Optimizing first-line therapy for double-expressor lymphoma: a systematic review and meta-analysis of novel agent-augmented R-CHOP regimens

Double-expressor lymphoma (DEL) shows an inferior survival with R-CHOP therapy. While R-CHOP combined with novel agents (R-CHOP + X) demonstrates promising benefits in DEL, the optimal front-line regimen remains controversial. Therefore, we performed a systematic review and meta-analysis to compare the efficacy and safety of R-CHOP + X regimens and identify optimal first-line strategies for DEL. PubMed, OVID, Cochrane Library, and clinical trial registries were systematically searched (up to May 31st, 2025) for studies evaluating first-line treatment with R-CHOP, R-DA-EPOCH, or R-CHOP + X including BTK inhibitors (BTKi), polatuzumab vedotin, lenalidomide, venetoclax, tucidinostat, and bortezomib in DEL. Outcomes included 2-year progression-free survival (PFS), 3-year overall survival (OS), complete remission (CR) rates, and adverse events (AEs) incidence. Single-arm, pairwise, and Bayesian network meta-analyses were performed using R software (version 4.3.2) and RevMan 5.4. Efficacy rankings were assessed via Surface Under the Cumulative Ranking Curve (SUCRA). Twenty-three studies (2,735 patients) evaluating eight regimens were included. Single-arm meta-analysis showed that R-CHOP + X achieved pooled 2-year PFS of 72%, 3-year OS of 85%, and CR rate of 75%, without increasing the incidence of AEs compared with R-CHOP. Pairwise meta-analysis indicated that R-CHOP + X was significantly superior to R-CHOP in 2-year PFS odds ratio (OR) 1.69, 95% confidence interval (CI) 1.39–2.05, 3-year OS (OR 1.51, 95% CI 1.08–2.11), and CR rate (OR 1.56, 95% CI 1.24–1.95). Based on SUCRA-based ranking probabilities from the network meta-analysis, R-CHOP+BTKi tended to rank highest for 2-year PFS (SUCRA 0.79) and ranked second for 3-year OS (SUCRA 0.76), although these rankings should be interpreted cautiously given the predominance of indirect comparisons. Crucially, among R-CHOP + X regimens, the BTKi-containing combination emerged as the sole intervention demonstrating concurrent significant outperformance over R-CHOP in both 2-year PFS OR 2.07, 95% credible interval (CrI) 1.24–3.70 and 3-year OS (OR 1.76, 95% CrI 1.07–2.93). Notably, R-CHOP + X did not increase the incidence of severe hematological toxicities or infections in comparison to R-CHOP alone. R-CHOP + X regimens, particularly BTKi-based combinations, may improve PFS and OS versus standard R-CHOP in newly diagnosed DEL, without a clear signal of excess hematologic toxicity or infections in the available evidence, pending confirmation in prospective comparative trials. These results suggest that incorporating targeted agents into frontline R-CHOP backbones could be a promising strategy.