双表达弥漫大B细胞淋巴瘤的诊治进展

Emerging biologic subsets and new prognostic markers are significantly and adversely affecting curability after standard chemoimmunotherapy for aggressive B‐cell lymphomas. The identification of concurrent MYC and B‐cell CLL/lymphoma 2 (BCL2) deregulation, whether at a genomic or protein level, has opened a new era of investigation within the most common subtype of aggressive B‐cell lymphomas. Double‐hit lymphoma (DHL), defined as a dual rearrangement of MYC and BCL2 and/or B‐cell CLL/lymphoma 6 (BCL6) genes, is an uncommon subset accounting for 5% to 7% of all diffuse large B‐cell lymphomas (DLBCLs), and long‐term survivors are rare. Double‐expressor lymphoma (DEL), defined as overexpression of MYC and BCL2 proteins not related to underlying chromosomal rearrangements, is not a distinct entity in the current World Health Organization classification but accounts for 20% to 30% of DLBCL cases and also has poor outcomes. There are many practical considerations related to identifying, determining the prognosis of, and managing DHL and DEL.

Abstract Double-expressor lymphoma (DEL) is a newly identified special subtype of diffuse large B-cell lymphoma (DLBCL), which is predominantly found in the activated B-cell-like (ABC) subtype of DLBCL. Characterized by concurrent overexpression of BCL2 and MYC, DEL is associated with poorer prognosis. Standard chemoimmunotherapy can achieve clinical cure in nearly 70% of DLBCL cases. DEL mainly presents with intermediate-to-high-risk international prognostic index scores, advanced stage at diagnosis, and may involve specific chromosomal rearrangements, mainly influencing older patients. These factors are interconnected and contribute to less favorable treatment outcomes. We review emerging drugs and clinical trial data potentially effective against DEL, formulating treatment recommendations based on evidence levels to provide a theoretical foundation for the clinical treatment of DEL.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, including one-third of cases overexpressing MYC and BCL2 proteins (double expressor lymphoma, DEL) and 5-10% of patients with chromosomal rearrangements of MYC, BCL2 and/or BCL-6 (double/triple-hit lymphomas, DH/TH). TP53 mutations are detected in 20-25% of DEL. We report the efficacy of dose-adjusted EPOCH and rituximab (DA-EPOCH-R) in a series of 122 consecutive patients, including DEL (n=81, 66%), DEL-MYC (n=9, 7%), DEL-BCL2 (n=13, 11%), or high-grade lymphomas (DH/TH) (n=19, 16%). Central nervous system (CNS) prophylaxis included intravenous methotrexate (n=66), intrathecal chemotherapy (IT) (n=40) or no prophylaxis (n=16). Sixty-seven patients (55%) had highintermediate or high International Prognostic Index (IPI) and 30 (25%) had high CNS-IPI. The 2-year progression-free survival (PFS) and overall survival (OS) for the entire study population were 74% and 84%, respectively. There was a trend for inferior OS for DH/TH (2-year OS: 66%, P=0.058) as compared to all the others. The outcome was significantly better for the IPI 0-2 versus IPI 3-5 (OS: 98% vs. 72%, P=0.002). DA-EPOCH-R did not overcome the negative prognostic value of TP53 mutations: 2-year OS of 62% versus 88% (P=0.036) were observed for mutated as compared to wild-type cases, respectively. Systemic CNS prophylaxis conferred a better 2-year OS (94%) as compared to IT or no prophylaxis (76% and 65%, respectively; P=0.008). DA-EPOCH-R treatment resulted in a favorable outcome in patients with DEL and DEL with single rearrangement, whereas those with multiple genetic alterations such as DEL-DH/TH and TP53 mutated cases still have an inferior outcome.

Objective To develop a PET/CT-based radiomics model for noninvasive prediction of the double-expressor lymphoma (DEL) subtype in diffuse large B-cell lymphoma (DLBCL). Materials and methods From January 2019 to July 2025 consecutively enrolled, 143 patients with DLBCL (55 DEL, 88 non-DEL) were randomly divided into a training set and an internal validation set in a 7:3 ratio. Radiomic features were extracted from peritumoral regions with different expansion distances (3, 5, and 10 mm) to identify the optimal peritumoral region. These features were then integrated using various fusion strategies (multi-region fusion, image fusion, and feature fusion) for combined intratumoral and peritumoral analysis. A transfer learning model built on a pretrained ResNet-50 was combined with a clinical model incorporating baseline PET features to develop three integrated models (Clinic+Rad+DL, Stacking, Ensemble). Model performance was evaluated to select the best-performing approach, and SHAP analysis was applied to enhance interpretability. Results The Rad_MLP model achieved the best performance by integrating intratumoral and 10-mm peritumoral features, with an accuracy of 85.3%, a sensitivity of 89.5%, and a specificity of 79.2%. The positive predictive value (PPV) and negative predictive value (NPV) were 0.773 and 0.905, respectively, with an F1 score of 0.829. Conclusion Rad_MLP, by integrating the most predictive intratumoral and peritumoral features, substantially improves the accuracy of noninvasive prediction of the DEL subtype in DLBCL.

Double‐expressor lymphoma (DEL) has a poorer prognosis than other subtypes of diffuse large B‐cell lymphoma (DLBCL). This study is a multicenter, prospective, single‐arm, phase 2 clinical study initiated by investigators to evaluate the efficacy and safety of combined zanubrutinib with R‐CHOP, which includes rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for patients with DEL (stage II or more), as well as to explore factors related to efficacy preliminarily.

Background c-MYC and BCL2 positivity are important prognostic factors for diffuse large B-cell lymphoma. However, manual quantification is subject to significant intra- and inter-observer variability. We developed an automated method for quantification in whole-slide images of tissue sections where manual quantification requires evaluating large areas of tissue with possibly heterogeneous staining. We train this method using annotations of tumor positivity in smaller tissue microarray cores where expression and staining are more homogeneous and then translate this model to whole-slide images. Methods Our method applies a technique called attention-based multiple instance learning to regress the proportion of c-MYC-positive and BCL2-positive tumor cells from pathologist-scored tissue microarray cores. This technique does not require annotation of individual cell nuclei and is trained instead on core-level annotations of percent tumor positivity. We translate this model to scoring of whole-slide images by tessellating the slide into smaller core-sized tissue regions and calculating an aggregate score. Our method was trained on a public tissue microarray dataset from Stanford and applied to whole-slide images from a geographically diverse multi-center cohort produced by the Lymphoma Epidemiology of Outcomes study. Results In tissue microarrays, the automated method had Pearson correlations of 0.843 and 0.919 with pathologist scores for c-MYC and BCL2, respectively. When utilizing standard clinical thresholds, the sensitivity/specificity of our method was 0.743 / 0.963 for c-MYC and 0.938 / 0.951 for BCL2. For double-expressors, sensitivity and specificity were 0.720 and 0.974. When translated to the external WSI dataset scored by two pathologists, Pearson correlation was 0.753 & 0.883 for c-MYC and 0.749 & 0.765 for BCL2, and sensitivity/specificity was 0.857/0.991 & 0.706/0.930 for c-MYC, 0.856/0.719 & 0.855/0.690 for BCL2, and 0.890/1.00 & 0.598/0.952 for double-expressors. Survival analysis demonstrates that for progression-free survival, model-predicted TMA scores significantly stratify double-expressors and non double-expressors (p = 0.0345), whereas pathologist scores do not (p = 0.128). Conclusions We conclude that proportion of positive stains can be regressed using attention-based multiple instance learning, that these models generalize well to whole slide images, and that our models can provide non-inferior stratification of progression-free survival outcomes.

Purpose: Double-expressor lymphoma (DEL) is associated with a poor prognosis. The standard treatment for patients with DEL remains controversial. A comparison of the safety and feasibility of R-CHOP and DA-EPOCH-R as the first-line therapy for patients with DEL is urgently needed. Methods: The clinical and treatment outcomes of 75 DEL patients were retrospectively analyzed. The role of DA-EPOCH-R was determined and compared to that of R-CHOP in DEL patients. PubMed, Embase, the Cochrane Central Library, and ClinicalTrials.gov were systematically searched up to November 1, 2021 and were evaluated by Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Articles comparing DA-EPOCH-R versus R-CHOP in patients with DEL were included. Results: Overall, 49 and 26 DEL patients received R-CHOP and DA-EPOCH-R, respectively. Although the difference in response for patients who received R-CHOP and DA-EPOCH-R was not significant (P = .347), DA-EPOCH-R may improve the prognosis compared to R-CHOP (P = .056 for progression-free survival [PFS], P = .009 for overall survival [OS]). A systematic review and meta-analysis including 412 DEL patients in six articles were conducted. The event rate for 3-year PFS was significantly lower in patients receiving DA-EPOCH-R treatment than in those undergoing R-CHOP treatment (OR = 0.63, 95% CI = 0.42–0.94, P = .02), whereas no statistically significant difference was found in the HRs for both PFS and OS or the event rate for 3-year OS. Conclusion: The results of this study indicated that DA-EPOCH-R might improve the prognosis of DEL patients compared with R-CHOP.

"Double-hit" and "double-expressor" lymphomas represent distinct but overlapping subsets of aggressive B-cell non-Hodgkin lymphoma. The high rates of bone marrow involvement by these lymphomas pose a major therapeutic challenge due to the chemotherapy-resistant nature of the bone marrow microenvironment and the limited utility of rituximab-based salvage regimens in patients with relapsed/refractory disease. Preclinical studies utilizing high-dose cyclophosphamide in combination with the anti-CD52 monoclonal antibody alemtuzumab have recently shown promise in the treatment of intramedullary disease, and a Phase I human trial is now underway. In support of such efforts, here we perform CD52 target validation on a series of double-hit (n = 40) and double-expressor (n = 58) lymphomas using immunohistochemistry. CD52 expression levels varied considerably across samples, however positive staining was observed in 75% of both double-hit and double-expressor lymphomas. Similarly, high levels of CD52 expression were seen in patients whose disease was associated with high-risk clinical features, including primary refractory status (73%), higher IPI score (76%), and bone marrow involvement (74%). CD52 expression was not significantly correlated with diagnostically relevant pathologic features such as morphology, cytogenetic findings or other immunophenotypic features, but was notably present in all cases lacking CD20 expression (n = 6). We propose that CD52 expression status be evaluated on a case-by-case basis to guide eligibility for clinical trial enrollment.

Primary cutaneous diffuse large B-cell lymphomas (pcDLBCL) are rare hematological neoplasms. pcDLBCL category includes primary cutaneous large B-cell lymphoma "leg type" (pcDLBCL-LT), characterized by a particularly unfavorable outcome, and primary cutaneous large B-cell lymphoma "not otherwise specified" (pcDLBCL-NOS), a widely debated sub-entity with a more indolent course. The negative prognostic impact of double expressor status (DE status, given by coexpression of MYC and BCL2) and double/triple hit status (DH/TH status, given by translocations of MYC and BCL2 and/or BCL6) in nodal DLBCL is well-known; however, no unanimous conclusions regarding relevance of DE and DH/TH status have been reached in pcDLBCL. Therefore, our purpose has been to investigate the presence and prognostic relevance of DE and DH/TH status among a retrospective multicentric cohort of 16 pcDLBCL-LT and 17 pcDLBCL-NOS. All cases were thoroughly re-evaluated, both on a morphological and immunoistochemical level, and tested by means of fluorescence hybridization in situ for MYC, BCL2 and BCL6 rearrangements. DE status was observed in 69% of pcDLBCL-LT and in 24% of pcDLBCL-NOS; however, it did not impact on prognosis in any of the groups examined. Combining molecular results, we highlighted a relevant fraction of DH pcDLBCL (three pcDLBCL-LT and one pcDLBCL-NOS) and the very first case of TH pcDLBCL-LT reported to date. All DH cases were characterized by MYC and BCL6 rearrangements. Overall, DH/TH cases represented 15% (5/33) of all pcDLBCLs and were mostly pcDLBCL-LTs. DH/TH status and DH status alone were associated with poorer OS and DSS (both p<0,05) among all pcDLBCLs, without reaching statistical significance in pcDLBCL-LT and pcDLBCL-NOS groups. In conclusion, MYC, BCL2 and BCL6 cytogenetical testing could be useful in identifying a putative subset of more aggressive pcDLBCLs, although this observation has to be confirmed by further studies.

