BACKGROUND:Pomalidomide-daratumumab-dexamethasone (DPd) has been shown to be effective in lenalidomide-exposed patients with multiple myeloma (MM). We aimed to evaluate this combination in patients with del(17p), for whom there is no specific treatment. PATIENTS AND METHODS:The phase II DEDALO study enrolled patients with relapsed/refractory (RR)MM, del(17p), and ≤ 3 previous therapy lines including lenalidomide. Patients received DPd according to the approved schedule. The primary endpoint was minimal residual disease (MRD) negativity (by next-generation sequencing, 10-5 sensitivity). RESULTS:Fifty patients were enrolled, and 45 were eligible. A del(17p) clone size ≥ 55% was observed in 26/45 patients, while TP53 mutations in 10/31. One patient achieved MRD negativity. With a median follow-up of 18.7 months, the median progression-free survival (PFS) was 7.0 months (4.3-13.9) overall, 6.5 in patients with a del(17p) clone size < 55%, 7.6 in those with a clone size ≥ 55%, 3.2 in those with biallelic TP53 alteration, and 11.8 in those with isolated del(17p). Toxicity was consistent with previous studies. CONCLUSION:This is the first study testing a specific treatment for MM patients with del(17p). We confirmed the severity of this abnormality, particularly in the presence of double TP53 inactivation, and the importance of a thorough biological characterization.

7006 Background: Patients (pts) with advanced R/R MCL have poor outcomes, especially pts with high-risk features or those progressing after BTKi therapies. Glofitamab is a CD20xCD3 2:1 bispecific antibody that redirects T cells to eliminate malignant B cells. A Phase 1/2 trial (NCT03075696) evaluated glofitamab monotherapy, given with step-up dosing (SUD) after obinutuzumab pretreatment (Gpt), in pts with R/R MCL. Prior analyses showed high response rates and manageable safety, regardless of prior BTKi exposure (Phillips, et al. ASCO 2024). We report longer follow-up data from this MCL cohort. Methods: Pts with R/R MCL after ≥1 prior line of systemic therapy received Gpt (single 1000 mg dose or 2000 mg split over 2 days, as needed) on cycle (C)1 day (D)1. Glofitamab SUD was given on C1D8 (2.5 mg) and C1D15 (10 mg), then the target dose of 16 or 30 mg every 3 weeks on D1 of C2–12. Efficacy endpoints included investigator-assessed complete response (CR) rate, overall response rate (ORR), duration of CR (DoCR), duration of response (DoR), progression free survival (PFS), and overall survival (OS). Results: As of Sept 8, 2025, 61 pts with R/R MCL were enrolled (Gpt: 1000 mg, n=17; 2000 mg, n=44); 60 pts were treated. The median number of prior lines of therapy was 2 (range 1–5), median age was 72.0 years (range 41–86), 86.9% of pts had Ann Arbor stage III/IV, and 26.3% had a simplified MCL International Prognostic Index score of ≥6. Pts had high-risk disease features such as Ki-67 proliferation index ≥30% (62.3%), blastoid/pleomorphic variants (9.8%), and TP53 mutation (19.7%). The median number of glofitamab cycles received was 12 (range 1–13). With a median OS follow-up of 41.5 months (mo; 95% CI: 37.4–48.7), the ORR and CR rate were 82% and 77%, respectively. Median DoCR was 40.8 mo (95% CI: 14.1–NE); 48.9% of pts had ongoing CRs at the data cut-off. Estimated 33-mo DoCR and DoR rates were 50.5% and 47.4%, respectively. Median (95% CI) PFS was 18 mo (11.3–42.8) and OS was NE (26.9–NE). For pts who received prior BTKi therapy (n=34 [55.7%]), the ORR and CR rate were 73.5% and 70.6%, respectively. Median (95% CI) DoCR was 15.4 mo (8.3–NE), PFS was 11.3 mo (5.1–32.6), and OS was 29.9 mo (11.3–NE). Estimated 33-mo DoCR and DoR rates were 42.7% and 41.0%, respectively. No new safety signals were observed. Cytokine release syndrome remained the most common adverse event (n=42/60, 70%; Grade 1–2, 58.3%; Grade 3–4, 11.6%), with lower rates in the 2000 mg (n=28/44, 63.6%) vs 1000 mg (n=14/16, 87.5%) Gpt cohorts. Conclusions: Updated data on fixed-duration glofitamab monotherapy in heavily pretreated pts with R/R MCL show robust efficacy and manageable safety, including in BTKi-exposed pts. Glofitamab monotherapy is a suitable treatment for pts with R/R MCL in need of rapid disease control and is under investigation in the Phase 3 GLOBRYTE trial. Clinical trial information: NCT03075696 .

