Abstract Background: Double-expressor diffuse large B-cell lymphoma (DE-DLBCL), characterized by MYC and BCL2 protein overexpression without gene rearrangements, has a poor prognosis under R-CHOP therapy, with a 5-year overall survival (OS) rate of approximately 30% (Yetisir AE et al., Med Sci Discov, 2020; Hu S et al., Blood, 2013). Its aggressiveness results from MYC-driven proliferation and BCL2-mediated apoptosis resistance. Bruton's tyrosine kinase inhibitors (BTKis) represent a rational strategy by targeting BCR signaling and downstream NF-κB and PI3K/AKT pathways to restore apoptotic sensitivity (Wen T et al., Leukemia, 2021). A phase II clinical trial, zanubrutinib (a covalent BTKi) combined with R-CHOP (ZR-CHOP) achieved 2-year PFS and OS rates of 81.25% and 93.75% in DE-DLBCL (Yin X et al., Cancer, 2025). To further evaluate its real-world efficacy, we conducted a multicenter retrospective study comparing ZR-CHOP and R-CHOP in newly diagnosed DE-DLBCL patients. Methods: This retrospective study included 281 newly diagnosed DE-DLBCL patients treated between January 2018 and September 2024 at Sun Yat-sen University Cancer Center, Dongguan People's Hospital and Foshan First People's Hospital. All cases were pathologically confirmed as DE-DLBCL based on fluorescence in situ hybridization (FISH) and immunohistochemistry. Patients received either six cycles of R-CHOP or ZR-CHOP (R-CHOP plus zanubrutinib, 160 mg BID). All patients underwent response evaluation with PET-CT. In the ZR-CHOP group, patients achieving complete remission (CR) received either zanubrutinib maintenance or surveillance. In the R-CHOP group, CR patients underwent surveillance. Patients with partial remission (PR), stable disease (SD), or progressive disease (PD) received appropriate second-line therapy. Results: At the cutoff date of July 25, 2025, 187 patients received R-CHOP and 84 received six cycles of ZR-CHOP. Baseline characteristics, including age (60 years: 62% vs. 52%, p = 0.139), cell-of-origin subtype (non-GCB: 86% vs. 80%, p = 0.183), disease stage (stage III–IV: 68% vs. 61%, p = 0.279), and IPI score (IPI ＞2 :42% vs.35%, p = 0.826), were comparable between the ZR-CHOP and R-CHOP groups. Treatment was well tolerated in the ZR-CHOP cohort, with no dose reductions or interruptions. Grade ≥3 adverse events (AEs) occurred in 36 patients (38.3%), most commonly neutropenia (28 patients; 29.8%). At the end of treatment, CRR and ORR were 69.5% and 82.4% in the R-CHOP group, and 73.0% and 82.6% in the ZR-CHOP group, respectively, with no significant difference (CRR: p = 0.667; ORR: p = 1.000). The ZR-CHOP regimen demonstrated significantly superior progression-free survival (PFS) compared to R-CHOP at 1, 2, and 3 years (90.4% vs. 66.3%, 88.3% vs. 56.7%, and 88.3% vs. 52.4%, respectively; all p 0.001). OS) was also significantly improved with ZR-CHOP, with 1-, 2-, and 3-year OS rates of 98.9%, 98.9%, and 97.9%, respectively, compared to 91.4%, 78.6%, and 73.8% in the R-CHOP group (p = 0.040, 0.001, and 0.001, respectively). The ZR-CHOP group had a significantly shorter mean follow-up (724 vs. 1381 days, p 0.001) and a higher rate of multiple extranodal involvements (38% vs. 26%, p = 0.037). To reduce bias, 1:1 propensity score matching (PSM) was performed. After matching, the PFS benefit of ZR-CHOP remained significant at 1, 2, and 3 years (90.4%, 88.3%, 88.3%) versus R-CHOP (62.8%, 53.2%, 48.9%; all p 0.001). Similarly, OS rates remained higher in the ZR-CHOP group (98.9%, 98.9%, 97.9%) compared to R-CHOP (89.4%, 69.1%, 61.7%; all p 0.01). Subgroup analyses before and after matching demonstrated consistent PFS and OS benefits with ZR-CHOP across subgroups. In the overall population, ZR-CHOP significantly improved both outcomes compared to R-CHOP (PFS OR: 0.12 pre-PSM, 0.11 post-PSM; OS OR: 0.06 pre-PSM, 0.04 post-PSM; all p 0.001). Conclusion: This retrospective study demonstrated that ZR-CHOP significantly improves survival outcomes in DE-DLBCL, representing a promising therapeutic option. Keywords: BTKi, double-expressor lymphoma, Zanubrutinib, R-CHOP
Cai et al. (Mon,) studied this question.