Background. Diffuse large B-cell lymphoma is the most common aggressive B-cell lymphoma mainly affecting elderly patients. The treatment goal is usually cure, however, older and frail patients typically exhibit a growing number of comorbidities that significantly increase treatment-related morbidity and mortality thus limiting the treatment goal due to switching to less effective treatments. Particular in the frail population there is an urgent medical need to establish highly effective therapies suitable for patients with limited functional organ reserve. To this end, we developed the chemotherapy-light combination therapy R-Pola-Glo, which is composed of the anti-CD20 antibody rituximab in combination with the antibody-drug conjugate polatuzumab vedotin (anti-CD79b) and the bispecific antibody glofitamab (CD20×CD3). Here, we report the safety data report of the run-in phase following treatment of the first 10 patients with this first-in-human chemotherapy-light combination. Methods. R-Pola-Glo (EudraCT No.: 2022-003398-51) is a prospective, bi-national (Germany/Austrian), multicenter, one arm, phase II trial designed to estimate the 1-year progression free survival of the chemotherapy-light combination rituximab, polatuzumab vedotin and glofitamab as the primary endpoint. Previously untreated DLBCL patients above 60 years of age, who are not eligible for a fully dosed R-CHOP-like therapy were eligible for enrollment, including patients with a lymphoma-related ECOG 3 and reduced kidney function. The study treatment plan includes a mandatory prephase with prednisolone or dexamethasone followed by 12 treatment cycles of 3 weeks each (Fig. 1). The step-up cycle (cycle 1) is comprised of intravenous (i.v.) application of obinutuzumab 1000 mg on D1, followed by i.v. application of polatuzumab vedotin 1.8 mg/kg on D2 and i.v. application of glofitamab in escalating doses of 2.5 mg on D8 and 10 mg on D15. This is followed by the target dose phase (cycles 2-6). Each of the 5 target dose cycles included rituximab 375 mg/m 2 and polatuzumab 1.8 mg/kg, both administered i.v. on D1 and i.v. glofitamab 30 mg on D2. The consolidation phase (cycles 7-12) comprises 6 cycles of glofitamab 30 mg administered intravenously on D1. As this is the first in human combination of these antibodies, the initial 10 patients were analyzed in a planned safety run-in phase and are reported here. Results. The median age of the first 10 patients was 79 years (range 69-81), with 70% of patients presenting with stage III/IV disease and elevated LDH; ECOG of all patients was <3 (ECOG 0: 4 patients; ECOG 1: 4 patients; ECOG 2: 2 patients). Extranodal involvement was present in 40%. Overall, 70% patients had a high-intermediate/high-risk IPI representing a high-risk population. The median follow-up time presented here from registration to time of data cut July 20, 2023 is 62 days (range 38-122) and longer follow-up will be presented at the time of the meeting. We observed 34 adverse events (AEs) including infections (6/10 patients; grade 1: 2; grade 2: 2; grade 3:2; no grade 4/5), neuropsychiatric issues (prednisone induced psychosis, fatigue, dysgeusia (4/10; all grade 1), CRS (3/10; all grade 1), cardiovascular side effects (3/10; all grade 2), infusion related reactions (2/10; grade 2), anemia (1/10; grade 2), bleeding (1/10; grade 3), and renal toxicity (1/10; grade 3). Notably, so far neither polyneuropathy nor ICANs were reported. Ten of the AEs occurring in 5 patients over all courses administered so far required hospitalization and were therefore classified as serious AEs and included infections (4 in two patients, peribronchitis and urosepsis) CRS (2), renal toxicity (1), deep vein thrombosis (1) and bleeding (1). Neither of the events were life threatening and no death occurred. Conclusion. R-Pola-Glo is a chemotherapy-light treatment regimen that exhibits an excellent safety profile in a vulnerable patient population. Specifically, no life-threating adverse events, ICANS, high grade polyneuropathy or deaths of any cause occurred, and CRS events were limited to grade 1. Acknowledgements. Study sponsor of R-Pola-Glo (EudraCT No.: 2022-003398-51) is the Institut für Klinische Krebsforschung (IKF) Frankfurt, Germany; financial support is provided by F. Hoffmann-La Roche Ltd. TM and RWK contributed equally as first authors; RG and BC contributed equally as senior authors.