Functional and myocardial tissue modifications can occur in treatment-naïve cancer patients, driven by uncontrolled inflammation and neuro-hormonal activation. These mechanisms may result in myocardial alterations that serve as subclinical imaging markers of potential cardiac dysfunction. This study aims to evaluate the role of cardiac magnetic resonance in investigating cancer-associated immune activation and identifying early biomarkers of myocardial damage in treatment-naive cancer patients. This prospective study enrolled 100 participants, including 50 treatment-naive cancer patients affected by diffuse large B cell lymphoma and 50 age- and gender-matched healthy controls. All participants underwent comprehensive cardiac magnetic resonance imaging before starting chemotherapy. Correlation analysis was conducted to identify differences in myocardial tissue characterization and functional parameter between the two groups. Native T1 values were significantly higher in the cancer cohort compared to controls (1007 ± 29 ms vs. 976 ± 29 ms; p < 0.001), while global longitudinal strain was significantly reduced (− 14 ± 2

There is an unmet need for effective, off-the-shelf therapies for relapsed or refractory aggressive B cell non-Hodgkin lymphoma (B-NHL). Part 2 of the current study was an open-label, nonrandomized, phase 1 study of escalating doses of the CD19-4-1BBL co-stimulatory molecule, englumafusp alfa, in combination with glofitamab in patients with relapsed or refractory B-NHL. Obinutuzumab pretreatment was administered 7 days before the first glofitamab dose. Glofitamab step-up dosing in cycle 1 was followed by 11 cycles of glofitamab plus englumafusp alfa. Englumafusp alfa was administered at escalating doses, with the initial dose on cycle 2 day 8 (C2D8) or cycle 1 day 10 (C1D10). Primary objectives were to establish the maximum tolerated dose, and safety and tolerability. A total of 134 patients were enrolled, including 109 with aggressive B-NHL and 25 with indolent B-NHL. The maximum tolerated dose of englumafusp alfa was not reached; one dose-limiting toxicity occurred (grade 5 Pneumocystis jirovecii pneumonia). Adverse events were reported in 98.5% of all patients, with grade 3/4 adverse events in 59.0%. Grade 5 adverse events occurred in ten patients. In the subgroup of C2D8 patients with aggressive B-NHL (n = 83), overall response and complete metabolic response rates were 68.7% and 56.6%, respectively; among those without previous exposure to chimeric antigen receptor T cell therapy (n = 41), the corresponding rates were 73.2% and 65.9%. Pharmacodynamic changes following englumafusp alfa administration supported its co-stimulatory mode of action. These data demonstrate that the addition of englumafusp alfa to glofitamab is associated with encouraging efficacy and robust pharmacodynamic modulation, as well as a safety profile consistent with glofitamab monotherapy, in patients with relapsed or refractory B-NHL. CTIS identifier: 2022-502616-37-00 ; ClinicalTrials.gov identifier: NCT04077723 .

