Frontline intensified vs standard immunochemotherapy in high-risk diffuse large B-cell lymphoma: A systematic review and meta-analysis.

7065 Background: While the phase III CALGB 50303 trial comparing frontline REPOCH vs standard RCHOP for diffuse large B-cell lymphoma (DLBCL) showed comparable outcomes overall, it suggested a potential benefit of intensified therapy in high-risk patients, including high-grade (HG) and double/triple-expressor (DE/TE) disease. Subsequent studies evaluating REPOCH in HG and DE/TE DLBCL have been small, retrospective and nonrandomized, with conflicting results. Despite limited evidence and greater toxicity, REPOCH is commonly used in these cohorts. We conducted a systematic review and meta-analysis to assess outcomes after frontline REPOCH vs RCHOP in HG and DE/TE DLBCL, comprising the largest high-risk cohort to date. Methods: Original research studies evaluating outcomes after frontline REPOCH or RCHOP in HG or DE/TE DLBCL from 2009 to 2025 were included. HG was defined by MYC translocation, including double/triple-hit (DH/TH; MYC and BCL2 and/or BCL6 translocation). DE/TE was defined by MYC and BCL2 and/or BCL6 by IHC. Studies were excluded if they had <10 subjects or used agents in addition to the RCHOP or REPOCH backbones. RCHOP-like regimens with comparative substitutions were included (e.g., RCOMP). We used random effects models to calculate pooled response rates and survival outcomes. Results: 69 studies were included with 3979 total patients (1818 HG; 2161 DE/TE). 2698 patients (68%) were treated with RCHOP, and 1281 (32%) with REPOCH. Limited reporting of patient characteristics in HG or DE/TE cohorts precluded multivariable analysis of prognostic factors. While overall response rate (ORR) did not differ between treatment groups (relative risk [RR] 1.04, CI 0.92-1.19), patients treated with REPOCH were more likely to achieve complete response (CRR; RR 1.12, CI 1.01-1.23). This difference was especially notable in the HG subgroup (RR 1.4, CI 1.21-1.61), but there was no difference in the DE/TE subgroup (RR 1.04, CI 0.93-1.17). Across all patients, REPOCH was associated with significantly improved progression-free survival (PFS; hazard ratio [HR] 0.5, CI 0.39-0.65) and overall survival (OS; HR 0.59, CI 0.43-0.82). Landmark 2-year PFS (65% vs 52%, p = 0.013) and OS (75% vs 50%, p < 0.0001) were significantly higher for REPOCH. Subgroup analysis showed significantly improved 2-year OS with REPOCH in both HG (72% vs 47%, p < 0.0001) and DE/TE (67% vs 51%, p = 0.032) disease. Conclusions: In this large cohort, REPOCH was associated with significantly improved CRR, PFS and OS relative to RCHOP in HG and DE/TE DLBCL. Reported patient characteristics were limited, and the REPOCH arm may have preferentially included younger patients with better performance status. Nevertheless, our analysis provides evidence in an area lacking randomized trial data. While not definitive, our findings support the common clinical practice of treating select high-risk patients with REPOCH.