… double expressor') is recently emerging as one of the strongest and most unfavorable prognostic factor for diffuse large B-cell lymphoma … association between double expressor DLBCL …

… at diagnosis, of which diffuse large B-cell lymphoma is the most … as double expressor lymphoma, an indicator of poor prognosis [1]. Recently, patients with PCNSL with double expressor …

… In conclusion, this study has identified a group of clinically high-risk patients with DLBCL who coexpress MYC and BCL2 proteins, a clinical scenario that is more common than patients …

Simple Summary Diffuse large B-cell lymphoma (DLBCL) with co-expression of MYC and BCL2 proteins is referred to as double expressor lymphoma. Multiple studies have identified double expressor status to be an adverse predictive factor for response to standard chemotherapy regimens. The revised 2016 WHO classification recommends cutoff values of 40% for MYC and 50% for BCL2 protein expression; however, actual cutoff values have varied widely among published studies. Increasing recognition of the potential prognostic value of double expressor status prompted this systematic review and meta-analysis of the worldwide literature. Our findings indicate that approximately 23% of de novo DLBCL tumors express both MYC and BCL2 proteins above the indicated thresholds. Remarkably, different immunohistochemical cutoff values did not significantly affect the proportion of tumors attaining double expressor status. Cases lacking MYC/BCL2 co-expression were associated with a significantly higher probability of complete remission, thereby reaffirming the value of this predictive biomarker. Abstract MYC/BCL2 protein co-expression (i.e., double expressor) has been shown to be a negative predictor of outcome in diffuse large B-cell lymphoma (DLBCL). We aimed to establish the incidence of double expressor status in patients with de novo DLBCL and identify the predictive value of this biomarker on treatment response through systematic review and meta-analysis. PubMed and Embase were searched for studies published through December 2019 that reported proportions of double expressor DLBCL. The pooled proportions of MYC and BCL2 expression, both alone and in combination, were computed using the inverse variance method for calculating weights and by the DerSimonian–Laird method. The pooled odds ratios (ORs) of complete remission (CR) rate were calculated, and meta-regression analysis was conducted to explore heterogeneity. Forty-one studies (7054 patients) were included. The pooled incidence of double expressor status in DLBCL was 23% (95% confidence interval [CI], 20–26%), with an adjusted estimate of 31% (95% CI, 27–36%). Neither MYC/BCL2 protein cutoff values, race, mean, or median age of included patients, or overall study quality was a significant factor of heterogeneity (p ≥ 0.20). Cases without double expressor status demonstrated a higher probability of CR to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone treatment (OR, 2.69; 95% CI, 1.55–4.67). Our results reaffirm the predictive power of this important biomarker.

Key Points Dual expression of MYC and BCL2 is associated with an increased risk of CNS relapse in DLBCL treated with R-CHOP.

… BCL2 and MYC protein may also be coexpressed in DLBCL … which MYC is translocated to non-IGH partner or MYC and BCL2 … implications of MYC aberrations in DLBCL and determine …

Numerous studies have investigated the prognostic values of MYC and/or BCL2 protein overexpression in diffuse large B-cell lymphoma (DLBCL). However, the results still demonstrate discrepancies among different studies. We aimed to do a systematic review and meta-analysis on the relationships between overexpression MYC and/or BCL2 and DLBCLs treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). This study followed the guidelines of PRISMA and Cochrane handbook. The hazard ratios (HRs) for overall survival (OS) were pooled to estimate the main effect size. Twenty studies recruited a total of 5576 patients were available for this meta-analysis. The results showed that MYC (HR = 1.96, 95%CI (confidence interval) = 1.69–2.27)without heterogeneity(I2 = 17.2%, P = 0.280), BCL2 (HR = 1.65, 95%CI = 1.43–1.89, I2 = 20.7%, P = 0.234) protein overexpression, and co-overexpression (HR = 2.58, 95%CI = 2.19–3.04, I2 = 17.2%, P = 0.275) had a poor prognosis in R-CHOP treated DLBCL patients, respectively. The current analysis indicated that MYC and/or BCL2 protein overexpression, and particularly co-overexpression was related to short overall survival in R-CHOP treated DLBCL patients, showing that application of the two new biomarkers can help to better stratify DLBCL patients and guide targeted treatment.

Introduction In the phase 3, double-blind, placebo (pbo)-controlled PHOENIX trial (NCT01855750), 838 patients (pts) with non-germinal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL) were randomized 1:1 to ibrutinib (IBR; 560 mg/day orally) + rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or pbo + R-CHOP. IBR + R-CHOP did not improve event-free survival (EFS) in the intent-to-treat (ITT) non-GCB population (hazard ratio [HR] 0.934; 95% confidence interval [CI], 0.726-1.200). However, in an exploratory analysis, pts < 60 years benefited from the addition of IBR (HR 0.579; 95% CI, 0.380-0.881 for EFS), whereas pts ≥ 60 years did not (HR 1.228; 95% CI, 0.887-1.699 for EFS) due to increased toxicity and reduced R-CHOP exposure. Based on evidence that co-expression of BCL2 and MYC by immunohistochemistry (IHC) have a worse outcome with R-CHOP, we examined their clinical prognostic effect in the 2 arms of the PHOENIX trial. Methods Pretreatment formalin-fixed paraffin-embedded biopsy samples were collected. RNA was extracted and profiled with Illumina RNAseq. Raw sequence reads were aligned to the hs37d5 genome build with STAR v2.5.1b, and gene-level quantification was conducted using RSEM v1.2.23. The median transcript per million mapped reads (TPM) values for BCL2 and MYC gene expression across all pts with RNAseq data (n = 766) were used as the cutoffs between high and low expression for each gene. BCL2 IHC data were available from 184 pts, and based on these, the threshold expression value from RNAseq data that could best approximate positive calls from IHC (≥ 50% lymphoma cells positive) was determined. This threshold value was very close to the median level calculated above and therefore supported the use of the median expression levels as the cutoffs to define high and low expressors in the subsequent analyses. The relationship between expression by RNAseq and survival (EFS, overall survival [OS]) in the 2 study arms was analyzed by Kaplan-Meier estimate with Cox regression to determine HRs and log-rank testing to assess significance. Results Based on a cutoff at the median TPM value, the percentage of non-GCB pts with BCL2-high + MYC-high (n = 234, 30.5%) was consistent with previous literature. In the IBR + R-CHOP (n = 386) and pbo + R-CHOP (n = 380) arms, respectively, 123 (31.9%) and 111 (29.2%) pts were MYC-high + BCL2-high by RNAseq. In the pbo + R-CHOP arm, pts with MYC-high + BCL-2-high had worse EFS (HR 1.820; 95% CI, 1.264-2.620; p = 0.0011) and OS (HR 1.662; 95% CI, 1.014-2.724; p = 0.0415) versus those with low expression of 1 or both markers in the ITT population (Figure), consistent with known poor outcomes associated with these genes. However, there was no difference in outcome for high versus low expression of these genes in the IBR + R-CHOP arm in the ITT population. In the ITT population, pts with MYC-high + BCL2-high had better EFS (HR 0.648; 95% CI, 0.423-0.993; p = 0.045) with IBR + R-CHOP versus pbo + R-CHOP, but there was no significant difference in OS (HR 0.783; 95% CI, 0.446-1.372; p = 0.39; Figure). We also examined the outcome of the 97 (30.6%) pts < 60 years of age (n = 317) with MYC-high + BCL2-high and observed an improved EFS and OS with IBR + R-CHOP versus pbo + R-CHOP (HR 0.393; 95% CI, 0.198-0.780; p = 0.0056 for EFS; HR 0.191; 95% CI, 0.055-0.666; p = 0.0037 for OS; Figure). There was no significant difference in EFS or OS in pts < 60 years with MYC-low + BCL2-low or in pts ≥ 60 years with MYC-high + BCL2-high in the 2 arms. Conclusions In this exploratory analysis, IBR was associated with improved EFS in combination with R-CHOP compared with pbo + R-CHOP in pts with MYC-high + BCL2-high expression in the ITT (non-GCB) population, without a significant improvement in OS. In pts aged < 60 years, both EFS and OS were significantly better with IBR, while there was no significant difference in older pts. These data suggest that IBR + R-CHOP may particularly benefit pts with MYC-high + BCL2-high-expressing lymphomas, a hypothesis warranting further testing in other DLBCL cohorts. Johnson: Novartis: Honoraria; Genmab: Honoraria; Kite: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; Incyte: Honoraria; Boehringer Ingelheim: Honoraria. Balasubramanian:Janssen: Employment; Johnson & Johnson: Equity Ownership; Gilead Sciences: Equity Ownership; Celgene: Equity Ownership; Vertex: Equity Ownership; AbbVie: Equity Ownership. Hodkinson:Janssen: Employment. Schaffer:Johnson & Johnson: Equity Ownership; Janssen: Employment. Parisi:Janssen: Employment. Shreeve:Johnson & Johnson: Equity Ownership; Janssen: Employment. Sun:Janssen: Employment; Johnson & Johnson: Equity Ownership. Vermeulen:Johnson & Johnson: Equity Ownership; Janssen: Employment. Sehn:Abbvie: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Janssen-Ortho: Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Lundbeck: Consultancy, Honoraria. Staudt:Nanostring: Patents & Royalties. Younes:AstraZeneca: Research Funding; Biopath: Consultancy; Genentech: Research Funding; Pharmacyclics: Research Funding; Syndax: Research Funding; BMS: Research Funding; HCM: Consultancy; Epizyme: Consultancy, Honoraria; Xynomics: Consultancy; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria.

Micro‐Abstract: We investigated the significance of BCL‐2 and BCL‐6 expression in MYC+ diffuse large B‐cell lymphoma. Immunohistochemistry was performed to evaluate the expression of BCL‐2, BCL‐6, and MYC. BCL‐2 played a more important role than MYC in patients with double‐expression lymphoma. Besides, BCL‐6− expression might also be a negative prognostic factor for such patients. Background: Double‐expression lymphoma (DEL) is a rare subgroup of diffuse large B‐cell lymphoma (DLBCL), which has coexpression of MYC and BCL‐2. Coexpression of MYC and BCL‐2 is considered a prognostic marker portending poor outcomes. However, the prognostic effect of BCL‐2 and BCL‐6 expression in DLBCL remains controversial. Materials and Methods: Immunohistochemical staining was performed to detect MYC, BCL‐2 and BCL‐6 expression in 212 patients with newly diagnosed DLBCL and assess the prognostic effects of BCL‐2 and BCL‐6 expression. The DLBCL patients were treated with R‐CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone)–like regimens. Results: Retrospective analysis revealed that BCL‐2+ and BCL‐2+/MYC+ were prognostic factors indicative of poor outcomes. Patients with BCL‐2+ and/or MYC+ expression had a poorer prognosis than that of patients with BCL‐2− and/or MYC− expression. Patients with BCL‐2+/MYC− expression showed a trend toward poorer survival than those with BCL‐2−/MYC+ expression, suggesting that BCL‐2 plays a more important role than MYC. Also, patients with BCL‐6−/MYC+ expression had poorer progression‐free survival than those with BCL‐6+/MYC+ expression. In addition, patients with BCL‐2+/MYC+/BCL‐6− expression had the worst prognosis, suggesting that BCL‐6− is a prognostic factor for poor outcomes for MYC+ DLBCL patients. Altogether, our findings have shown that BCL‐2 is an independent prognostic factor and possibly plays a more important role than MYC in MYC+ DLBCL patients. Furthermore, we found that BCL‐6− expression could also be a prognostic factor portending poor outcomes for MYC+ DLBCL patients.

… Translocations that target the oncogenes MYC and BCL2, as well as BCL6, in DLBCL have … MYC-break positive DLBCL cases may also coexpress high levels of BCL2, and up to half …

… with MYC/BCL2 co-expression did not show any predominance of the 2 subtypes in our cases. Furthermore, patients with MYC/BCL2 co-expression … that MYC/BCL2 co-expression is …

… DLBCL patients with MYC and BCL2 coexpression shown by immunohistochemistry have a poor prognosis in the absence of concurrent MYC and BCL2 … MYC and BCL2 coexpression …

… MYC and BCL2 rearrangements were more frequently observed in GCB-DLBCL and BCL6 … protein overexpression had poor prognostic impact when BCL2 protein was coexpressed. …

… DLBCLs show an activated B-cell-like subtype characteristic and have multiple expressions of C-MYC, BCL-2, BCL-… factor to predict the outcome and guide treatment of PCNS-DLBCLs. …

Backgroud Diffuse large B-cell lymphoma (DLBCL) is the most commonly occurred non-Hodgkin's lymphoma (NHL). With the development of chemotherapy and immunotherapy, some patients get a good prognosis, but still a considerable number of patients suffer from a strongly aggressive DLBCL with poor treatment effects. Due to the discovery of "double hit" of MYC/Bcl-2 genes, the coexpression of these two proteins has attracted more attention. Further investigations will be necessary to investigate the role of MYC/Bcl-2 co-expression in the clinical features of DLBCL as well as its relationship with prognosisto explore the significance of MYC/Bcl-2 protein coexpression in DLBCL. Methods 89 confirmed DLBCL cases treated with the chemotherapy regimen of CHOP or R-CHOP between February 2008 and March 2014 were collected. Complete clinical data and paraffin-embedded tissues samples were available from these cases. immunohistochemistry analysis of MYC and Bcl-2 protein expression were carried out. In addition, the relationship between MYC/Bcl-2 protein coexpression and factors such as the age, gender, primary site, Ann Arbor staging, international prognostic index (IPI), immunohistochemical Hans type, and Ki-67 expression rate of patients were statistically analyzed in this paper. Furthermore, we investigated how the abovementioned indicators and whether or not Rituximab or MYC/Bcl-2 coexpression was applied were associated with the progression-free survival (PFS) and overall survival (OS) of patients. Results 1. 89 cases with DLBCL were collected. The median age was 65 years with a range of 18-82. 54 cases were over 60 years old. 64 patients had a primary tumor in the lymph nodes .As per the IPI score, there were 30 low-risk cases (IPI&lt;3). There were 27 cases at Ann Arbor stage I-II, 62 cases at stage III-IV, 31 GCB cases, 58 nonGCB cases. For 61 cases, the expression rate of Ki-67 was more than 70%.There were 41 cases treated with the chemotherapy regimen of R-CHOP and 48 cases treated with chemotherapy regimen of CHOP.MYC/Bcl-2 coexpression was associated with high-risk IPI score (P = 0.022). 2. 37 cases had high MYC protein expression, accounting for 41.5%. Also, 51cases (57.3%) had high Bcl-2 protein expression. There were 29 cases (32.6%) of MYC/Bcl-2 co-expression Compared with non-coexpression group, the median PFS (16m VS 33m, P&lt;0.001) of the co-expression group decreased significantly.but there was not a significantly difference of the median OS. Moreover, Compared the MYC or Bcl-2 single expression group with the non-expression group, there were no significant differences among them. 3. Single factor analysis with other common risk factors indicated that in the high-risk group, including advanced aged (grouping by 60 years old)、treating without rituximab III-IV stages, and high IPI score, both PFS and OS decreased, and the difference was statistically significant (P&lt;0.05); When grouping by immunohistochemical Hans classification, primary site and Ki-67 expression (divided by 70%), OS comparison of the two groups showed no significant difference (P&gt; 0.05). 4. In the multivariate regression analysis, It was found that MYC/Bcl-2 coexpression, IPI score, age, and use of rituximab, staging were independent prognostic factors to PFS (P &lt;0.05), while IPI score, staging and age were independent prognostic risk factors to OS (P&lt;0.05). However,MYC/Bcl-2 coexpression temporarily could not be considered as an independent risk factor for OS. Conclusions Bcl-2/MYC protein coexpression is significantly associated with IPI score of high-risk patients. Patients with MYC/Bcl-2 coexpression had a poorer prognosis than non-coexpression, with shortened PFS. They had a prognosis poorer than single high expressions of MYC or Bcl-2. The influence of MYC/Bcl-2 coexpression to the OS of DLBCL needs a longer follow-up time to study.MYC/Bcl-2 coexpression, IPI score, age, and use of rituximab, staging were independent prognostic factors to prognosis. Disclosures No relevant conflicts of interest to declare.