INTRODUCTION:Endothelial dysfunction is key in COVID-19 pathogenesis. This randomized, double-blind phase IIb trial investigated continuous intravenous infusion of defibrotide in patients hospitalized with SARS-CoV-2 infection and respiratory failure. METHODS:One-hundred and fifty patients were randomized (2:1) to defibrotide or placebo, stratified by disease severity (WHO COVID-19 severity scale 4/5 vs. 6). The primary endpoint was clinical improvement time (days from first improvement through Day 30). RESULTS:Median clinical improvement time was not significantly different with defibrotide versus placebo (15.0 [IQR: 0-24] vs. 20.0 [IQR: 9-25] days; p = 0.10). Day-30 (23.0% vs. 22.0%) and Day-60 (26.0% vs. 22.0%) mortality, reduction in mean fraction of inspired oxygen during treatment, and median duration of hospitalization did not differ with defibrotide versus placebo. Defibrotide demonstrated favorable safety, with no differences versus placebo in serious adverse events (34.0% vs. 36.0%), hypotension (16.0% vs. 12.0%), or hemorrhage (13.0% vs. 8.0%). Exploratory pre-specified biomarker analyses showed greater early d-dimer reduction and lymphocyte recovery with defibrotide, although these results require validation. CONCLUSION:Continuous intravenous infusion of defibrotide was safe but did not improve clinical outcomes in severe COVID-19. Further analyses will explore mechanistic actions and pharmacokinetics of defibrotide and the pathophysiology of endothelial dysfunction in COVID-19. TRIAL REGISTRATION:EudraCT identifier: 2020-001409-21. CLINICALTRIALS:gov identifier: NCT04348383.

The prognosis of peripheral T-cell non-Hodgkin lymphomas (PTCL) is dismal, particularly in the relapsed/refractory (r/r) setting, where 3-year overall survival (OS) is 20%-30%. No superior second-line therapy for PTCL has been universally established, and durable remissions rely on consolidation with allogeneic haematopoietic stem cell transplantation (alloHSCT). Enhancing response rates to salvage therapy is, therefore, crucial to increase transplant eligibility. We retrospectively evaluated the efficacy of bendamustine, gemcitabine and vinorelbine combination (BeGeV) in 24 consecutive patients with r/r PTCL treated at our centre since 2017. BeGeV achieved an overall response rate (ORR) of 66% and a complete remission rate (CRR) of 41%. After a median follow-up of 41.8 months, 1-year progression-free survival (PFS) and OS were 37.5% and 58.3% respectively. Outcomes differed by histology: PTCL not otherwise specified (PTCL-NOS) showed inferior responses (ORR 41%, CRR 16%) compared with T-follicular helper lymphomas (PTCL-TFH; ORR 100%, CRR 75%) and systemic anaplastic large cell lymphoma (sALCL; ORR 75%, CRR 50%). Survival analyses confirmed substantial differences across subtypes, with 12-month PFS and OS rates of 8.3% and 41.7% for PTCL-NOS, 50% and 75% for sALCL and 75% and 75% for PTCL-TFH respectively. Despite the limitations of small sample size and retrospective design, this study provides preliminary evidence supporting BeGeV as a potential bridge to alloHSCT in r/r PTCL-TFH and sALCL.

The European Group for Blood and Bone Marrow transplantation Practice Harmonization and Guidelines Committee together with the Lymphoma Working Party convened 23 experts in Hodgkin lymphoma, transplantation, and radiation oncology, to develop consensus recommendations on the use of autologous and allogeneic haematopoietic cell transplantation (HCT) in relapsed or refractory Hodgkin lymphoma. Through a structured literature review and a 2-day workshop in Berlin, Germany, on Sept 29 and 30, 2025, the panel established guidance across major clinical decision points. The outcome of this review and workshop include the following recommendations. Salvage therapy should include brentuximab vedotin or checkpoint inhibitors, or both, with metabolic complete response preferred before autologous HCT. BEAM (carmustine, etoposide, cytarabine and melphalan) remains the most commonly used conditioning regimen, and autologous HCT continues to be the standard for chemosensitive relapse. Peri-transplantation radiotherapy could be considered for PET-positive or residual disease. Brentuximab vedotin consolidation is recommended for patients at high-risk. Allogeneic HCT is advised for eligible patients who relapse after autologous HCT, ideally with reduced intensity conditioning and post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis. Routine maintenance after allogeneic HCT is not recommended; relapse management should be tailored and can involve donor lymphocyte infusion, brentuximab vedotin, checkpoint inhibitors, chemotherapy, radiotherapy, or clinical trial enrolment.

