AFFILIATIONS
1 Charité-University Medical Center Berlin, Campus Benjamin Franklin, Berlin, Germany
2 Charité-University Medical Center Berlin, Campus Benjamin Franklin, Berlin, Germany
3 Institute for Medical Informatics, Statistics, and Epidemiology, University of Leipzig, Leipzig, Germany
4 Charité-University Medical Center Berlin, Campus Benjamin Franklin, Berlin, Germany
5 Charité-University Medical Center Berlin, Campus Benjamin Franklin, Berlin, Germany
6 Charité-University Medical Center Berlin, Campus Benjamin Franklin, Berlin, Germany
7 Institute for Medical Informatics, Statistics, and Epidemiology, University of Leipzig, Leipzig, Germany
8 University Hospital St Pölten, Karl Landsteiner University of Health Sciences, Clinical Department for Internal Medicine, St. Pölten, Austria
9 Steinenberg Clinic, Clinical Department for Internal Medicine, Reutlingen, Germany
10 University Hospital Muenster, Department of Medicine A, Hematology, Oncology and Pneumology, Münster, Germany
11 Hanusch Hospital, 3rd Medical Department for Haematology and Oncology, Vienna, Germany
12 Knappschaft Kliniken University Hospital Bochum, Hämatologie, Onkologie, Stammzelltransplantation und zelluläre Immuntherapie, Bochum, Germany
13 Helios Klinikum Berlin-Buch, Department of Hematology and Cell Therapy, Berlin, Germany
14 University Hospital of Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg (FAU), Department of Internal Medicine 5 - Haematology and Oncology, Erlangen, Germany
15 Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Dept. of Hematology, Stem Cell Transplantation, Oncology and Palliative Medicine, CVK, Berlin, Germany
16 Ordensklinikum Linz GmbH, Barmherzige Schwestern, Internal Medicine I: Medical Oncology and Hematology, Linz, Austria
17 Medical University of Vienna, Division of Hematology and Hemostaseology, Medicine I, Vienna, Germany
18 Ortenau Hospital Offenburg, Department of Medical Oncology, Offenburg, Germany
19 The Frankfurt Institute of Clinical Cancer Research IKF, Frankfurt Am Main, Germany
20 Institute of Pathology, Kepler University Hospital, Medical Faculty, Johannes Kepler University, Linz, Austria
21 Johannes Kepler University, Department of Hematology/Oncology, Kepler University Hospital, Medical Faculty, Linz, Austria
22 Medical Clinic A, Clinic Ludwigshafen, Ludwigshafen, Germany
23 Klinikum Chemnitz gGmbH, Department of Internal Medicine III, Chemnitz, Germany
24 University Hospital Würzburg, Medical Clinic and Polyclinic II, Würzburg, Germany
25 University of Leipzig Medical Center, Department of Hematology, Cellular Therapies, Hemostaseology and Infectious Diseases, Leipzig, Germany
26 University Hospital Regensburg, Clinic and Polyclinic for Internal Medicine III Hematology and Internal Oncology, Regensburg, Germany
27 Martin-Luther-Universität Halle-Wittenberg, Department of Internal Medicine IV (Hematology and Oncology), Halle (Saale), Germany
28 Evang. Kliniken Essen-Mitte, Clinic for Hematology, Oncology and Stem Cell Transplantation, Essen, Germany
29 Ordensklinikum Linz GmbH, Elisabethinen, Internal Medicine I: Hematology, Stem Cell Transplantation, Hemostaseology and Medical Oncology, Linz, Austria
30 University Hospital Jena, Department of Internal Medicine II, Hematology and Medical Oncology, Jena, Germany
31 West German Cancer Center and German Cancer Consortium (DKTK partner site Essen), University Hospital Essen, University of Duisburg-Essen, Department of Haematology and Stem Cell Transplantation, Essen, Germany
32 University Hospital St Pölten, Karl Landsteiner University of Health Sciences, Clinical Department for Internal Medicine, St. Pölten, Austria
33 Steinenberg Clinic, Clinical Department for Internal Medicine, Reutlingen, Germany
34 Hanusch Hospital, 3rd Medical Department for Haematology and Oncology, Vienna, Austria
35 Knappschaft Kliniken University Hospital Bochum, Hämatologie, Onkologie, Stammzelltransplantation und zelluläre Immuntherapie, Bochum, Germany
36 Charité-University Medical Center Berlin, Campus Benjamin Franklin, Berlin, Germany
37 Charité-University Medical Center Berlin, Campus Benjamin Franklin, Berlin, Germany
38 Technical University of Munich (TUM), Department of Medicine III, School of Medicine and Health, Munich, Germany
39 University Hospital Düsseldorf, Department of Hematology, Oncology and Clinical Immunology, Düsseldorf, Germany
40 University Hospital Innsbruck, Department of Internal Medicine III, Hematology and Medical Oncology, Innsbruck, Germany
41 Otto-von-Guerike University Magdeburg, Magdeburg, Germany, Dept. of Hematology, Oncology, and Cell Therapy, Magdeburg, Germany
42 University Hospital Schleswig-Holstein, Clinic for Internal Medicine II (Hematology and Oncology), Kiel, Germany
43 The Frankfurt Institute of Clinical Cancer Research IKF, Frankfurt Am Main, Germany
44 Kepler University Hospital, Internal Medicine 3 - Hematology and Internal Oncology, Linz, Austria
45 Julius Maximilians Universität Würzburg, Institute of Pathology, Würzburg, Germany