Simple Summary Diffuse large B-cell lymphoma (DLBCL) with MYC/BCL2 double-expression (DE), a recently proposed poor prognostic group, can be easily identified by immunohistochemistry in routine clinical practice. However, clinical outcomes of DE-DLBCL patients vary immensely after R-CHOP immunochemotherapy and prognostic impact of MYC/BCL2-DE was conflicting according to the cell-of-origin, i.e., between germinal center-B-cell (GCB)- and non-GCB-DLBCLs. This implies the heterogeneity within DE-DLBCLs and emphasizes a need for proper risk stratification to select the patients who require more intensive therapy. By analyzing a prospectively immunoprofiled cohort of consecutively diagnosed DLBCL patients, we confirmed the poor prognostic value of MYC/BCL2-DE in DLBCL patients treated with R-CHOP irrespective of the cell-of-origin and international prognostic index. DE-DLBCLs with a concurrent risk factor, especially, elevated serum lactate dehydrogenase (LDH), had the worst survival and DE-DLBCL patients with normal LDH had clinical outcomes similar to those of non-DE-DLBCL patients. Risk stratification of DE-DLBCL based on serum LDH may guide clinical decision-making for DE-DLBCL patients. Abstract Diffuse large B-cell lymphoma (DLBCL) patients with MYC/BCL2 double expression (DE) show poor prognosis and their clinical outcomes after R-CHOP therapy vary immensely. We investigated the prognostic value of DE in aggressive B-cell lymphoma patients (n = 461), including those with DLBCL (n = 417) and high-grade B-cell lymphoma (HGBL; n = 44), in a prospectively immunoprofiled cohort. DE was observed in 27.8% of DLBCLs and 43.2% of HGBLs (p = 0.058). DE-DLBCL patients were older (p = 0.040) and more frequently exhibited elevated serum LDH levels (p = 0.002), higher international prognostic index (IPI; p = 0.042), non-germinal-center B-cell phenotype (p < 0.001), and poor response to therapy (p = 0.042) compared to non-DE-DLBCL patients. In R-CHOP-treated DLBCL patients, DE status predicted poor PFS and OS independently of IPI (p < 0.001 for both). Additionally, in DE-DLBCL patients, older age (>60 years; p = 0.017), involvement of ≥2 extranodal sites (p = 0.021), bone marrow involvement (p = 0.001), high IPI (p = 0.017), CD10 expression (p = 0.006), poor performance status (p = 0.028), and elevated LDH levels (p < 0.001) were significantly associated with poor OS. Notably, DE-DLBCL patients with normal LDH levels exhibited similar PFS and OS to those of patients with non-DE-DLBCL. Our findings suggest that MYC/BCL2 DE predicts poor prognosis in DLBCL. Risk stratification of DE-DLBCL patients based on LDH levels may guide clinical decision-making for DE-DLBCL patients.

Double expression (DE) is a World Health Organization‐recognized adverse prognostic factor in diffuse large B‐cell lymphoma (DLBCL). However, the prognostic value of DE in the genetic subtyping era and potential mechanisms remain to be explored. We enrolled 246 DLBCL patients diagnosed between December 2021 and September 2023 in a Jiangsu Province Hospital cohort and included 930 DLBCL patients from three published studies in an external cohort. Double‐expression DLBCL (DEL) in the external cohort was mainly distributed in the OTHER subtype (42.0%), EZB subtype (28.3%), and MCD subtype (15.0%), whereas the MCD subtype exhibited the highest ratio of DEL. DEL was significantly related to unfavorable overall survival (OS) and progression‐free survival (PFS) in DLBCL, but only in EZB and OTHER subtypes that DEL retained remarkably adverse impacts on survivals compared to non‐DEL. We explored the prognostic value of clinical and genetic parameters in DEL patients and found only ST2 showed better OS than A53 in DEL patients, whereas the other subtypes showed no significant difference. DEL showed similarities with the MCD subtype in mutation profiles. Furthermore, RNA‐sequencing analyses exhibited upregulation in tumor proliferation‐related pathways in DEL patients, but downregulation in extracellular matrix organization, T‐cell activation and proliferation, type II interferon production, and pathways associated with cell death might contribute to the poor outcomes of DEL patients.

Supplementary Figure from Genetic Subtyping and Phenotypic Characterization of the Immune Microenvironment and MYC/BCL2 Double Expression Reveal Heterogeneity in Diffuse Large B-cell Lymphoma

Diffuse large B-cell lymphomas with aberrations in MYC, BCL2 and/or BCL6 by genetic alterations or protein expression represent a group of high grade B-cell lymphomas with inferior outcomes when treated with standard RCHOP chemotherapy. As a result, intensified induction regimens have been suggested in an effort to improve outcomes. Conclusions to date have largely been drawn from retrospective data although prospective data is slowly starting to emerge. Chemoimmunotherapy refractoriness is problematic and relapse rates are high. Patients with double hit lymphoma appear to have increased risk of CNS involvement and prophylaxis is recommended. There is insufficient evidence available to date to strongly recommend for or against consolidative stem cell transplant in this population. Collaborative clinical trials will be needed to establish a preferred therapeutic regimen and an appropriate standard of care in this unique group of patients with DLBCL.

… In 86 patients with MYC/BCL2 double expression lymphoma, the 36 patients with tumors … effect of P53 in MYC/BCL2 double-positive lymphoma and demonstrated that expression of P53 …

Both the 2022 WHO HAEM5 and the International Consensus Classification of lymphoma have refined the way we now approach high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements moving the previous generation of classification a step forward. The unifying biology of MYC/BCL2 tumours has been clearer and their inferior prognosis confirmed compared to those with morphological similarities but lacking the classifying cytogenetic abnormalities. FISH testing has largely become population based and we have learnt much from this. We can readily define molecular categories and apply these widely to clinical practice. Uncertainty has however been shed upon the place of double MYC/BCL6 translocations in defining a common disease group. We have enhanced knowledge of outcomes and the role of therapy intensification to overcome chemotherapy resistance. For those patients failed by initial induction chemotherapy, immunotherapy approaches, including CAR-T therapies, are improving outcomes. Novel inhibitors, targeting dysregulated oncogenic proteins are being explored at pace. The rare, but difficult, diagnostic classification HGBL (NOS) remains a diagnosis of exclusion with limited data on an optimal clinical approach. The days of talking loosely of double and triple hit lymphoma are numbered as this review synergises the current data on biology, prognosis, and therapies in HGBL.

Introduction Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, the spectrum of which is increasing with time. The 2016 World Health Organization (WHO) update on hematopoietic tumors recognized a prognostic subgroup of DLBCL called double-expressor DLBCL. Double-expressor DLBCL is defined by the co-expression of c-MYC and BCL-2 by using immunohistochemical (IHC) studies. To our knowledge, very few studies have looked into the pathological features of this newly defined prognostic category of DLBCL; therefore, in this study we evaluated the frequency of the double-expressor phenotype of DLBCL and its association with other clinicopathological parameters. Methods We conducted a retrospective observational study in the Department of Histopathology, Liaquat National Hospital and Medical College, from November 2017 till December 2020. Pathological and clinical records were retrieved from departmental archives. All cases diagnosed as DLBCL were included in the study. More than 40% c-MYC expression in the presence of more than 50% BCL-2 expression was defined as double-expressor DLBCL. Results The mean age of the patients was 52.1±16.9 years. The mean Ki67 index was 73.0±17.0%. A total of 48.6% cases were of germinal center B-cell-like (GCB) subtype, and 59.6% cases were nodal. Double-expressor phenotype was noted in 35.8% of DLBCL cases. A significant association of double-expressor phenotype was noted with age, gender, Ki67 index and subtype of DLBCL. Double-expressor DLBCL had a higher mean age than non-double-expressor DLBCL. Similarly, double-expressor DLBCL had a higher Ki67 index. Moreover, double-expressor phenotype was associated with non-GCB subtype DLBCL. Conclusion We found a high proportion of double-expressor phenotype DLBCL in our population. Moreover, double-expressor phenotype DLBCL was associated with female gender, higher age, higher Ki67 and non-GCB subtype. The association of double-expressor DLBCL with a high Ki67 index and non-GCB subtype confers a poor prognostic significance of this variant of DLBCL, requiring more aggressive therapy.

Double expressor lymphoma (DEL), defined as overexpression of BCL2 and MYC, is an aggressive subtype of diffuse large B cell lymphoma (DLBCL). Here we report a case of a 64-year-old female diagnosed with abdominal DEL transformed from jejunum follicular lymphoma (FL). 18F-fluorodeoxyglucose (FDG)-positron emission tomography showed diffuse accumulation of FDG into the peritoneum and small bowel wall. Double balloon-assisted enteroscopy revealed whitish submucosal tumors in the proximal jejunum. Aggregation of atypical lymphocytes positive for CD20, CD79a, and BCL2 was seen in the jejunal biopsy samples. These atypical lymphocytes were monoclonal since cell surface expression of Ig light chains was limited to κ chain by flow-cytometry. Thus, immunohistochemical and flowcytometric analyses data were consistent with FL of the jejunum. Neoplastic lymphocytes obtained from ascites were positive for CD10, CD20, CD79a, BCL2, and BCL6. Fluorescence in situ hybridization (FISH) showed formation of BCL2/IgH fusion gene and extra copies of MYC, the former of which is a characteristic chromosomal abnormality of FL. These genetic alterations and protein expression profiles of ascitic fluid cells were consistent with those of DEL transformed from FL. Given that a significant population of patients with indolent FL of the gastrointestinal tract developed into aggressive DLBCL, it is likely that primary FL of the jejunum transformed into the abdominal aggressive DEL in this case. This case is unique in that concurrent occurrence of FL and DEL was confirmed by immunohistochemical and FISH analyses and that abdominal DEL transformed from jejunal FL was highly suspected.

… Aims: This study aimed to determine the HBV seropositivity prevalence in lymphoma … adult patients (18 years) newly diagnosed with lymphoma who received rituximab-based therapy at …

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements constitutes a distinct clinicopathological entity characterized by aggressive behavior, inherent resistance to conventional immunochemotherapy, and suboptimal clinical outcomes. Within our cohort, MYC/BCL2 rearrangements defined double-hit lymphoma (DHL), MYC/BCL6 as DHL-BCL6, and concurrent MYC/BCL2/BCL6 as triple-hit lymphoma (THL). Here, we delineated the clinical characteristics and genetic aberrations of 112 DHL/THL patients to investigate the factors influencing lymphoma relapse and optimize treatment strategies. Compared to 80 DHL-BCL6 patients, DHL/THL manifested distinct features, including an increased prevalence of the germinal center B-cell-like subtype and co-expression of MYC/BCL2, and demonstrated significant associations with abbreviated progression-free and overall survival. Univariate and multivariate analyses identified Ann Arbor stage and serum lactate dehydrogenase elevation as independent prognostic determinants. Therapeutic intensification employing R-DA-EDOCH was correlated with enhanced survival outcomes, while consolidative autologous stem cell transplantation significantly improved prognosis in patients who achieved remission after first-line immunochemotherapy. Regarding genetic aberrations, oncogenic mutations were detected in 102 evaluable patients. EZH2 mutation occurred more frequently in DHL/THL, while TNFRSF14 mutation exhibited greater prevalence in THL. The EZB genotype was predominantly observed in DHL/THL patients, and those with TP53 abnormalities exhibited a further diminished prognosis. In terms of the immune microenvironment, the depleted lymphoma microenvironment (LME-DP) subtype, characterized by diminished immune cell infiltration, demonstrated a propensity for increased frequency in DHL/THL patients. Collectively, these findings advance the comprehensive understanding of DHL/THL pathobiology, underscoring the imperative for novel targeted agents and therapeutic approaches.