Aggressive large B-cell lymphomas (LBCL) include a range of disease types characterized by heterogenous histopathologic, molecular, and genetic features. In this review, we summarize the main standardized disease assessments, treatments and patient journey and we discuss some of the questions that we will face in interpreting and applying their results in clinical practice in the next few years. Specific methodologies borrowed from FDA clinical trials indications to settle the more important goals (both for fit and unfit patients) - key aspects to be considered in clinical management-were used. The Expert Panel was conceived to reach a consensus on defining unsettled and controversial issues while envisioning possible solutions for current challenges in treating newly diagnosed patients with advanced-stage LBCL not only in the Italian context but also for other Countries sharing similar health care system. The fast-evolving treatment scenario for LBCL holds promise of improving outcomes in these high-risk setting, and we eagerly await new treatment regimens to further optimize patient outcomes.

Checkpoint blockade therapy (CBT) involving anti-PD1 antibodies represents the standard approach for cHL patients who do not respond to second-line therapy. Nonetheless, only 20% of relapsed/refractory (R/R) cHL patients treated with CBT achieve complete remission. In this study, we extensively examined the immune dynamics in eight R/R cHL patients treated with CBT, consisting of four complete responders (CR) and four experiencing disease progression (PD), by single cell analysis of peripheral blood mononuclear cells (PBMCs). Our unique approach encompassed longitudinal analysis with three time points, providing a comprehensive understanding of the evolving immune responses during anti-PD1 therapy. Through gene expression profiling, we identified a stable and distinctive KLRG1+/FOS+/JUN+/GZMA+/CD8+ T cell phenotype in patients achieving complete responses. This specific CD8+ T cell subset exhibited sustained activation, underscoring its potential pivotal role in mounting an effective immune response against cHL. Furthermore, T cell receptor (TCR) analysis revealed that in responder patients there is clonal expansion between TCR clonotypes specifically in the KLRG1+/FOS+/JUN+/GZMA+/CD8+ T cell subset. Our longitudinal study offers unique insights into the complex immune dynamics of multiply relapsed/highly pre-treated cHL patients undergoing anti-PD1 therapy.

ABSTRACT:This study analyzed the genetics of classic Hodgkin lymphoma (cHL) by using circulating tumor DNA (ctDNA). Two genetic subtypes were identified, differing in genetic instability mechanisms: one subtype (64% of cases) showed a higher mutation load and a higher fraction of mutations associated with activation-induced cytidine deaminase and microsatellite instability signatures, whereas the other subtype (36% of cases) exhibited chromosomal instability with more somatic copy number alterations. Whole-genome duplication was more common in cHL compared with other B-cell tumors and emerged as a prognostic biomarker for patients undergoing Adriamycin (doxorubicin)-bleomycin-vinblastine-dacarbazine-based therapy. Noncoding regulatory mutations, similar to those in diffuse large B-cell lymphoma, were highly prevalent in 86% of cHL. A recurrent somatic expression quantitative trait locus (seQTL) involving the BCL6 gene was found in 30% of cases. The seQTL of BCL6 aligned with accessible chromatin and increased H3K27 acetylation in cHL, disrupted PRDM1 binding, and co-occurred with BCL6 expression in cHL cells. Weak to strong expression of BCL6 was observed in 68% of cases, and BCL6 expression associated with gene repression similarly in cHL and germinal center B cells. After BCL6 degradation, the core set of genes directly bound and regulated by BCL6 was derepressed in cHL, and proliferation was impaired. The number and clonality of neoantigens was associated with tumor microenvironment type and response to checkpoint blockade. Finally, ctDNA analysis was suggested as a tool to distinguish ambiguous positron emission tomography/computed tomography-positive lesions after treatment.