46 University Hospital Regensburg, Department of Nuclear Medicine, Regensburg, Germany
47 University Hospital Düsseldorf, Department of Hematology, Oncology and Clinical Immunology, Düsseldorf, Germany
48 Helios Klinikum Berlin-Buch, Department of Hematology and Cell Therapy, Berlin, Germany
49 University Hospital Muenster, Department of Medicine A, Hematology, Oncology and Pneumology, Münster, Germany
50 Charité-University Medical Center Berlin, Campus Benjamin Franklin, Berlin, Germany
51 Institute for Medical Informatics, Statistics, and Epidemiology, University of Leipzig, Leipzig, Germany
52 Paracelsus Medical University, 3rd Medical Department with Hematology, Medical Oncology, Rheumatology and Infectiology, Salzburg, Austria
53 Paracelsus Medical University, 3rd Medical Department with Hematology, Medical Oncology, Rheumatology and Infectiology, Salzburg, Austria
ABSTRACT
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. Anthracycline-based chemo-immune therapy (R-CHOP/Pola-R-CHP) achieves high cure rates in fit patients, but elderly/frail and medically unfit patients require attenuated regimens that compromise efficacy. To overcome the unmet need for effective therapies while sparing patients the toxicities associated with conventional chemotherapies, we developed R-Pola-Glo, comprising the anti-CD20 antibody rituximab (R), the antibody-drug conjugate polatuzumab vedotin (anti-CD79B; Pola), and the bispecific, T-cell engaging antibody glofitamab (CD20×CD3; Glo). We recently reported the initial cohort (n=80) with high and durable response rates and a favorable 1-year survival (progression free survival [PFS] 85%; overall survival [OS] 90%). Here, we report the preplanned, combined analysis of the initial and extension cohorts (n=126) with longer follow-up of the initial cohort.
This prospective, multicenter, single-arm phase II trial (AGMT-NHL-16/GLA2022-10/IKF062; EUCT#: 2024-513949-37) enrolled previously untreated elderly/frail or medically unfit DLBCL patients ineligible for full-dose R-CHOP. Treatment comprised a mandatory steroid pre-phase, cycle 1 with obinutuzumab/Pola/step-up Glo, cycles 2-6 with full-dose level R-Pola-Glo, and cycles 7-12 with Glo consolidation. Response was assessed by PET/CT per Lugano criteria after cycles 2, 6, and end of treatment (EOT); toxicities were graded per CTCAE/ASTCT. This combined analysis includes 126 patients, comprised of the initial cohort (n=80) and the extension cohort (n=46). Primary endpoint was 1-year PFS; secondary endpoints included event-free survival (EFS), OS, response rates, and toxicity. Data cut: 25.06.2026.
Baseline characteristics of the combined cohort were consistent with the initial cohort (median age, 80y; pts>85y, 18%; simplified geriatric assessment [sGA] unfit/frail, 92%; high intermediate/high-risk IPI, 64%), reemphasizing that this is a representative real-world cohort of medically unfit/frail patients with high treatment complexity.
Therapy adherence was high in the combined cohort, with 78% (98/126) of patients completing treatment as planned. The extension cohort allowed outpatient treatment also in C1-C6, and 46% (111/243) of therapy cycles C1-C6 were completed in the outpatient setting. Treatment was generally well tolerated with no new unexpected toxicities: grade 3-5 AEs in 64% of patients, grade 3-5 infections in 24% (including 4 fatal events: COVID-19 pneumonia, COVID-19 and RSV infection, infection of unclear focus, and septic shock with multi-organ failure), CRS in 30% (grade 3:2%; grade 4/5: 0), and ICANS in 6% (grade 3: 2%; grade 4/5: 0).
In the combined cohort, the overall response rate and complete metabolic response rate (CMR) at EOT was 88% and 80%, respectively, preserving the high response rates as reported for the initial cohort. Late CMR conversions were frequent: 57% (28/49) of patients in PR after cycle 2 converted to CMR by cycle 6, and 43% (9/21) of patients still in PR after cycle 6 converted to CMR by end of treatment, underscoring the value of extended Glo exposure.
With a median follow-up of 25 months in the combined cohort, 1-y PFS was 86% (95% CI 80-93), 1-y EFS was 83% (95% CI 77-90), and 1-y OS was 91% (95% CI 86-96), closely matching the initial cohort's outcomes. Extended follow-up also allows robust assessment of the 2-y PFS of 80% (95% CI 73-88), 2-y EFS of 79% (95% CI 72-87), and 2-y OS of 86% (95% CI 80-93). Patients who completed treatment as planned (n=98/126) had a 2y-PFS, 2y-EFS and 2y-OS of 91%, 90% and 95%, respectively. Notably, PFS and OS was consistent across sGA and IPI risk groups.
In summary, this combined and preplanned analysis with longer follow up confirms that R-Pola-Glo delivers high, durable response rates and favorable 2-year survival estimates with a manageable safety profile. By providing a highly effective, chemotherapy-free regimen specifically tailored for elderly, frail, or medically unfit patients, these data address a significant unmet clinical need and firmly establish R-Pola-Glo as a compelling therapeutic option, providing the foundation for the upcoming phase 3 trial.