Diffuse large B-cell lymphoma (DLBCL) exhibits clinical, genetic, and immunohistochemical heterogeneity. However, the differences between primary extranodal or nodal DLBCL and double-expressor lymphoma (DEL), which is characterized by high MYC and BCL2 expression, remain unclear. This study aimed to elucidate the clinicopathological features, response to therapy, and clinical outcomes of primary extranodal (n=61) and nodal (n=128) DLBCL. Patients with primary nodal DLBCL had higher BCL2 expression than those with extranodal DLBCL (p=0.048), with high MYC expression and DEL as poor prognostic factors. Conversely, in patients with primary extranodal DLBCL, high BCL2 expression, low BCL6 expression, non-germinal center B-cell-like type, and DEL indicated poor prognosis. DEL was significantly associated with progression free survival and overall survival in patients with primary extranodal DLBCL (p=0.014 and p=0.021, respectively) but not in patients with primary nodal DLBCL (p=0.37 and p=0.084, respectively). Our findings highlight primary extranodal DEL as a strong adverse prognostic factor in DLBCL.

Background: MYC protein is expressed in 30-50% of diffuse large B cell lymphoma (DLBCL) and is associated with concomitant expression of BCL2 in 20% to 35% of cases. DLBCLs with co-expression of MYC and BCL2 are called double-expressor lymphomas (DELs); whereas double-hit lymphomas (DHLs) have MYC and BCL2 or BCL6 rearrangement as detected by fluorescence in situ hybridization (FISH) or standard cytogenetics and are currently classified by the World Health Organization as high grade B cell lymphoma (HGBL). MYC/BCL2 double expression is an independent risk factor of DLBCL relapse or progression. In several studies, DELs were shown to have worse outcomes than other DLBCLs, but not as much aggressiveness as the DHLs (HGBL). Poor response to standard chemotherapy CHOP or R-CHOP is seen with DHLs and DELs with a median overall survival of &lt;12 months. The purpose of this study was to characterize DELs amongst veteran patients with DLBCL and their outcomes. Methods: This is an IRB-approved, retrospective study of patients diagnosed with DLBCL between 1/1996 and 1/2016 at the Washington DC Veterans Affairs Medical Center. Sixty nine DLBCL patients were identified. All patients with unavailable tissue for pathology testing were excluded. Immunohistochemistry (IHC) stains were reviewed for CD3, CD5, CD10, CD20, CD30, BCL2, BCL6, C-MYC, MUM-1, MIB1, Cyclin-D1, and p53. DELs were defined by concomitant expression of MYC and BCL2 detected by IHC (cutoffs-30% MYC, 40% BCL2). We did not sub-classify our patients into DHLs because of unavailability of MYC and BCL2 rearrangement results by FISH. Demographic and laboratory data at diagnosis, treatment regimens and outcomes in terms of relapse and death were analyzed. Student's t-test was used to compare means and chi-square to compare proportions. Results: Sixty nine eligible cases of DLBCL were identified, 31 were excluded because of insufficient tissue for full characterization, leaving us with 38 cases for analysis. All cases were CD20 positive with high MIB1. MYC was positive in 19 cases (50%) of whom 17 were as well positive for BCL2 (44.7%) (DELs); the remaining 21 were non-DELs. Median age at diagnosis for all patients was 65 years. Stages at diagnosis for all patients were as follows: I (2 patients; 5.3%), II (8; 21.1%), III (7; 18.4%), IV (20; 52.6%). Stage and presence of extra-nodal disease were not significantly different in the DEL vs the non-DEL groups. The majority of DEL patients had an IPI score of 3 (intermediate-high) compared to a score of 2 (low-intermediate) in non-DEL patients (difference was not significant). Mean LDH at diagnosis for all patients was 365.7 ±273 IU/L (133-1285); higher in DEL (422.9±340.5) as compared to non-DEL (314±182) patients. Within the DEL group, 5 patients (29.4%) received R-CHOP; 11 (64.7%) received R-EPOCH as first line chemotherapy. Four out of the 5 (80%) treated initially with R-CHOP relapsed and eventually died. Of the 11 DEL patients treated with R-EPOCH, 2 (18.2%) relapsed and one of these two died. The relapse rate between the 2 treatment groups of DEL was significantly higher for R-CHOP (p=0.042). Of 21 non-DEL patients, 14 (66.7%) remained in remission; 2((9.5%) relapsed; and 5(23.8%) were lost-to-follow-up. Nineteen (50%) patients died and median overall survival (OS) was 18.5 months for the whole group (20.4 vs 36.1 in the DEL vs non-DEL groups respectively; no statistical significance). Conclusions: The proportion of DELs identified amongst DLBCL in our study is consistent with the literature. As expected, patients with DEL had a worse OS than non-DEL patients in our study, which is consistent with DEL's poor prognosis. Although the sample size in our study is small, there was a more favorable outcome with R-EPOCH treatment of DEL. Larger prospective and interventional studies are needed to confirm these results, develop new treatment strategies for DEL, and better characterize the underlying biology driving its poor prognosis. Figure 1 Kaplan-Meier survival curves comparing overall survival in DEL vs non-DEL groups Figure 1. Kaplan-Meier survival curves comparing overall survival in DEL vs non-DEL groups Disclosures No relevant conflicts of interest to declare.

A 60-year-old female presented with abdominal pain and distension. Following computed tomography scans of the abdomen and pelvis, she was taken urgently to the operating room, with the belief that she had appendicitis with perforation. At laparotomy, the findings were consistent with an ovarian carcinoma; there was extensive infiltration of the ovary, bowel, and omental deposits. Cytoreductive surgery was performed including total abdominal hysterectomy and bilateral salpingo-oophorectomy. The final pathology, however, revealed infiltration with medium-sized atypical lymphoid cells positive for CD20, CD10, MYC, BLC2, and BCL6 by immunohistochemistry. MYC and BCL2 translocations were identified by fluorescence in situ hybridization consistent with a diagnosis of high-grade B-cell lymphoma with rearrangements of MYC and BCL2. With the current data available, what is the optimal treatment of this patient?

Background Double-expressor lymphoma (DEL), defined by concurrent MYC and BCL2 protein overexpression in diffuse large B-cell lymphoma (DLBCL), is associated with poor prognosis, but precise risk quantification and optimal treatments remain unclear. Methods We conducted a two-stage evidence synthesis. First, a systematic review and meta-analysis quantified hazard ratios for progression-free survival (PFS) and overall survival (OS) comparing DEL with non-DEL and identified prognostic factors within DEL. Second, a network meta-analysis ranked the efficacy and safety of regimens including rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-EPOCH-R); R-CHOP plus lenalidomide (R2-CHOP); R-CHOP plus ibrutinib (I+R-CHOP); R-CHOP plus zanubrutinib (Z+R-CHOP); and R-CHOP plus venetoclax (Ven-R-CHOP). Results In 66 studies (9,808 patients), DEL was significantly associated with inferior PFS (hazard ratio 1.78, 95% confidence interval 1.50–2.10) and OS (1.90, 1.68–2.15). Within DEL, high International Prognostic Index, advanced age, elevated lactate dehydrogenase, B symptoms, and advanced stage predicted inferior PFS and OS; TP53 mutation and poor Eastern Cooperative Oncology Group performance status predicted inferior OS. In 13 treatment studies (1,803 patients), Z+R-CHOP and Ven-R-CHOP showed the highest efficacy. Z+R-CHOP demonstrated favorable hematological toxicity compared with other novel regimens. Conclusion DEL is a distinct high-risk subtype with quantifiable prognostic detriment. Z+R-CHOP emerges as a promising strategy requiring validation in prospective studies.

Background Diffuse large B-cell lymphomas (DLBCLs) are a heterogeneous group with variable prognosis. Double-expressor (DE) and triple-expressor (TE) lymphomas have emerged as uncommon indistinct subgroups of high-grade B-cell lymphomas that may have prognostic value. This study aimed at evaluating the role of immunohistochemistry (IHC) in the detection of DE and TE lymphomas as well as correlating them with clinicopathological parameters. Materials and methods This is a retrospective study conducted on 100 cases of DLBCL. Tissue microarray blocks were constructed and immunostained with antibodies for MYC, BCL2, BCL6, CD10, MUM1, and P53 to determine the germinal center, activated B cell, DE, and TE phenotypes. Results We have found a statistically significant correlation between both DE and TE lymphomas and reduced disease-free survival (P=0.03) as well as with nodal location (P=0.006). No statistically significant correlation was found with clinicopathological parameters such as age, sex, stage, international prognostic index score, or response to therapy. No statistically significant difference was found between DE and TE groups. Conclusion DE and TE lymphomas can be considered as poor prognostic subgroups of DLBCL associated with reduced disease-free survival. Our study stresses the value of immunohistochemistry in the detection of such adverse groups of DLBCL.

Background: Approximately 20%–30% of diffuse large B-cell lymphoma (DLBCL) cases are classified as double-expressor lymphoma (DEL), characterized by the co-expression of the MYC and BCL2 proteins. However, the most effective therapeutic strategy for DEL remains unidentified. Objectives: To evaluate the efficacy of a novel histone deacetylase inhibitor, chidamide, in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (CR-CHOP) in the treatment of DEL. Design: This was a retrospective study. Methods: This study included 62 DEL patients from December 2016 to December 2020. All patients were administered a first-line treatment with CR-CHOP. The short-term efficacy, survival status, and adverse reactions in this population were observed, and the prognostic factors were analyzed. Results: The median age was 53.9 years (range, 19–77). All patients received a median of six cycles (range, 1–8) of treatment, with 79.0% achieving complete response (CR) and an overall response rate of 88.7%. With a median follow-up of 45.5 months (range, 1–82), the median progression-free survival (PFS) and median overall survival (OS) had not yet been reached. However, the 3-year PFS rate was 71% (95% CI: 61–83), the 3-year OS rate was 87% (95% CI: 79–96), the 5-year PFS rate was 67% (95% CI: 55–80), and the 5-year OS rate was 85% (95% CI: 77–95). Age and autologous stem cell transplantation after CR or partial response were independent prognostic factors for PFS, while various clinical factors were not associated with OS outcomes. The most common grades 3–4 hematologic and nonhematologic toxicity were leukopenia (46.7%) and infection (21%), respectively. Conclusion: This long-term follow-up study indicates that CR-CHOP in untreated DLBCL with the DEL phenotype demonstrates high short-term efficacy and safety as well as promising survival outcomes.

Double-expressor lymphoma (DEL) is a diffuse large B cell lymphoma that exhibits co-expression of MYC and BCL2 proteins by immunohistochemistry. Patients with double-expressor lymphoma have a poor prognosis after standard chemoimmunotherapy or after high-dose chemotherapy with autologous transplantation, but the prognostic impact of DEL after allogeneic hematopoietic cell transplantation has not been well characterized. We retrospectively analyzed 60 consecutive patients with de novo diffuse large B cell lymphoma or transformed follicular lymphoma who underwent allogeneic transplantation at our center and had available immunohistochemistry data. Thirty-seven patients (62%) had DEL. The 2-year progression-free and overall survival rates were lower in patients with DEL than in those without DEL (20% versus 78%; overall P <.001 and 46% versus 77%; overall P = .016, respectively). The cumulative incidence of disease progression at 2 years was higher in patients with DEL (60% versus 13%; overall P = .005). The cumulative incidence of nonrelapse mortality did not differ statistically in the 2 groups. Even in patients with DEL and chemosensitive disease at transplantation, the 2-year progression-free survival rate was only 27% due to early disease progression. Multivariate analysis showed associations between DEL and increased risks of progression-free survival events (hazard ratio [HR], 4.58; 95% confidence interval [CI], 2.07-10.2; P <.001), overall mortality (HR, 2.29; 95% CI, 1.03-5.09; P = .042) and disease progression (HR, 3.60; 95% CI, 1.38-9.44; P = .009). Patients with DEL had poor outcomes after allogeneic transplantation. Innovative strategies are needed to improve outcomes in this population.

Background Double-expressor lymphoma (DEL) was found to account for 20–30% of DLBCL. We conducted this study to analyze the survival, the clinical presentation, and the factors associated with treatment outcomes in DEL-DLBCL. Methods A retrospective study of 291 patients diagnosed with DLBCL during January 2015 – December 2018 was conducted. Results Of the 291 patients, the median age was 63 years, germinal center B cell-like DLBCL (GCB) and non-GCB subtypes were found in 32% and 68%, respectively. DEL was found in 46% of 264 patients with available immunohistochemistry staining for MYC protein. Patients with DEL was significantly more common in elderly patients (p= 0.017) and non-GCB subtype (p= 0.006). High serum lactate dehydrogenase (LDH) levels and high Ki-67 index were significantly found in DEL patients than non-DEL patients (p= 0.024 and p= 0.04, respectively). The 3y-OS rate was shorter in the DEL group than in the non-DEL group, 58.7% versus 78.9% (p=0.026), whereas no significant difference in 3y-DFS was identified between these groups (58.4% versus 67.7%, p= 0.343). Independent factors affecting OS and DFS in DEL patients were ECOG 3–4, high LDH levels, extranodal involvement> 1 site, high IPI, and stage III-IV in univariate analysis. Conclusions High incidence of DEL was observed in this study, especially in patients aged 60 years or older and non-GCB subtype. Patients with DEL showed dismal DFS and OS.

