What question did this study set out to answer?

Evaluate the feasibility and efficacy of molecularly adapted therapy in newly diagnosed diffuse large B-cell lymphoma (DLBCL).

April 16, 2026Open Access

Molecularly Adapted Antitumor Therapy for Newly Diagnosed Diffuse Large B-Cell Lymphoma: Two-Year Follow-Up Results

Key Points

Evaluate the feasibility and efficacy of molecularly adapted therapy in newly diagnosed diffuse large B-cell lymphoma (DLBCL).
Single-center, prospective, non-randomized study with 43 adults diagnosed with DLBCL.
Participants underwent tumor genotyping using a 19-gene or a 60-gene panel.
Initial R-CHOP therapy was followed by R-CHOP-X, incorporating agents based on molecular subtype.
Response assessed via PET/CT and adverse events recorded per NCI CTCAE v5.0.
Overall response rate was 100% with complete response rate also at 100% among those who finished therapy.
At two years, overall survival was 92% and progression-free survival was 94%.
Use of a 60-gene panel significantly reduced unclassifiable cases from 34% to 12%.
Notable adverse events included grade 3–4 neutropenia (26%) and thrombocytopenia (12%), but no treatment discontinuations were noted.

Abstract

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is molecularly heterogeneous, and approximately 30-50% of patients fail to achieve cure with standard R-CHOP. Genotype-directed first-line therapy may improve outcomes by targeting subtype-specific oncogenic pathways. This study evaluated the feasibility, efficacy, and safety of a molecularly adapted R-CHOP-X strategy with two-year follow-up. Methods: In this single-center, prospective, non-randomized study conducted between September 2023 and the data cut-off (16 September 2025), 43 adults with newly diagnosed DLBCL (excluding high-grade B-cell lymphoma, primary immune-privileged, and primary mediastinal large B-cell lymphomas) underwent tumor genotyping using the LymphGen classification after targeted sequencing: a 19-gene Sanger panel (Cohort 1, n = 35) or an expanded 60-gene panel (Cohort 2, n = 8; proof-of-concept). All patients received one initial cycle of R-CHOP as bridge therapy pending molecular profiling results, followed by five cycles of R-CHOP-X, with the additional agent (vorinostat, acalabrutinib, decitabine, or lenalidomide) selected according to molecular subtype. Response was assessed by PET/CT per Lugano criteria; adverse events were graded per NCI CTCAE v5.0. Results: The overall study population was predominantly high-risk: 72% had an IPI of 3–5, 58% had stage III–IV disease, and 67% exhibited a non-GCB immunophenotype. Expansion from the 19-gene to the 60-gene panel reduced unclassifiable (NOS) cases from 34% to 12%. The overall response rate was 100% (43/43); complete response among patients completing therapy was 100% (35/35). At two years, overall survival was 92% (95% CI 83–100%) and progression-free survival was 94% (95% CI 86–100%). Two early relapses occurred (NOS and N1 subtypes), both resulting in death. Grade 3–4 neutropenia, thrombocytopenia, and anemia occurred in 26%, 12%, and 7% of patients, respectively; no dose reductions or treatment discontinuations were recorded. Conclusions: Molecularly adapted R-CHOP-X is feasible and associated with high response rates and favorable two-year survival in newly diagnosed DLBCL, comparing favorably with historical R-CHOP outcomes in high-risk populations. Expanded genomic panels substantially improve molecular classifiability. These findings warrant validation in larger, multicenter, randomized clinical trials.

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