Pölten, Department of Internal Medicine, St. Pölten, Austria
Angela Huster
4Steinenberg Clinic, Clinical Department for Internal Medicine, Reutlingen, Germany
Andrea Kerkhoff
7Medizinische Klinik A, University Hospital Münster, Münster, Germany
Michael Panny
6Hanusch Hospital, 3rd Medical Department for Haematology and Oncology, Vienna, Austria
Roland Schroers
18Medical Clinic II-Hematology and Oncology, Ruhr-University Bochum, Bochum, Germany
Anna Ossami Saidy
21Department of Hematology and Cell Therapy Helios Klinikum Berlin-Buch, Berlin, Germany
Fabian Müller
Friedrich-Alexander-Universität Erlangen–Nürnberg, Erlangen, Germany
Frederik Damm
Charité–Universitätsmedizin Berlin, Berlin
Manuel Orlinger
11Ordensklinikum Linz GmbH, Barmherzige Schwestern, Internal Medicine I: Medical Oncology and Hematology, Linz, Austria
Philipp Staber
19Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
Carsten Schwaenen
13Ortenau Hospital Offenburg, Department of Medical Oncology, Offenburg, Germany
Luisa Wohn
14The Frankfurt Institute of Clinical Cancer Research IKF, Frankfurt Am Main, Germany
Clemens Schmitt
15Kepler University Hospital, Internal Medicine 3 - Hematology and Internal Oncology, Linz, Austria
Martin Hoffmann
Mathias Hänel
7Department III of Internal Medicine, Klinikum Chemnitz, Chemnitz, Germany
Johannes Duell
16Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany
Simone Heyn
19University of Leipzig Medical Center, Department of Hematology, Cellular Therapies, Hemostaseology and Infectious Diseases, Leipzig, Germany
Stephanie Mayer
20University Hospital Regensburg, Clinic and Polyclinic for Internal Medicine III Hematology and Internal Oncology, Regensburg, Germany
Thomas Weber
Peter Reimer
22Evang. Kliniken Essen-Mitte, Clinic for Hematology, Oncology and Stem Cell Transplantation, Essen, Germany
Natalia Magdalena Rotter
23Ordensklinikum Linz Krankenhaus der Elisabethinen Linz GmbH, Interne Abteilung, Linz, Austria
Ulf Schnetzke
2Klinik für Innere Medizin II, Abteilung für Hämatologie und Iinternistische Onkologie, Universitätsklinikum Jena, Jena, Germany
Bastian von Tresckow
1Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, and German Hodgkin Study Group, Cologne, Germany
Gabriel Kammerer
26University Hospital St Poelten, Karl Landsteiner University of Health Sciences, Clinical Department for Internal Medicine, St. Poelten, Austria
Julia Rasvina
4Steinenberg Clinic, Clinical Department for Internal Medicine, Reutlingen, Germany
Barbara Lehner
27University Hospital St Pölten, Karl Landsteiner University of Health Sciences, Clinical Department for Internal Medicine, St. Pölten, Austria
Thomas Mika
28Knappschaft Kliniken University Hospital Bochum, Hämatologie, Onkologie, Stammzelltransplantation und zelluläre Immuntherapie, Bochum, Germany
David Böckle
29Charité -University Medical Center Berlin, Campus Benjamin Franklin, Department of Hematology, Oncology, and Cancer Immunology, Berlin, Germany
Corinna Leng
29Charité -University Medical Center Berlin, Campus Benjamin Franklin, Department of Hematology, Oncology, and Cancer Immunology, Berlin, Germany
Anna Lena Illert
Bettina Altmann
5Institute for Medical Informatics, Statistics and Epidemiology, University Leipzig, Leipzig, Germany
Birte Friedrichs
32University Hospital Düsseldorf, Department of Hematology, Oncology and Clinical Immunology, Düsseldorf, Germany
Ella Willenbacher
33University Hospital Innsbruck, Department of Internal Medicine III, Hematology and Medical Oncology, Innsbruck, Austria
Dimitrios Mougiakakos
Christiane Pott
6University Hospital Schleswig-Holstein, Department of Internal Medicine II, Kiel, Germany
Salah-Eddin Al-Batran
Krankenhaus Nordwest, University Cancer Center (UCT) Frankfurt, and Frankfurt Institute of Clinical Cancer Research (IKF), Frankfurt, Germany
Andreas Rosenwald
Dirk Hellwig
37University Hospital Regensburg, Department of Nuclear Medicine, Regensburg, Germany
Sascha Dietrich
Bertram Glass
21Department of Hematology and Cell Therapy Helios Klinikum Berlin-Buch, Berlin, Germany
Georg Lenz
Ulrich Keller
Marita Ziepert
5Institute for Medical Informatics, Statistics and Epidemiology, University Leipzig, Leipzig, Germany
Thomas Melchardt
Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology, and Rheumatology, Cancer Research Laboratory of the Department of Internal Medicine III, Paracelsus Medical University, Salzburg, Austria
Richard Greil