159 | R‐POLA‐GLO – CHEMO‐LIGHT FRONTLINE THERAPY INDUCES HIGH RESPONSE RATES WITH A FAVORABLE SAFETY PROFILE IN ELDERLY/FRAIL PATIENTS WITH AGGRESSIVE LYMPHOMA

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Introduction: Diffuse large B-cell lymphoma, the most common aggressive lymphoma, mainly affects older adults.While R-CHOP-like therapies achieve high cure rates in fit patients (pts), elderly/frail and medically unfit pts need reduced-intensity regimens, compromising efficacy.The need for effective therapies for pts with limited organ reserve led us to develop R-Pola-Glo as a first-line treatment for pts ineligible for full-dose R-CHOP, combining the anti-CD20 antibody rituximab (R), the antibody-drug conjugate polatuzumab vedotin (anti-CD79b, Pola) and the bispecific antibody glofitamab (CD20 � CD3, Glo).Here, we report R-Pola-Glo's pre-planned end of treatment (EOT) response and safety profile.Methods: This phase II multicenter trial (AGMT-NHL-16/ GLA2022-10/IKF062; EUCT#: 2024-513949-37) evaluates R-Pola-Glo in 80 previously untreated, medically unfit/elderly/ frail pts.Treatment includes a steroid pre-phase followed by 12 q3w cycles with PET/CT response assessment after cycles 2, 6 and EOT.Cycle 1 includes obinutuzumab, Pola, and Glo with step-up dosing (2.5 mg and 10 mg); cycles 2-6 include R, Pola, and Glo (30 mg), followed by 6 Glo consolidation cycles (30 mg).Supportive care included growth factor support and anti-infective prophylaxis.Toxicities were graded per CTCAE/ASTCT; PET/CT-response was locally assessed per Lugano 2014 criteria.The data cut-off was Feb. 17, 2025, after the last patient completed EOT-PET.Results: Median age of the 80 enrolled pts was 80 yo (range: 66-92); 19% (15/80) > 85 yo.Most pts (65%[52/80]) had advancedstage disease, elevated lactate dehydrogenase (63% [50/80]), and 28% (22/80) had an ECOG > 1.According to IPI, 65% had intermediate (IPI 3: 32.5%) or high-risk disease (IPI 4/5: 32.6%).Treatment was well-tolerated, with 61 grade (Gr) ≥ 3 serious adverse events (SAEs) across all cycles (Gr 4: 6; Gr 5: 3), including three fatal infections (COVID:1; COVIDþRSV: 1; unclear focus: 1).Main SAEs were infections (Gr 3: 20; Gr 4: 0; Gr 5: 3) and cytopenia (Gr 3: 6; Gr 4: 5).Cytokine release syndrome occurred in 21%, mostly low-grade, in early cycles (Gr 3: 2).Immune effector cell-associated neurotoxicity syndrome occurred in 3 pts (Gr 2: 3; Gr 3: 2).Overall, 53% (42/80) had no Gr ≥ 3 SAEs.The overall response rates at cycles 2, 6, and EOT were 93% (95% CI: 84.4-97.2),93% (84.4-97.2),and 90% (81.2-95.6),respectively.Remarkably, corresponding complete metabolic response rates (CMR) were 55% (43.5-66.2),74% (62.7-83.0),and 82% (71.0-89.1).Notably, CMR conversion rates from partial response from cycle 2 to 6 were 50% (31.3-68.7)and 46.7% (21.3-73.4)from cycle 6 to EOT, demonstrating a conversion even at later timepoints.At data cut-off, 90% (72/80) of pts were alive.Conclusions: R-Pola-Glo demonstrates high CMR rates with manageable safety, supporting further clinical investigation as a first-line treatment option for elderly/frail and medically unfit pts with aggressive lymphoma.

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