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

Cancer Cell International, vol. 26

Abstract

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Authors 4

1. Min-Yue Zhang

   Shanghai Jiao Tong University · Renji Hospital

   Affiliation as printed

   Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, PR China

2. Fei Xiao

   Shanghai Jiao Tong University · Renji Hospital

   Affiliation as printed

   Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, PR China

3. Zi-Hua Li Aachen Department of Clinical Epidemiology

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Epidemiology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, South Holland, Netherlands

4. Honghui Huang corresponding

   Shanghai Jiao Tong University · Renji Hospital

   Affiliation as printed

   Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, PR China. huanghonghui@renji.com