Functional and myocardial tissue modifications can occur in treatment-naïve cancer patients naive, driven by uncontrolled inflammation and neuro-hormonal activation. These mechanisms may result in myocardial alterations that serve as subclinical imaging markers of potential cardiac dysfunction. This study aims to evaluate the role of cardiac magnetic resonance (CMR) in investigating cancer-associated immune activation and identifying early biomarkers of myocardial damage in treatment-naive cancer patients. This prospective study enrolled 70 participants, including 35 treatment-naive cancer patients (19 breast cancer, 16 DLBCL) and 35 age- and gender-matched healthy controls. All participants underwent comprehensive CMR imaging before starting chemotherapy. Correlation analysis was conducted to identify differences in myocardial tissue characterization and functional parameter between the two groups. Native T1 values were significantly elevated in the cancer cohort compared to controls (1013 ± 27 ms vs. 981 ± 31 ms; p < 0.001), while GLS was significantly reduced (-15 ± 2% vs. -22 ± 7%; p < 0.001). Native T2 values showed a marginal increase but did not significantly correlate with GLS. Correlation analysis identified native T1 as an independent predictor of GLS impairment (R = -0.5; p = 0.001). No significant differences in LV mass were observed, suggesting that myocardial tissue changes may precede structural remodeling. Treatment-naive cancer patients exhibit subclinical myocardial alterations, characterized by elevated native T1 and reduced GLS. Cardiac magnetic resonance emerges as a valuable tool for identifying early biomarkers of myocardial dysfunction, offering opportunities for risk stratification and proactive management in cardio-oncology.CMR findings in the study population

7022 Background: Glofitamab is a CD20xCD3 T-cell engaging bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells in patients (pts) with relapsed or refractory non-Hodgkin Lymphoma. We characterized mechanisms driving CD20 loss in pts from a Phase I/II trial (NP30179) receiving Glofitamab monotherapy for Relapsed/Refractory Large B-cell lymphoma (R/R LBCL). Methods: Pts with LBCL and ≥2 prior therapies received obinutuzumab pretreatment followed by fixed-duration Glofitamab at the approved dose in phase I/II trial NP30179 ( NCT03075696 ) (Dickinson, et al. N Engl J Med 2022). Tumor biopsies were collected prior to treatment (Baseline, BL) in 128 pts, during treatment (tx) or at progression (PD) in 11 pts. The proportion of CD20+ tumor cells was determined by immunohistochemistry (IHC) using a dual CD20+ PAX5+ assay. Expression of MS4A1 , the gene encoding CD20, was measured by RNA-sequencing (RNA-seq) in 105/139 biopsies. MS4A1 mutation profiling was performed by next-generation sequencing on Cell-free circulating tumor DNA (ctDNA) from 133 pts. We subsequently characterized the functional consequences of identified mutations in vitro. Results: CD20 levels evaluated by IHC were high (>75% CD20+ tumor cells) in 110/128 BL biopsies. At BL, CD20 loss (<5% CD20+ tumor cells) was seen in 4/128 (3.1 %) biopsies. For 11 pts with BL and on-tx or at-PD biopsies, 7/11 (63.6%) pts presented CD20 loss on-tx/at-PD and 4/11 (36.4%) did not. Evaluation of gene expression profile showed a good correlation between CD20 gene and protein expression. Among the 7 pts with CD20 loss on-tx/at-PD biopsies, there were 4 biopsies with available gene expression data, and decreased CD20 expression was identified in 2/4. Evaluation of CD20 mutation revealed 11/134 (8.2%) pts harbored 16 MS4A1 mutations at BL or on-tx/at-PD. IHC data were available for 8/11 pts at BL where 2/8 presented CD20 loss (<5% CD20+ tumor cells), and for 1 pt at-PD who presented CD20 loss. 12/16 mutations were not previously reported. We characterized 14 mutations in vitro and subsequently demonstrated that 8 frameshift or deletion mutations lead to truncation of the protein, and 4 missense mutations lead to disruption in the transmembrane domain of CD20. These 12 mutations lead to loss of intracellular and extracellular CD20 expression, and abrogation of Glofitamab-mediated cytotoxicity in vitro. Conclusions: In pts with R/R LBCL treated with Glofitamab, loss of tumor antigen CD20 expression is one resistance mechanism to Glofitamab. Genetic alterations (fs, del or missense mutations) and transcriptional downregulation can contribute to loss of CD20 expression and they were both observed in pts treated with Glofitamab. Acknowledgments: The NCT03075696 study is sponsored by F. Hoffmann-La Roche Ltd.