Dear editor, Diffuse large B-cell lymphoma (DLBCL) stands as the predominant subtype of non-Hodgkin ’ s lymphoma (NHL) among adults, accounting for 30 – 40% of cases globally. Apart from its marked invasiveness, DLBCL demonstrates signi fi cant heterogeneity across various parameters, including cellular origin, morphological characteristics, immunohistochemical phenotype, cellular molecular genetics, sites of occurrence within and outside lymph nodes, response to chemotherapy, and survival rates [1]. Double expressor diffuse large B-cell lymphoma (DE-DLBCL) is a distinct subtype characterized by heightened expression of MYC ( ≥ 40%) and BCL-2 (the cut-off varied considerably in the literature, but a fi gure of ≥ 50% is recommended) as determined by immunohistochemistry (IHC) [2]. DE-DLBCL currently lacks standardized treatment regimens. Compared to non-double-expressor DLBCL, DE-DLBCL patients exhibit inferior outcomes when treated with standard immunochemotherapy [3]. Notably, a review of outcomes revealed markedly lower 5-year overall survival rates (OS) and progression-free survival rates (PFS) for DE-DLBCL, at 36% and 32%, respectively, in stark contrast to those observed for non-double-expressor DLBCL (71% and 65%) [4]. Furthermore, investigations indicated that the application of the R-CHOP regimen in DE-DLBCL treatment resulted in a 2-year PFS rate of approximately 54% [5]. While more intensive chemotherapy regimens such as DA-EPOCH-R, R-hyperCVAD alternating with MTX/cytarabine, and cyclophosphamide,

The poor outcome of high-grade B-cell lymphoma, with rearrangements of MYC, BCL2 and/or BCL6, also known as double-hit lymphoma or triple-hit lymphoma (DHL or THL), has been well documented, while the clinical significance of extra copies of MYC, BCL2 or BCL6 are still less well known. In total, 130 cases of diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS) were included in our study. Fluorescence in situ hybridization and immunohistochemistry were performed in all cases to evaluate the genetic status and protein expression levels of MYC, BCL2 and BCL6. Among the 130 cases of DLBCL, the prevalence rates of extra copies of MYC, BCL2 and BCL6 were 10.8, 20.0 and 14.6%, respectively, and the corresponding rates of gene rearrangement were 10.0, 14.6 and 16.9%, respectively. In total, 7.7% (10/130) of patients were DHL/THL; 9.2% (12/130) of patients were DLBCL with MYC and BCL2 and/or BCL6 gene abnormalities including rearrangements or extra copies, while excluded DHL/THL. The positive protein expression rates of MYC, BCL2 and BCL6 were 46.9% (61), 75.4% (98) and 70.0% (91), respectively. Among the 51 cases with MYC/BCL2 co-expression, 14 cases showed concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities, and the remaining 37 cases were classified as double-expressor lymphoma (DEL). MYC and BCL2 rearrangement and BCL2 extra copies were all associated with upregulated protein expression. Cases with concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities were both associated with MYC/BCL2 co-expression. Patients with concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities excluded DHL/THL had shorter OS (P < 0.001) than patients with DLBCL with no genetic change, and showed no statistical different with patients with DHL/THL (P = 0.419). Extra copies of MYC was independent prognostic factors for DLBCL. Patients with MYC and BCL2 and/or BCL6 gene extra copies might show a trend towards poor prognosis, and the detection of extra copies of MYC, BCL2 and BCL6 might deserve more attention.

Primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) is a rare aggressive extranodal B-cell lymphoma. 1,2 Despite intensive protocols such as methotrexate, cytarabine, thiotepa, and rituximab (

Abstract Predicting MYC and BCL2 double-expressor lymphoma prognosis using the system immune-inflammatory index (SII) and prognostic nutritional index (PNI) (DEL). From January 2015 to December 2021, 281 diffuse large B-cell lymphoma (DLBCL) wax blocks were used to make tissue chips. Screening double expressor lymphoma (DEL) instances involved immunocytochemistry and fluorescence in situ hybridization. Academic analysis used clinicopathological characteristics and follow-up data. SII, PNI, and DEL prognosis were correlated using univariate and multivariate cox regression analysis. The median age of 78 DEL patients is 60 (range: 43–74). SII and PNI cut-off values of 603.5, 3.07, and 144 predict PFS and OS well. Lower SII is associated with longer PFS (HR for SII = 0.34, 95% CI 0.15–0.76, P = 0.006; HR for NLR = 0.46, 95% CI 0.22–0.99, P = 0.048; HR for PLR = 0.39, 95% CI 0.17–0.94, P = 0.025; LMR = 0.39, 95%, CI 0.17–0.94, P = 0.025) and OS (HR for SII = 0.16, 95% CI 0.05–0.51, P = 0.005; HR for PNI = 0.20, 95% CI 0.06–0.62, P = 0.002). SII and PNI are promising predictors for twofold expressor DLBCL. Combining these increase prediction accuracy.

INTRODUCTION To evaluate the prognostic significance of double-expressor phenotype (DEP), International Prognostic Index (IPI) score, and treatment-related factors in patients with primary testicular diffuse large B-cell lymphoma (PT-DLBCL), and to explore a risk stratification model integrating DEP and IPI. PATIENTS AND METHODS In this multicenter retrospective cohort study, 67 patients with PT-DLBCL treated at 3 tertiary hospitals in China between February 2013 and December 2024 were included. Clinical, pathological, and treatment-related data were collected from electronic medical records. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method. Univariable and multivariable Cox regression analyses were performed to identify prognostic factors. Based on the independent predictors for OS, an exploratory DEP-IPI risk model was constructed. RESULTS Among the 67 patients, DEP positivity was associated with significantly inferior OS and PFS, while patients with an IPI score ≥ 3 had significantly worse OS. In multivariable analysis, IPI score ≥ 3 (adjusted hazard ratio = 13.61, P = .042) and DEP positivity (adjusted hazard ratio =13.52,P = .005) remained independent adverse prognostic factors for OS. By contrast, no variable retained independent significance for PFS in the multivariable model. Contralateral testicular radiotherapy was associated with improved OS in Kaplan-Meier analysis but was not significant in Cox regression. Based on IPI and DEP status, patients were stratified into low-, intermediate-, and high-risk groups, which showed significantly different OS (P < .001). Treatment patterns did not differ significantly among the 3 risk groups. CONCLUSION IPI score ≥ 3 and DEP positivity are independent adverse prognostic factors for OS in PT-DLBCL, whereas no variable retained independent significance for PFS in multivariable analysis. An exploratory DEP-IPI model may help identify clinically distinct risk groups and provide additional prognostic stratification. Further large-scale prospective studies are needed to validate its clinical utility.

Background: Diffuse large B-cell lymphoma (DLBCL) is a neoplasm of medium or large B lymphoid cells with a diffuse histopathologic growth pattern. Co-expression of MYC and BCL2 proteins in DLBCL by immunohistochemistry (IHC) is referred to as the double-expresser (DE) phenotype and is associated with inferior survival. Objectives of this study were to assess the DE status in DLBCL and to assess its utility in predicting the prognosis in DLBCL. Methods: This was a retrospective study conducted in a tertiary care cancer centre. Study population included all the cases of DLBCL, NOS diagnosed in the centre in 2012. MYC and BCL2 protein expression were analysed by immunohistochemistry. The prognostic significance of double-expressers was analysed by comparing progression free survival (PFS) and overall survival (OS) of double-expressers and non-double expressers using appropriate statistical methods. All the data were analysed using SPSS 11 software. Kaplan-Meier method was used to estimate the survival probability. A significant difference in survival between various prognostic factors was tested using the log-rank test. Prognostic factors were assessed using univariate and multivariate Cox-regression model. A P- value < 0.05 was considered to be statistically significant. Results: Double-Expresser lymphoma (DEL) constituted 22.2% (n=18) of all cases of DLBCL, NOS. DE status was associated with shorter PFS (P-value = 0.049) and OS (P-value = 0.015). Conclusion: DE status is associated with poor prognosis in DLBCL, NOS. Assessment of MYC and BCL2 by IHC represents a rapid and inexpensive approach to risk-stratify patients with DLBCL at the time of diagnosis.

… double expressor status (co-expression of both MYC and BCL-2) is well established in systemic de novo DLBCL, its prognostic … diagnostic histology reports and double expressor (DE) …

… called double hit lymphoma (DHL). These groups have poor outcome survival compared to … the clinicopathological profile of double expressor lymphoma among Indian population. …

Prognostic significance of double expressor lymphoma subtype in patient with diffuse large B-cell lymphoma Hermawan Istiadi1*, Udadi Sadhana1, Dik Puspasari2, Ika Pawitra Miranti1, Vega Karlowee1, Devia Eka Listiana2, Awal Prasetyo1 Background: DLBCL is the most common type of non-Hodgkin lymphoma in Asia and Indonesia. DLBCL, based on cell of origin is divided into germinal center B-cell-like (GCB) and non-GCB subtypes. 20% of patients have a molecular profile double expressor lymphoma (DEL), which has a worse prognosis. The study aims to determine the relationship between DEL subtypes and cell of origin subtypes with clinical stage and 3-year overall survival of double large B-cell lymphoma (DLBCL) patients in Kariadi General Hospital Semarang. Methods: This study sample was 36 DLBCL patients in Kariadi General Hospital from January to September 2017. The data collection including age of diagnosis, location, stage, cell of origin subtype, DEL subtype and 3-year overall survival. Data analysis using chi-square test and Kaplan Meier curve. Results: DLBCL DEL subtype patients were significantly associated with advanced-stage (p: 0.028). DLBCL non-GCB subtype and DEL subtype patients had a 3-year overall survival that was significantly worse than GCB subtype and non-DEL subtypes (p: 0.026 and p: 0.006, respectively), with a 3-year survival rate of non-GCB subtypes was 38.9% and DEL subtypes were 33.3%. DLBCL patients with advanced stages also have a 3-year overall survival significantly worse than the early stage (p: 0.000), with a 3-year survival rate of 14.3%. Conclusion: DLBCL non-GCB subtype patients, DEL subtypes and advanced stages have a lower 3-year overall survival rate and thus have a worse prognosis.

Background Previous work has linked the inferior prognosis of patients with newly diagnosed large B cell lymphoma (LBCL) of activated B cell (ABC) cell of origin (COO) by gene expression profiling (GEP) with both double expressor (DE) features (PMID 23449635) and MCD genetic subtype (PMID 32289277 and 34739844). However, it is unknown whether these findings apply to LBCL tumors diagnosed in routine clinical practice, for which COO is typically assigned by immunohistochemistry (IHC) and genetic subtype based upon targeted next generation sequencing (NGS) panels. Methods We retrospectively compiled patients with newly diagnosed LBCL from multiple data sets (PMID 32780847, 30523716, and Hematological Oncology, 43: e180_70094). Inclusion criteria were cases with non-GCB COO by Hans algorithm, treatment with R-CHOP, known DE status (cutoffs MYC IHC ≥40% and BCL2 IHC ≥50%), known MYC rearrangement (MYC-R) status, calculable International Prognostic Index (IPI) score of <3 vs ≥3, available NGS data, and >12 months of follow-up without evidence of disease progression. MCD-like subtype by LymphPlex (PMID 37032379) and MYD88 subtype (PMID 34378195) were assigned based upon available variant data. Results Of 689 total cases, 218 met inclusion criteria and were analyzed. Baseline characteristics included IPI score ≥3 46%, MYC-R 6%, DE 43%, TP53 mutation 24%, any MYD88 mutation 31%, MYD88 L265P mutation 22%, PIM1 mutation 33%, ETV6 mutation 14% (tested in 83 cases), TBL1XR1 mutation 16% (tested in 83 cases), MCD-like subtype 16%, and MYD88 subtype 22%. Of note, for 138 cases for which COO was also reported by Lymph2Cx, 72% were assigned ABC, 9% GCB, and 19% unclassified. DE was associated with the presence of MYC-R (p=0.046), MCD-like subtype (p=0.09), and MYD88 subtype (p=0.02), but no other baseline characteristic. As was the case for DE, neither MCD-like nor MYD88 subtype were associated with IPI score. Neither MCD-like nor MYD88 subtype was associated with MYC-R, and MYD88 subtype was not associated with TP53 mutation (noting cases with TP53 mutation were assigned to an independent cohort by LymphPlex). For the entire cohort, with a median length of follow-up was 70 months (range 37-123 months across cohorts), the 3-year progression-free survival (3yPFS) was 65% (95% confidence interval [CI] 58-71%) and estimated 3-year overall survival (3yOS) was 71% (95% CI 64-77%). Inferior 3y PFS was associated with IPI score ≥3 (p<0.001), MYC-R (p=0.008), DE (p=0.002), TP53 mutation (p=0.07), MYD88 mutation (p=0.02), and MYD88 L265P mutation (p=0.004) by univariate analysis (UVA) with significance level p<0.10; however, only IPI score ≥3 (hazard ratio [HR] 2.2, 95% CI 1.4-3.5, p=0.001) and DE (HR 1.9, 95% CI 1.2-3.0, p=0.007) remained significant on multivariate analysis (MVA) with significance level p<0.05. On UVA, inferior 3yOS was associated with IPI score ≥3 (p<0.001), MYC-R (p=0.001), and DE (p<0.001), with all remaining significant on MVA: IPI score ≥3 (HR 3.1, 95% CI 1.8-5.4, p<0.001), DE (HR 2.3, 95% CI 1.4-3.9, p=0.002), and MYC-R (HR 2.3, 95% CI 1.1-5.0, p=0.03). For patients with vs without DE, 3yPFS was 53% (95% CI 42-62%) vs 74% (95% CI 65-81%) (p=0.001) and 3yOS 57% (95% CI 47-67%) vs 81% (95% CI 77-87%) (p<0.001). Finally, one cohort (PMID 30523716) reported genetic classification by LymphGen, in which 16% of cases were classified as MCD genetic subtype. Subgroup analysis of this cohort (n=122) revealed an association between DE and MCD genetic subtype by LymphGen (p<0.001). Additionally, MCD genetic subtype by LymphGen was associated with inferior 3yPFS on UVA (p=0.06), but not MVA (HR 1.4, 95% CI 0.7-2.7, p=0.32) when incorporating IPI score and DE, both of which remained significant. MCD genetic subtype by LymphGen was not significantly associated with 3yOS on UVA (p=0.20). Conclusions DE is a biomarker of inferior 3yPFS and 3yOS independent of IPI score or genomic features analyzed in this multi-national cohort of newly diagnosed non-GCB LBCL patients. MCD genetic subtype as well as genetic subtypes approximating MCD are associated with DE but are not independently prognostic in this patient population. These findings have implications for non-GCB LBCL patients diagnosed in routine clinical practice, and support further exploration of common molecular features that predict for chemoresistance, as well as evaluation of the efficacy of targeted therapies, in newly diagnosed non-GCB DE LBCL patients.

Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL). A distinct, high-risk subset-double expressor DLBCL shows immunohistochemical (IHC) co-expression of BCL2 and c-MYC. Objective To evaluate the clinicopathological spectrum and prognostic significance of double expressor DLBCL. Methods This retrospective study included 49 patients diagnosed with DLBCL over a four-year period at a tertiary care center. IHC analysis using a non-Hodgkin lymphoma panel was performed, and subtyping was done using the Hans algorithm to classify cases as germinal center B-cell-like (GCB) or non-germinal center B. Double expressor status was defined by IHC expression thresholds for BCL2 and c-MYC. Results Of the 49 cases, 27 (55.1%) were GCB and 22 (44.8%) were non-GCB. Twenty-three patients (46.9%) met criteria for double expressor DLBCL-11 GCB (47.8%) and 12 non-GCB (52.2%). Follow-up data from 27 patients revealed a significantly higher early mortality rate among double expressor cases, particularly within the first six months, suggesting an unfavorable prognosis. Histopathology showed diffuse effacement of lymph node architecture with proliferation of medium- to large-sized atypical lymphoid cells. Conclusion Double expressor DLBCL represents a clinically aggressive variant with a distinctly worse prognosis than DLBCL-not otherwise specified (NOS). Double expressor DLBCL poses a significant prognostic challenge within DLBCL-NOS and must be recognized as a key determinant in patient stratification and management.

Double-expressor diffuse large B-cell lymphoma (DLBCL) with 17p deletion is an aggressive and refractory disease. Immune checkpoint blockade and epigenetic drugs have been widely used, but the efficacy of different combined applications varied. We report a case with “double-expressor” DLBCL treated with a combined regimen which consisted of programmed cell death protein 1 (PD-1) inhibitor, DNA methyltransferase inhibitor (DNMTi), and histone deacetylase inhibitor (HDACi). A 50-year-old man presented with a 6-month history of hoarseness, and 10 days of progressive shortness of breath was diagnosed of DLBCL, stage IV. The patient failed to respond to the 1st line (R-EPOCH: rituximab, etoposide, vincristine, cyclophosphamide, doxorubicin, and dexamethasone), 2nd line (R-EPOCH + lenalidomide + ibrutinib), and a 3rd line chemotherapy combined with PD-1 inhibitor (sintilimab), decitabine, and GDP (gemcitabine, DDP, and dexamethasone). Surprisingly, patient's condition was improved after treatment with PD-1 inhibitor in combination with DNMTi/HDACi. Restaging PET revealed dramatically radiological response.

ObjectivesStandard treatment with a thiotepa-based regimen in countries with a limited resource is less feasible. Aims of the study were to evaluate the treatment outcome, and identify the prognostic factors in patients with primary central nervous system lymphoma (PCNSL).MethodsWe conducted a retrospective study of 43 patients diagnosed with PCNSL, DLBCL subtype, who were treated with either HDMTX-based regimen, whole brain radiotherapy (WBRT), or both between 2010 and 2017.ResultsThere were 43 patients with a median age of 65 years (range 34–89 years). Protein expression of CD10, Bcl6, MUM1, Bcl2 and MYC were found in 19, 86, 91, 91 and 23%, respectively. Both germinal center B cell (GCB) and double-expressor (MYC+/Bcl2+) lymphomas were found in 21%. Multiple brain lesions and maximum tumor diameter (MTD) ≥5 cm were seen in 27 and 10 patients, respectively. Chemotherapy combined with WBRT, chemotherapy and WBRT were given to 20, 14 and 9 patients, respectively. Overall complete remission (CR) rate was 55.8%. Those receiving a combined-modality therapy had a higher CR rate than those treated with either chemotherapy (75% versus 36%, p = 0.036) or WBRT (75% versus 44%, p = 0.109). Median follow-up time was 17 months, and a 7-year overall survival (OS) was 40%. Features associated with a prolonged OS were an ECOG score ≤ 2 (p = 0.001), multiple brain lesions (p = 0.010), multiple area of brain involvement (p = 0.023), MTD < 5 cm (p = 0.004), GCB subtype (p = 0.003) and positive CD10 staining (p = 0.007). Expression of Bcl2 protein was associated with a significantly worse OS in the non-GCB DLBCL patients.DiscussionThe factors affecting treatment outcomes in PCNSL were cell of origin of DLBCL, lesion characteristics, patients’ status and treatment regimen.

… -hit lymphomas are associated with significantly worse survival 12 … These double-expressor cases have not been assigned a … patients with double-hit and double-expressor lymphomas. …

Background. Central Nervous System (CNS) relapse is a rare and usually fatal event in diffuse large B-cell lymphoma (DLBCL). Prophylaxis of CNS relapse is currently based on high-dose methotrexate (HD MTX), a strategy associated with significant toxicity in elderly pts. Lenalidomide (LEN), an immunomodulatory agent, has shown activity in DLBCL, but also in association with rituximab in R/R PCNSL. In this analysis we explore the potential role of LEN given as maintenance for 2 years after R-CHOP to decrease the risk of CNS relapse Methods. The REMARC study is an international multicentre double-blind randomized phase III trial that assessed lenalidomide (LEN) maintenance therapy (n=323) versus placebo (PBO) (n=327) in 650 DLBCL patients aged 60-80, responding to R-CHOP (NCT01122472). CNS prophylaxis was permitted including either 4 intrathecal (IT) MTX; or 2 intraveinous (IV) HD MTX: MTX 1.5g/m² 3 weeks and 6 weeks after the D1 of the last cycle of R-CHOP. The primary objective was to analyze the CNS relapse risk comparing LEN and PBO arms. Secondary objectives were to determine the clinical and biological risk factors associated with the CNS relapse risk. Results . Median age was 68 (58-80), 392 pts (63%) had elevated LDH, 575 pts (89%) presented disseminated disease and 374 pts (60%) an elevated aaIPI (2-3). 333 pts (51%) received CNS prophylaxis during the R-CHOP induction phase. In LEN arm, 168 (52%) pts received a CNS prophylaxis: IT alone in 164 pts (98%) and HD MTX in 4 patients (2%). In PBO arm, 165 (50%) pts received a CNS prophylaxis with 160 pts (97%) with IT alone, 2 pts (1%) with HD MTX and 3 pts (2%) with both IT MTX and HD MTX. We retrospectively classified patients into groups of low- (n= 30, 5%), intermediate- (n= 377, 61%), and high-risk (n=215, 35%) CNS-IPI. MYC, MYC/BCL2, MYC/BCL2/BCL6 rearrangements were present in 10, 5 and 1 pts respectively. MYC expression alone, double expressor (DEL) (MYC/BLC2) were present in 79 pts (40%) and 71 pts (34%), respectively. 180 pts (46%) were GC, and 213 pts (54%) non-GC according to Hans score. Using Nanostring, 202 pts (50%) were classified GC-like DLBCL, 144 (36%) ABC-like DLBCL and 57 (14%) unclassified. With a median follow-up at 81.1 months, 274 (42%) patients presented a relapse. Among them, 22 pts presented a CNS relapse (3.4%). Median time for CNS relapse was 12.2 months (95%CI: 7-48) compared to 24 months (95%CI: 19-26) for relapse other than CNS. Median OS for the group with CNS relapse was 18 months (95%CI: 11-62) compared to 64 months (95%CI: 53-75) for the group with relapses other than CNS. Pts with a CNS relapse presented an aaIPI 2-3 and were classified as intermediate-risk (n=12, 54.5%) or high-risk CNS-IPI (n=10, 45.5%). Among them, 10/16 pts (63%) were ABC. MYC rearrangement, DHL and THL were not detected. DEL was found in 45% of data available patients. According to the maintenance arm, 16 CNS relapses (73%) occurred in LEN group and 6 (27%) in placebo group. Risk factors significantly associated with CNS relapses compared to no relapse were ABC profile (63% vs 28%, p=0.037), IPI 3-5 (91% vs 67%, p=0.028), and elevated LDH (38% vs 15%, p=0.012). Patients with high CNS-IPI were significantly associated with a worse PFS and OS in comparison with low-CNS-IPI (respectively HR=2.09, p = 0.035 and HR=2.70, p=0.032). In multivariable analysis, high CNS-IPI, age≥70, ABC profile assessed by NanoString and partial response at the end of R-CHOP were associated with poor OS. Conclusion LEN in maintenance for 2 years was not associated with a lower rate of CNS relapse. High CNS-IPI was confirmed as a poor prognosis factor for CNS-specific PFS, PFS and OS. The best strategy to decrease the risk of CNS relapses in DLBCL remains to be defined. Bernard: Janssen: Other: Travel and accommodation . Ghesquieres:Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; CELGENE: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria. Casasnovas:Amgen: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding. Gomes Da Silva:Janssen: Other: Travel and accommodation ; Abbvie: Other: Travel and accomodation ; Roche: Other: Travel and accommodation ; Gilead science: Other: travel and accomodation , Research Funding. Feugier:abbvie: Consultancy, Honoraria, Research Funding; roche: Consultancy, Honoraria, Research Funding; gilead: Consultancy, Honoraria, Research Funding; janssen: Consultancy, Honoraria, Research Funding; astrazeneca: Consultancy, Honoraria, Research Funding. Morschhauser:Genentech, Inc.: Consultancy; F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy. Trotman:F. Hoffmann-La Roche: Research Funding; PCYC: Research Funding; Celgene: Research Funding; Takeda: Research Funding; BeiGene: Research Funding. Greil:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Daiichi Sankyo, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Astra zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; MSD Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS/celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding. Caballero:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: travel; BMS: Other: travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel; Gilead: Other: travel; Roche: Other: travel. Haioun:Servier: Honoraria; Takeda: Honoraria; Miltenyi: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Thieblemont:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Bayer: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Hospira: Research Funding; Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).

Abstract High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements or both, commonly called double-hit lymphoma (DHL), is an aggressive B-cell lymphoma that is molecularly distinct from diffuse large B-cell lymphoma (DLBCL) and is associated with poor outcomes. Recent advances in the molecular classification of DLBCL have identified distinct subsets, including genetic signatures which correlate with DHL and survival. DHL with concomitant TP53 mutation appears to be associated with a very poor prognosis. Standard chemo-immunotherapy is not an effective treatment for these patients and personalized, innovative strategies are needed. In this review, we summarize recent advances in the subclassification of DLBCL, with a focus on DHL. We also incorporate early, promising clinical trial data using CAR T and targeted therapies. Rationally designed clinical trials for DLBCL are needed to advance the care of patients with DHL and other adverse risk DLBCL subgroups.

