Introduction:

Diffuse large B cell lymphoma (DLBCL) is genetically heterogenous, comprising distinct molecular subtypes (MCD, BN2, N1, EZB, A53, and ST2) according to the LymphGen classification (Cancer Cell 2020:37:551-568). The simplified LymphPlex algorithm (38 genes) categorizes DLBCL into TP53-mutated, MCD-like, BN2-like, N1-like, EZB-like, and ST2-like subtypes, demonstrating strong concordance with LymphGen (Sig Transduct Target Ther 2023:8:145). These subtypes exhibit divergent clinical behavior and prognosis. The phase II GUIDANCE-01 trial further established that subtype-guided immunochemotherapy (R-CHOP-X) improves antitumor efficacy with acceptable safety (Cancer Cell 2023:41:1705-1716). Nevertheless, real-world data on treatment practices and outcomes across subtypes remains scarce. This multicenter, nationwide study characterizes clinical practice and therapeutic effectiveness in a large Chinese DLBCL cohort stratified by genetic subtype, informing precision therapy approaches.

Methods

This real-world study (NCT06026488) included DLBCL patients with TP53-mutated, MCD-like, BN2-like, N1-like, EZB-like, ST2-like, or other subtypes from 27 Chinese centers. Retrospective data included demographics, clinical characteristics, genetic profiles, treatments, response assessments, and survival outcomes. Effectiveness endpoints were progression-free survival (PFS), complete response rate (CRR), objective response rate (ORR), and overall survival (OS).

Results

By May 15, 2025, a total of 3,539 patients with DLBCL (male, 53.0%) were analyzed, with a median age of 60 years (IQR, 50-69 years). Additionally, 56.5% of patients had stage III/IV disease, 55.9% had non-GCB subtype, 45.7% exhibited elevated lactate dehydrogenase levels, and 29.0% had >2 extranodal sites. High-risk features included IPI score 3-5 (35.5%), MYC/BCL-2 dual expression (28.3%), and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements (3.2%). Common genetic subtypes: TP53-mutated was identified in 19.3% of patients, MCD-like in 16.1%, BN2-like in 8.9%, and other genetic subtypes in 29.5%. The most common first-line therapies comprised R-CHOP-based therapy (68.5%), R-CHOP plus targeted agents (10.1%), and DA-EPOCH-R (3.2%).

Among 2,973 patients with effectiveness data, the overall CRR was 70.9% and ORR was 80.5%. CRR was higher with R-CHOP plus targeted agents (78.3%). In MCD-like patients (n=333) who received R-CHOP-based or R-CHOP plus Bruton tyrosine kinase inhibitor (BTKi), propensity score-matched analysis showed numerically higher CRR with R-CHOP plus BTKi versus R-CHOP (77.2% vs 68.4%). Orelabrutinib was the most common BTKi, and R-CHOP plus orelabrutinib achieved a CR rate of 81.4% in MCD-like subgroup. Survival data collection is ongoing.

Conclusions: This large-scale real-world study provides treatment patterns and outcomes across DLBCL genetic subtypes in China. R-CHOP plus BTKi demonstrated enhanced efficacy in MCD-like patients, supporting subtype-directed therapy. Updated survival and safety data will be presented.

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2025
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