7042 Background: In recent years, bispecific T cell Engagers (BsTCE) targeting CD3 and CD20 have emerged as a potent new class of therapeutics for NHL; however, a subset of patients still experience relapsed or refractory disease. Patients undergoing treatment with BsTCEs could benefit from longitudinal screening via liquid biopsy to identify baseline (primary) and treatment-induced (acquired) resistance mutations and tailor treatment accordingly. Here we present the results from a pilot study screening patients treated with Glofitamab (CD20xCD3) using a single gene Primer Extension Target Enrichment (PETE) strategy for MS4A1 (CD20 gene) in liquid biopsies. Methods: Our pilot study was conducted using libraries from the plasma of 134/155 patients with relapsed or refractory large B cell lymphoma (r/r LBCL) who underwent Glofitamab treatment at approved dose in the phase I/II trial NP30179 ( NCT03075696 ) (Dickinson, et al. N Engl J Med 2022), and paired PBMC/PDB available in 91 cases. Primers were designed against the coding regions of the MS4A1 gene. Enrichment was performed using a workflow optimized for the detection of somatic variants in cell-free DNA isolated from plasma. Results were analyzed using a modified AVENIO circulating tumor (ct) DNA (Roche; For Research Use Only) analysis workflow. Variants detected by the analysis pipeline were further filtered based on inclusion criteria: allele fraction > 0.1%, rarity in the cohort, impact on protein function in silico , and if sample was available, absence in germline. Tumor burden as assessed by ctDNA was obtained from retrospective sequencing data. Response to treatment was assessed by PET/CT using the Lugano Criteria. Results: Using inclusion criteria a total of 11/134 (8.2%) patients were identified with a total of 16 unique MS4A1 candidate mutations at baseline or during treatment. The Best Overall Investigator Response (BOR) was progressive disease (PD) for 7 patients and partial metabolic response (PR) for 4 patients. All patients with BOR PR experienced disease progression before treatment completion. Sufficient samples were available to demonstrate expansion of the candidate mutation by the end of treatment (EOT) timepoint for 5 patients. Four of the identified mutations were previously reported in the literature, the remaining mutations were novel, and in vitro characterization demonstrated their functional impact. Conclusions: This work identifies known and novel mutations in CD20 in plasma samples as a potential contributing mechanism to relapsed or refractory cases of NHL. Although the prevalence appears to be low, this is consistent with previous reports and supports investigation of the clinical utility, including utility as a potential predictive biomarker, of sequencing this gene during treatment with CD20xCD3 BsTCE. Future and ongoing work will screen additional cohorts and therapy combinations.