Introduction: Preclinical data have suggested that B-cell receptor-associated genes are upregulated in diffuse large B cell lymphoma (DLBCL) with increased expression of MYC protein, as well as MYC and BCL2 protein, also known as "double expressor" lymphoma (DEL) (Am J Surg Pathol. 2017 Apr;41(4):541-549 and PLoS One. 2017 Feb 17;12(2):e0172364). Patients (pts) with DEL respond poorly to cytotoxic chemotherapy; thus novel treatment approaches are needed for this disease. Here, we report outcomes of pts with relapsed/refractory (R/R) DLBCL and high grade B cell lymphoma (HGBL) treated with ibrutinib (ibr) monotherapy. Methods: Pts analyzed were those with R/R DLBCL or HGBL treated with ibr monotherapy at University of Pennsylvania, Ohio State University or Cleveland Clinic with immunohistochemical (IHC) stains for MYC and BCL2 from the tissue specimen obtained most recently prior to initiation of ibr available for hematopatholoigst (HP) review, and determined to have IHC scores of ≥40% for MYC and ≥50% for BCL2, meeting criteria for definition of DEL. Exclusion criteria were HIV positivity, post-transplant lymphoproliferative disorder, prior chronic lymphocytic leukemia and inadequate data. All available IHC stains for MYC and BCL2 were scored as positive or negative as per the aforementioned cutoffs by a HP at the treating center (HP1) as well as a second HP at one of the other centers (HP2) through review of digital slide images. In cases of disagreement, the score assigned in the clinical pathology report (CPR) was used as a tiebreaker. Progression free survival (PFS) was defined as the interval between time of initiation of ibr and documented disease progression, change in therapy (tx) if no disease response or last follow-up in remission, and overall survival (OS) between time of initiation of ibr and death or last follow-up while alive. Data were censored on 7/1/18. Results: Twenty-five cases with IHC stains for MYC and BCL2 were reviewed, with 19 meeting criteria for DEL which were included in the analysis. Clinicopathologic characteristics at time of ibr initiation were median age 69 years, 32% female, 63% stage III-IV, 74% elevated LDH, 11% bone marrow (BM) involvement, 11% B symptoms present, 21% extranodal (EN) disease at >1 site, 32% ECOG performance status (PS) >1, 58% with International Prognostic Index score (IPI)≥3, 26% HGBL, median Ki67 80% and 21% germinal center (GCB) cell of origin (COO) by Hans algorithm. Of pts with available fluorescence in situ hybridization (FISH) data, 50% (7/14), 25% (3/12) and 14% (1/7) demonstrated MYC, BCL2 and BCL6 rearrangements, respectively, and 3 pts were known to be double hit lymphoma. First-line tx was R-EPOCH in 26% and R-CHOP in 74%. Autologous stem cell transplantation was received by 42% prior to treatment with ibr. The proportion of pts receiving ibr as 2nd, 3rd, 4th and ≥5th line of tx was 21%, 37%, 21% and 21%, respectively. The time from initiation of the prior line of tx to initiation of ibr was <6 months (mo), 6-12 mo and >12 mo in 79%, 16% and 5%, respectively. Overall response to ibr was 47% (37% complete response and 10% partial response) and 5% with stable disease. All responses were seen in pts with non-GCB COO. The median PFS was 4.7 mo, median OS 5.5 mo and median duration of response 4.2 mo. For all cases reviewed (n=25), MYC IHC was scored by HP1 and HP2 and available in the CPR in 100%, 84% and 88%, respectively, and BCL2 IHC in 100%, 84% and 100%, respectively. Rates of concordance and kappa (κ) coefficient were as follows: HP1 and HP2 for MYC 85.7% (κ=0.49), BCL2 95.2% (κ=0.64) and DEL 84.0% (κ=0.61); HP1 and CPR for MYC 86.3% (κ=0.70), BCL2 96.0% (κ=0.78) and DEL 81.8% (κ=0.62); HP2 and CPR for MYC 66.7% (κ=0.18), BCL2 90.5% (κ=0.45) and DEL 68.2% (κ=0.34). In 4 cases with disagreement between HP1 and HP2 regarding DEL status, the CPR agreed with HP1, and 4 cases were identified as DEL by both HP1 and HP2 but not by CPR. Conclusion: An objective response to ibr was experienced by nearly half of pts with R/R DEL as defined by multicenter HP review in this series. Our data suggest a potential benefit to the use of ibr monotherapy as bridging tx to curative-intent cellular tx, as well as support the incorporation of ibr into clinical trials for the R/R DEL pt population. A relatively high rate of concordance between HP1 and CPR in identifying cases of DEL suggests that local review of MYC and BCL2 IHC may be a reasonable alternative for determining DEL status when central review is infeasible. Landsburg: Curis, INC: Consultancy, Research Funding; Takeda: Research Funding. Maddocks:Novartis: Research Funding; Pharmacyclics/Janssen: Honoraria; BMS: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; AstraZeneca: Honoraria; Teva: Honoraria. Hill:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dwivedy Nasta:Incyte: Research Funding; Merck: Other: DSMC; Pharmacyclics: Research Funding; Aileron: Research Funding; Roche: Research Funding; Takeda/Millenium: Research Funding; Rafael/WF: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Debiopharm: Research Funding. Svoboda:Regeneron: Research Funding; TG Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Pharmacyclics: Consultancy, Research Funding; KITE: Consultancy; Kyowa: Consultancy. Schuster:Physician's Education Source, LLC: Honoraria; Dava Oncology: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; OncLive: Honoraria; Genentech: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: Primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) is a rare subtype of non-Hodgkin lymphoma that specifically affects the brain, spinal cord, or cerebrospinal fluid, without involving other body parts. Currently, multi-drug chemotherapy, including high-dose methotrexate therapy, is the preferred first-line treatment for PCNS-DLBCL, regardless of age. However, treatment-associated adverse events are a significant concern that cannot be ignored. Aims: To reduce the incidence of treatment-associated adverse events in PCNS-DLBCL patients, we developed a regimen combining tislelizumab, zanubrutinib, and high-dose methotrexate (TZM). This study aims to assess the clinical efficacy and therapeutic tolerance of the TZM regimen in PCNS-DLBCL patients by systematically analyzing the response rates and adverse events in thirty-three patients treated with the TZM regimen. Methods: Newly diagnosed PCNS-DLBCL patients aged 18 to 90 years were enrolled from multiple centers in China between May 2022 and May 2024. Clinical information, objective response rates, and adverse events were collected. The TZM regimen details are as follows: Tislelizumab (200 mg) and high-dose methotrexate (3.5 g/m²) were administered intravenously on the first and second day of each 21-day cycle, respectively. Zanubrutinib (160 mg) was taken orally twice a day until two years after the sixth cycle of TZM treatment. All patients signed an informed consent form before participating in the clinical trial. Results: Thirty-three newly diagnosed PCNS-DLBCL patients, with a median age of 68 years (range 42-82 years), were enrolled. The male-to-female ratio was 2:1. Based on the IELSG risk score, 36.4% were assigned to the low-risk group, while 63.6% were in the intermediate or high-risk groups. The white blood cell, hemoglobin, and platelet counts were normal in all patients at enrollment. Most patients had normal levels of lactic dehydrogenase and β2 microglobulin, with only six and four patients showing abnormal results, respectively. The MYD88L265P gene mutation was detected in 81.8% of patients, and 90.9% were classified as non-GCB based on the Hans algorithm. Additionally, 45.5% of patients were diagnosed with double-expressor lymphoma, and 42.4% had a TP53 gene mutation. Among the patients, 32 completed at least two cycles of the TZM regimen, with an objective response rate (ORR) of 100% and a complete response rate (CRR) of 9.1% after two cycles. Twenty-two patients completed six cycles, achieving an ORR of 100% and a CRR of 81.8%. As of July 2024, the median follow-up time was 13 months (range 2-26 months). All patients were alive except for a 73-year-old male who died one week after the second cycle due to severe infection. Adverse events were generally mild, with six patients experiencing grade 3 or greater toxicities (four cases of acute renal failure, one case of rash, and one case of autoimmune liver dysfunction). Conclusion: The combination of tislelizumab, zanubrutinib, and methotrexate (TZM) shows promise as a treatment for PCNS-DLBCL, demonstrating high response rates and good tolerability, despite the limited sample size. This clinical trial is ongoing to further validate these findings (Clinical Trials No. ChiCTR2300071346).

Approximately 15% of patients with diffuse large B‐cell lymphoma (DLBCL) experience refractory or early relapsed disease after initial rituximab‐containing chemoimmunotherapy is regarded as a primary refractory disease. Although the standard treatment for relapsed DLBCL is high‐dose chemotherapy and autologous stem cell transplantation (HDC‐ASCT), the efficacy of this approach for primary refractory DLBCL is not well understood. We aimed to investigate the clinicopathological characteristics and outcomes of patients with primary refractory DLBCL.

Background: The Phase III POLARIX study reported improved progression-free survival (PFS) of polatuzumab vedotin (Pola) in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP) compared with rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in patients with previously untreated, intermediate- or high-risk DLBCL (Tilly et al. NEJM 2022). Following regulatory approvals, Pola-R-CHP has become a new standard of care therapy for first-line (1L) DLBCL globally, including in the US. Real-world evidence on the use of Pola-R-CHP in the US has been limited and has primarily included patients treated at academic cancer centers only, demonstrating that Pola-R-CHP has a manageable safety profile and is effective (with robust response rates and high survival rates) in patients with previously untreated DLBCL (Iyengar et al. ASH 2024; Thiruvengadam et al. EHA 2025; Thiruvengadam et al. ICML 2025). This study aimed to describe patient characteristics, treatment patterns, effectiveness, and safety of Pola-R-CHP in patients with previously untreated DLBCL in the US, including representation of patients from community cancer centers. Methods: This study used the electronic health record (EHR)-derived, US nationwide, de-identified real-world Flatiron Health Research Database. Data were abstracted from structured (e.g. treatment administration) and unstructured (e.g. clinical notes, radiology/pathology reports) parts of the EHR. Patients diagnosed with non-Hodgkin lymphoma, with ≥2 documented clinic visits and evidence of DLBCL within the EHR, and who had initiated 1L Pola-R-CHP between January 1, 2023 and April 30, 2025, were included. Efficacy was described using PFS, time to next treatment or death (TTNT-D), and overall survival (OS). Disease progression was assessed using the earliest evidence from radiography/pathology reports, physical exams, or other clinical evidence. Rates of pre-selected safety events documented in the EHR during 1L Pola-R-CHP treatment were described. Reasons for discontinuation of Pola were also abstracted from the EHR (available up to a cutoff date of February 28, 2025). Summary statistics and Kaplan-Meier estimates based on non-missing data were provided. Results: The study included 216 patients treated with 1L Pola-R-CHP. Median age was 70 years (range 21–85), 14% were aged ≥80 years, 42% were female, 83% were White, and 65% had an International Prognostic Index risk score of ≥2. Additionally, most patients (91%) had DLBCL not otherwise specified, 12% had DLBCL transformed from a prior indolent malignancy, 7% had double-hit lymphoma, and 30% had double-expressor lymphoma. The proportion of patients that had a cell of origin of germinal center B-cell (GCB) and non-GCB were similar (41% and 40%, respectively). Overall, 76% of patients received care from a community setting, 66% had commercial insurance, and 30% had a low socioeconomic status score (SES) of 1 or 2 (i.e. 30% of patients were in the lowest two SES quintiles). Median follow-up was 10 months. In terms of patient disposition, 81% of patients were in ongoing follow-up (with no documented second-line [2L] therapy), 12% had documented 2L therapy, and 7% had died with no documented 2L therapy. Median number of cycles for Pola-R-CHP was 6 (range 1–14); 63% had completed ≥6 cycles. Median PFS, TTNT-D, and OS were not reached. Event-free survival rates for PFS, TTNT-D, and OS were 92%, 87%, and 92% at 6 months, and 83%, 77%, and 87% at 12 months, respectively. Time-to-event estimates were consistent between the overall cohort, in patients with ≥6 months of follow-up (n=160), and in patients with ≥12 months of follow-up (n=111). Time-to-event estimates were also similar between subgroups of SES scores (1–2 vs 3–5) and cell of origin (GCB vs non-GCB). Among 139 patients with available data, 84% completed therapy and 7% discontinued Pola due to toxicity. Other reasons for discontinuation of Pola included progression, withdrawal by patient, and unrelated medical issues. Safety events after initiation of Pola-R-CHP included nausea/vomiting (39%), neutropenia (36%), diarrhea (35%), anemia (31%), and peripheral neuropathy (9%). Conclusions: This study adds to the evidence for the effectiveness of Pola-R-CHP as a standard of care therapy in clinical practice for patients with previously untreated DLBCL primarily originating from community cancer centers in the US.

… B-cell lymphoma after first-line immunochemotherapy with … -2 inhibitor approved for the treatment of chronic lymphocytic … Bcl-2 expression; double-expressor lymphoma (with high Myc …

The standard first-line R-CHOP regimen achieves cure in only approximately 50% of patients. Polatuzumab vedotin (Pola) is a novel antibody-drug conjugate targeting the B-cell receptor component CD79b; however, evidence regarding its real-world efficacy remains relatively limited. This retrospective study aims to evaluate the clinical efficacy of Pola in combination therapy. A retrospective analysis was conducted on 140 patients with complete clinical records treated at the Affiliated Hospital of Qingdao University between September 2022 and September 2025. Among them, 114 patients received combination regimens containing Pola, while 26 patients received regimens without Pola. Given the limited follow-up duration, this study primarily assessed interim efficacy, with preliminary survival data also reported. Among the 140 eligible patients, 4 deaths and 20 disease progressions occurred. The age range was 23–91, with a median age of 67; 45.0% were female. An ECOG performance status ≥2 was observed in 16.4% of patients, and 20.7% presented with B symptoms. Elevated LDH levels were found in 57.9% of patients. Ann Arbor stage III or IV disease was present in 65.0% of patients, and an IPI score >2 was recorded in 50.7%. Double-expressor lymphoma was diagnosed in 40.0% of cases. Bone marrow involvement was detected in 20.0% of patients, while 83.6% had lymph node extracapsular extension. Immunohistochemistry staining showed 36 patients (25.7%) with GCB subtype and 99 patients (70.7%) with non-GCB subtype. Median follow-up was 11 months (95% CI: 10.85–13.15). The objective response rate (ORR) was 94.4% in the Pola group and 70.0% in the non-Pola group (OR = 7.1, 95% CI: 2.0–27.2, P<0.001). Complete remission (CR) rates were 53.7% and 20.0%, respectively (OR = 4.6, 95% CI: 1.7–14.9, P = 0.002). The Pola group showed a statistically significant advantage in progression-free survival (PFS). Six-month PFS rates were 90.4% (95% CI: 84.8%–96.3%) for the Pola group and 76.9% (95% CI: 62.3%–94.9%) for the non-Pola group, while 12-month PFS rates were 87.2% (95% CI: 80.5%–94.6%) and 67.9% (95% CI: 51.7%–89.2%), respectively. Combination regimens containing Polatuzumab vedotin demonstrated a marked interim efficacy advantage, which may translate into potential long-term survival benefits.

… Estimates of rates of local recurrence, distant recurrence, PFS, and overall survival (OS) were calculated using the Kaplan Meier method from the completion of first-line systemic therapy…

Abstract Monomorphic post-transplant lymphoproliferative disorder (M-PTLD) occurring after solid organ transplant histologically resembles aggressive non-Hodgkin lymphomas, with diffuse large B-cell lymphoma being the most common. In a cohort of 40 patients with DLBCL-type M-PTLD, inferior progression free survival (PFS) was observed for Revised International Prognostic Index (R-IPI) >2 (p = 0.01) and high-risk pathologic features (p = 0.02), defined by double expressor lymphoma, MYC rearrangement, or increased copy number of either MYC or BCL2. Overall survival (OS) was inferior in R-IPI >2 (p = 0.002) and high-risk pathologic features (p = 0.003). Combining both R-IPI >2 and high-risk pathologic features resulted in well-delineated good, intermediate, and poor risk groups of DLBCL-type M-PTLD with respect to both PFS and OS (p < 0.001). Our results demonstrate a prognostic role for both the R-IPI score and presence of high-risk pathologic features in DLBCL-type M-PTLD.

