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.

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2025
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