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

Diffuse large B-cell lymphoma (DLBCL) is molecularly heterogeneous; genotype-directed first-line therapy may improve outcomes. We conducted a single-center, prospective, non-randomized interventional study evaluating a molecularly adapted R-CHOP-X strategy with two-year follow-up. Between February 2023 and the data cut-off (September 16, 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 LymphGen after targeted sequencing: an initial cohort had Sanger sequencing of a 19-gene panel (n = 35) and a second cohort an expanded 60-gene panel (n = 8). All patients received one cycle of R-CHOP followed by five cycles of R-CHOP-X, with the additional agent (vorinostat, acalabrutinib, decitabine, or lenalidomide) selected according to molecular subtype. Response assessment followed Lugano criteria; adverse events were recorded per NCI CTCAE v5.0. The overall response rate was 100% (n = 43); complete response among patients completing therapy (n = 35) was 100%. 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. These findings indicate that molecularly adapted R-CHOP-X is feasible and associated with high response rates and favorable two-year survival and warrant validation in larger randomized clinical trials.