Introduction: Newly diagnosed (ND) diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease that includes at least 5 molecular clusters (C1-C5) defined by distinct genetic signatures and responses to standard induction therapy. The clusters with inferior responses to frontline R-CHOP include: ABC-enriched C5 DLBCLs, characterized by frequent MYD88L265Pand CD79B mutations, 18q copy number gain, and extranodal tropism; GCB-predominant C3 tumors with BCL2 translocations, including a subset with concurrent MYC translocations, and mutations in chromatin modifiers, B-cell transcription factors, and PI3K pathway components; and cell-of-origin independent C2 DLBCLs with biallelic TP53 alterations and associated genomic instability (AGI). In contrast, C1 and C4 DLBCLs have more favorable responses to R-CHOP. We recently developed a neural network-based probabilistic molecular classifier, DLBclass, to prospectively assign tumors to their respective clusters (Chapuy et al., Blood 2025). Despite the interest in matching targeted therapies with molecularly defined subsets of ND DLBCL, novel agents are initially evaluated in patients (pts) with relapsed (R) tumors that have incompletely characterized genetic signatures. Herein, we investigate the molecular substructure of R DLBCL using the DLBclass framework. Methods: We performed whole exome sequencing and obtained the comprehensive genetic signatures (mutations [SNVs and indels], somatic copy number alterations [SCNAs], structural variants [SV] including translocations) and DLBclass assignments for 122 first-relapsed DLBCLs including 30 central nervous system (CNS) R, and a subset (42) of matched diagnostic (Dx) specimens from pts who were treated with anthracycline-based induction chemo-immunotherapy and had full clinical annotation.Our previously characterized cohort of ND DLBCLs and the NIH series with defined genetic signatures, DLBclass calls,and known clinical outcomes were used for comparison. Results: We used MutSig2CV to identify recurrent mutations in R DLBCL and found that ~80% of the alterations were DLBclass-defined features of ND DLBCL. This suggested that the propensity to relapse may be largely predetermined at diagnosis and provided the rationale for applying DLBclass in the R setting. In comparison to ND DLBCLs, R DLBCLs were enriched for C2 tumors (28.5% [ND] vs 41.8% [R], p=0.007), with a paucity of C1 lymphomas (15.5% [ND] vs 5.7% [R], p=0.004). Extranodal (EN) Rs, including CNS Rs, were more likely than nodal (N) Rs to be C5 DLBCLs (32.2% [EN] vs 3.65% [N], p=0.002). In contrast, N Rs were more likely to be C3 tumors (11.8% [EN] vs 30.8% [N], p=0.01). These findings link specific patterns of tissue tropism with distinct genetic programs. Of interest, late R (>24 mos) were enriched for C5 DLBCLs in comparison to early R (<12 mos) (35.3% vs 18.9%, p=0.06). Among pts with paired Dx and R samples, 31/42 (74%) retained their original molecular cluster IDs at R, whereas 8 of the remaining 11 acquired features of increased TP53-AGI and C2 cluster IDs. The higher frequency of TP53-AGI in R DLBCLs prompted us to further characterize the genes perturbed by focal CNAs in this setting. The more frequent focal CNAs at R included known immune response modulators and targets of inactivating mutations – CD70 (19p13.3del), B2M (15q15.3del), MHCI (6p21.33del), CD58 (1p13.1del), and FAS (10q23.31del). These findings potentially link TP53-AGI with additional CNA-dependent mechanisms of immune evasion at R. We also identified Dx features associated with an increased risk of R using the previously characterized ND DLBCLs from our earlier analyses, the NIH cohort and this series, annotated for outcome (R [250 tumors] vs no R [249 DLBCLs]). Chromosome 17pdel, TP53mut, and 6p23.33del (MHCI) were significantly more frequent in Dx tumors of pts who subsequently relapsed, further emphasizing the importance of TP53-AGI and MHCI loss. In a multivariate Cox model adjusted for DLBclass IDs, concurrent MYC and BCL2 SVs (HR=3.39) and MYC SVs (HR=2.33) retained adverse prognostic significance, highlighting the additional impact of these alterations on outcome. Conclusions: Relapse in DLBCL is largely driven by genetic programs present at diagnosis and defined by DLBclass. These signatures influence the clinical course of relapse, including tissue tropism, timing and immune escape, providing a framework for improved risk assessment and therapeutic targeting.