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.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin lymphoma and is characterized by pronounced molecular heterogeneity that is not always fully captured by standard histopathological assessment. Circulating tumor DNA (ctDNA) is increasingly regarded as a promising liquid-biopsy biomarker that enables non-invasive molecular tumor profiling, assessment of tumor burden, dynamic monitoring of treatment response, and detection of measurable/minimal residual disease (MRD). Modern analytical platforms, ranging from PCR-based assays to next-generation sequencing approaches, including CAPP-Seq and PhasED-Seq, have substantially expanded the possibilities of molecular monitoring in DLBCL. This review summarizes current data on the biological characteristics of ctDNA, contemporary methods for its analysis, concordance between ctDNA and tumor-tissue mutational profiles, and the clinical significance of baseline ctDNA levels, early molecular response, post-treatment MRD status, and molecular surveillance during remission. Special attention is given to ctDNA monitoring in patients receiving novel immunotherapies, including CAR-T cell therapy, bispecific antibodies, and antibody–drug conjugates. Emerging multi-omic approaches integrating genomic, epigenomic, and fragmentomic data are discussed as promising future directions. Key limitations of clinical implementation include insufficient standardization of preanalytical and analytical workflows, the confounding effect of clonal hematopoiesis of indeterminate potential, variability across technological platforms, and the lack of completed prospective randomized interventional studies demonstrating improved outcomes when therapy is modified according to ctDNA status. Overall, ctDNA is currently a highly informative prognostic biomarker in DLBCL; however, its full implementation as a predictive tool for treatment selection requires further harmonization, prospective validation, and confirmation in interventional clinical trials.

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.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin lymphomas and is characterized by pronounced molecular heterogeneity that is not always fully captured by standard histopathological assessment. At present, analysis of circulating tumor DNA (ctDNA) is regarded as a promising liquid biopsy tool that enables non-invasive molecular tumor profiling, assessment of tumor burden, and dynamic monitoring of minimal residual disease (MRD). Modern analytical platforms, ranging from PCR-based technologies to next-generation sequencing, including CAPP-Seq and PhasED-Seq, have substantially expanded the possibilities of molecular monitoring in DLBCL. This review summarizes data on the biological characteristics of ctDNA and contemporary methods for its analysis, as well as evidence regarding the concordance between ctDNA mutational profiles and tumor tissue. Particular attention is paid to the clinical significance of baseline ctDNA levels, early assessment of molecular eradication of the tumor clone, MRD status after completion of therapy, and molecular monitoring during remission. The principal limitations of clinical integration are also discussed, including insufficient standardization of the analytical workflow, the influence of clonal hematopoiesis, and the absence of completed interventional studies demon-strating improved clinical outcomes when therapy is modified according to molecular status. Thus, ctDNA currently represents a highly informative prognostic biomarker in DLBCL; however, its full implementation in routine clinical practice requires further standardization, validation, and confirmation of its role in treatment selection within personalized strategies.

Background: Diffuse large B-cell lymphoma (DLBCL) with TP53 abnormalities, corresponding to the LymphGen A53 molecular subtype, represents a biologically high-risk group associated with primary resistance to standard R-CHOP therapy. Epigenetic sensitization using hypomethylating agents may enhance chemosensitivity in this setting. We prospectively evaluated the clinical activity and safety of a molecularly adapted DAC-R-CHOP regimen in newly diagnosed A53-DLBCL. Methods: In this single-center prospective pilot cohort study, 70 consecutive patients with newly diagnosed DLBCL underwent targeted next-generation sequencing using a 60-gene panel with integrated copy number variation analysis. Six patients (8.5%) were classified as the A53 subtype. All patients received one cycle of standard R-CHOP. From cycle 2 onward, A53 patients received decitabine (10 mg/m² IV, days 1–5) prior to R-CHOP (DAC-R-CHOP), for a total of six cycles. The primary endpoint was complete metabolic response (CMR) according to Lugano 2014 criteria. Exact 95% confidence intervals (CI) were calculated. Results: The median age of the A53 cohort was 65 years. CMR was achieved in all six patients (100%; 95% CI, 54–100%). At a median follow-up of 6 months, all patients remained alive in confirmed CMR. Grade III–IV hematologic toxicity occurred in all cases. Febrile neutropenia developed in 100% of patients, requiring mandatory G-CSF support and anti-infective therapy; no treatment-related mortality or permanent dose reductions were observed. Two patients (33%) experienced gastrointestinal bleeding related to local tumor lysis, which was managed conservatively without protocol discontinuation. Conclusions: In this prospective molecularly stratified pilot cohort, integration of decitabine into front-line immunochemotherapy showed promising clinical activity in A53-DLBCL, albeit at the cost of substantial hematologic toxicity requiring intensive supportive care. Given the small sample size, short follow-up, and absence of a comparator arm, these findings should be considered hypothesis-generating and warrant validation in larger multicenter phase II studies with integrated translational biomarker analyses.

Background: Diffuse large B-cell lymphoma (DLBCL) predominantly affects older adults, who often have poorer outcomes compared to younger patients. Real-world data on treatment patterns and age-related prognostic factors remain limited. This study compared treatment patterns and survival outcomes in young and older patients with newly diagnosed DLBCL using the Moscow Cancer Registry. Methods: This retrospective, multicenter observational study included 1,060 patients with newly diagnosed DLBCL, stratified into young (≤65 years; n = 419) and older (>65 years; n = 641) groups. Clinicodemographic characteristics, first-line treatment regimens, and survival outcomes, including progression-free survival (PFS), overall survival (OS), were analyzed. Univariable and multivariable Cox regression analyses were used to identify independent prognostic factors. Results: Older patients more frequently had poor performance status (ECOG ≥2), high International Prognostic Index (IPI) risk, and received reduced-intensity (R-miniCHOP) or anthracycline-free (BR, R-CVP) regimens. Younger patients more often received intensive treatment protocols. At a median follow-up of 24 months, 2-year PFS was 51% in younger patients and 40% in older patients (p = 0.047), while 2-year OS was 77% and 66%, respectively (p < 0.0001). In multivariable analyses, age >65 years was not an independent adverse prognostic factor after accounting for clinical risk factors and tumor immunophenotype. Conclusions: Outcomes were associated with performance status, IPI risk, and tumor immunophenotype, rather than chronological age alone. The use of anthracycline-free regimens was associated with inferior outcomes, likely reflecting baseline comorbidities. These findings underscore the necessity of integrating comprehensive geriatric assessment and molecular profiling into management algorithms for older patients with DLBCL.