ABSTRACT Introduction: Secondary central nervous system lymphoma (SCNSL) is a potentially fatal event in the setting of aggressive Non-Hodgkin Lymphomas. Nowadays, despite of the very poor outcome of SCNSL, several studies are going to identify the high-risk patients’ subgroup that could early develop this detrimental event and in whom the central nervous system (CNS) prophylaxis could improve survival. Areas covered: Herein, the authors will review the prophylactic and treatment strategy for SCNSL, focusing on the identification of high-risk subgroup. Expert opinion: The validated CNS International Prognostic Index score lacks sensitivity. The role of prophylaxis has been suggested as an important step for selected patients. Intrathecal prophylaxis is always less consolidated, due to its doubtful efficacy, whereas systemic high-dose methotrexate is becoming the favored option to reduce CNS relapse in high-risk aggressive lymphomas. However, there is no a clear guideline to help physicians in clinical practice. The encouraging results on treatment of primary CNS lymphoma prompted new therapeutic strategies for SCNSL, although larger and randomized prospective studies are needed. Future efforts should be addressed to better clarify these open questions.

… According to immunohistochemistry, a non‐germinal center phenotype was shown in 24% and 52% patients had doubleexpressor profile. Patients received R‐CHOP (71%) or R‐…

Background: For LS-DLBCL, clinical trials (FLYER, LYSA/GOELAMS 02-03, LYSA LNH09-1B, S1001) have shown that 4 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP4) without radiation (RT) leads to durable remissions in >90% of cases. However, only patients (pts) with non-bulky disease and/or international prognostic index (IPI) of 0 and complete metabolic response (CMR) on interim positron emission tomography (PET) scan, if performed, were eligible for RCHOP4 alone in these studies. Outcomes in trial-ineligible LS-DLBCL and the appropriate real-world candidates for RCHOP4 are still undefined. Methods: We conducted a multicenter retrospective study of adult pts with stage I/II DLBCL of any tumor bulk, IPI and with or without B-symptoms diagnosed after 2011 and treated with RCHOP4 +/- 2 cycles R from 21 U.S. centers. Pts with PMBCL, PTLD or receiving non-standard dose RCHOP for cycle (C) 1 or planned consolidative RT were excluded. The primary endpoint was PFS from C1 by Kaplan-Meier method, not counting indolent lymphoma relapse. Event free survival (EFS) was time to next therapy without progression (including unplanned RT for non-CR), progression or death. A competing risks analysis of non-relapse mortality (NRM) vs. DLBCL progression was performed. Results: The characteristics of the 428 pts were: median age 60 (18-88), 60% male, 11% Hispanic and 4% non-Hispanic Black, 62% stage I, 15% elevated LDH, 3% ECOG PS>1, 5% tumor bulk >7cm, 9% had B-symptoms and median Charlson Comorbidity Index (CCI) was 4 (2-12). IPI was 0, 1 and 2-3 in 42%, 46% and 12% and stage-modified IPI (smIPI) was 0, 1, 2 and 3-4 in 25%, 48%, 21% and 6% of pts. 66% had nodal (59% head/neck, 11% pelvic, 9% multiple above diaphragm, 7% abdominal) and 46% extranodal sites (37% head/neck, 20% gastric/intestinal, 9% spleen, 8% skin/soft tissue); 6% had transformed/concurrent FL/MZL or grade 3B FL, 33% (138/408) were non-GCB cell of origin (COO), 25% (90/357) double expressor (DEL) and 0.5% (2/379) double-hit. 13% had completely resected disease, 97% staging PET and 47% bone marrow biopsy. Median diagnosis to treatment interval was 30 days (IQR 20-43), 6% had dose reductions after C1, 77% had an interim PET (iPET) after C2 (33%) or C3 (67%), 15% received 2 additional cycles R and 4% CNS prophylaxis. CMR rates by iPET were 83% after C2 and 94% after C3, and 95% by end-of-treatment PET. iPET PMR was more likely if smIPI>2 or bulky disease. Median follow-up time was 2.7 years. There were 32 progression events: 14 occurred at the primary site and 17 at distant sites (1 unknown), and 12 occurred after 2 years. Another 11 pts received unplanned RT after RCHOP4 for non-CR. There were 24 deaths, 12 without prior progression. Cause of death was DLBCL in 7 and non-DLBCL in 17 cases (6 infection, 2 ILD, 2 heart failure, 2 second cancer, 1 seizure, 4 unknown). EFS, PFS and OS rates were 88%, 90% and 96% at 3 years. By univariable Cox regression, Black race, elevated LDH, smIPI>2, DEL, increasing CCI, multiple subdiaphragmatic nodal sites and iPET PMR were associated with worse PFS. Non-significant variables of note included COO, extranodal sites, complete resection, missing bone marrow biopsy, missing iPET and additional cycles R. By multivariable analysis (including age>60, stage, ECOG PS>1, elevated LDH, bulky disease, CCI, B-symptoms and DEL), ECOG PS>1 (HR 3.95 p=0.050), CCI (HR 1.29 p=0.003) and DEL (HR 2.02 p=0.069) were associated with worse PFS. Cumulative incidence of DLBCL progression and NRM were 8% and 2% at 3 years. Competing risk analysis by univariable models found that age>60, ECOG PS>1, smIPI>2, elevated LDH, CCI and bulky disease were associated with NRM, while DEL and B-symptoms were associated with DLBCL progression.Conclusion: Presented is the largest retrospective cohort of LS-DLBCL treated uniformly with RCHOP4 to date. Despite modest follow-up time and lack of an “intention-to-treat“ population, this study shows that abbreviated RCHOP4 leads to excellent outcomes in the real-world, albeit with continuous risk of late relapse. smIPI risk factors were associated with worse PFS, though this may in part be driven by risk of non-lymphoma death. As pts with advanced age, poor performance status or comorbidities may benefit from reduced treatment exposure, RCHOP4 should still be considered for these and other “trial-ineligible” pts, particularly if other high-risk features (iPET PMR, DEL or B-symptoms) are absent.

PURPOSE Alliance/CALGB 50303 (NCT00118209), an intergroup, phase III study, compared dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as frontline therapy for diffuse large B-cell lymphoma. PATIENTS AND METHODS Patients received six cycles of DA-EPOCH-R or R-CHOP. The primary objective was progression-free survival (PFS); secondary clinical objectives included response rate, overall survival (OS), and safety. RESULTS Between 2005 and 2013, 524 patients were registered; 491 eligible patients were included in the final analysis. Most patients (74%) had stage III or IV disease; International Prognostic Index (IPI) risk groups included 26% IPI 0 to 1, 37% IPI 2, 25% IPI 3, and 12% IPI 4 to 5. At a median follow-up of 5 years, PFS was not statistically different between the arms (hazard ratio, 0.93; 95% CI, 0.68 to 1.27; P = .65), with a 2-year PFS rate of 78.9% (95% CI, 73.8% to 84.2%) for DA-EPOCH-R and 75.5% (95% CI, 70.2% to 81.1%) for R-CHOP. OS was not different (hazard ratio, 1.09; 95% CI, 0.75 to 1.59; P = .64), with a 2-year OS rate of 86.5% (95% CI, 82.3% to 91%) for DA-EPOCH-R and 85.7% (95% CI, 81.4% to 90.2%) for R-CHOP. Grade 3 and 4 adverse events were more common ( P < .001) in the DA-EPOCH-R arm than the R-CHOP arm, including infection (16.9% v 10.7%, respectively), febrile neutropenia (35.0% v 17.7%, respectively), mucositis (8.4% v 2.1%, respectively), and neuropathy (18.6% v 3.3%, respectively). Five treatment-related deaths (2.1%) occurred in each arm. CONCLUSION In the 50303 study population, the more intensive, infusional DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP. The more favorable results with R-CHOP compared with historical controls suggest a potential patient selection bias and may preclude generalizability of results to specific risk subgroups.

The revised WHO classification moved all aggressive B‐cell lymphomas with a MYC translocation and a concurrent translocation of BCL2 and/or BCL6 into a single diagnostic category. These are the double‐ and triple‐hit lymphomas. These represent a group with typically a poor outcome to conventional therapy, and as a result, intensification of immunochemotherapy has been explored. The optimal approach is far from clear, and recent insight into the biology suggest that they may represent just a subgroup of molecular high‐grade B‐cell lymphomas that maybe identified by gene expression profiling. There are a number of novel therapeutic approaches under investigation.

MYC, as a powerful transcription factor, plays a vital role in various cancers. The clinical significance of MYC alterations in diffuse large B-cell lymphoma (DLBCL) has been investigated for a long time. In this study, we comprehensively summarize the different alterations of MYC in DLBCL, including MYC overexpression, MYC translocations, MYC mutations, and increased gene copy number of MYC. Noteworthy, lone MYC overexpression or MYC translocation is not significantly associated with poor clinical outcomes, and their detrimental effects depend on the genetic alterations of BCL2 or BCL6. Both double-expressor DLBCL (DE-DLBCL), defined as overexpression of MYC and BCL2 proteins, and double-hit lymphoma (DHL), defined as a dual translocation of MYC together with BCL2 or BCL6, represent the distinct subgroups of DLBCL with inferior clinical outcomes. The mechanism may be that MYC activation induces cell proliferation, without the threat of the apoptotic brake in the presence of BCL2 overexpression. In addition, most of MYC mutations are present with favorable prognosis, and the nonsignificant effect of MYC copy number amplification has been observed. It has been proved that cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab show limited effects for DHL or DE-DLBCL, and the rituximab plus dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin seem to be efficacious for DHL. The novel therapy is urgently needed for clinical improvement in DHL and DE-DLBCL.

received 20 Gy of irradiation for an intramedullary lesion at C3 of the cervical spinal cord. In addition, we initiated salvage therapy with polatuzumab vedotin (1.8 mg/kg) and bendamustine (90mg/m 2 ). After three cycles of Pola-B,

… -hit lymphomas (approximately 5% to 10% of patients) and double-expressor lymphomas, … Off study, the use of R-EPOCH induction (including central nervous system prophylaxis) is a …

BACKGROUND Managing double-expressor lymphomas (DEL) is controversial given the dearth of data and lack of standardized guidelines on this high-risk subset of lymphomas. No prospective and few retrospective studies limited by either their sample size or short follow-up address the question of initial treatment of choice for DEL. We performed the largest analysis to date exploring R-CHOP vs DA-EPOCH-R in DEL. METHODS Adults with DEL diagnosed from 6/2012-2/2021 at 4 unique sites were retrospectively analyzed. Progression-free survival (PFS) was the primary endpoint. Key secondary endpoints include overall survival (OS), overall and complete response rates (ORR and CRR), cumulative incidence of relapse, and autologous hematopoietic cell transplantation (autoHCT) utilization. RESULTS 155 patients were included, 61 treated with R-CHOP and 94 with DA-EPOCH-R. 3-year PFS and OS were similar between R-CHOP and DA-EPOCH-R, 33.2% vs 57.2%,(P = .063), and 72.2% vs 71.6% (P = .43) after median follow-up times of 2.43 and 2.89 years, respectively. Patients <65 had improved PFS with DA-EPOCH-R, hazard ratio 0.41 (P = .01). CRR and ORR rates were also similar. Relapse rates were not statistically different, 51.9% vs 28.6% (P = .069). AutoHCT utilization was higher with R-CHOP vs DA-EPOCH-R, 23.0% vs 8.5% (P = .017). CONCLUSIONS Our findings do not support the use of DA-EPOCH-R over R-CHOP for DEL. Patients <65 years may experience longer PFS with DA-EPOCH-R, but limitations to the analysis make this interpretation difficult.

To evaluate the efficacy and safety of the Bruton tyrosine kinase (BTK) inhibitor zanubrutinib in combination with salvage chemotherapy in patients with relapsed or refractory double-expressor diffuse large B-cell lymphoma (R/R DE-DLBCL). We performed a retrospective analysis of 35 patients with R/R DE-DLBCL treated at two hematology centers from June 2021 to June 2024. All patients received zanubrutinib combined with one of several salvage regimens, including zR-MINE, zR-DHAP, zR-GemOx, or zR2. Endpoints included objective response rate (ORR), complete response rate (CRR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). The median age was 60 years, and 91.4% of patients had the non-germinal center B-cell (non-GCB) subtype. At the end of therapy, the ORR and CRR were 45.7% (16/35) and 42.9% (15/35), respectively. After a median follow-up of 33.0 months, median PFS and OS were 8.0 and 12.0 months, respectively. Relapsed patients achieved a significantly higher CRR than refractory patients (56.5% vs. 16.7%, p = 0.034). On multivariate analysis, longer duration of response to prior therapy was an independent protective factor for OS (HR 0.88, 95% CI 0.77–0.99; p = 0.041). Grade 3–4 hematologic AEs were mainly neutropenia (42.8%) and thrombocytopenia (14.3%). Pulmonary infection was the most common non-hematologic AE (34.3%), and overall toxicity was manageable. Zanubrutinib combined with salvage chemotherapy demonstrates clinically meaningful activity with a manageable safety profile in patients with R/R DE-DLBCL and may represent a therapeutic option for this high-risk population. Sensitivity analysis confirmed the robustness of the observed survival benefit.

To evaluate the efficacy and safety of CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy in patients with relapsed/refractory double-expressor diffuse large B-cell …

Background Relevant studies have demonstrated the poor treatment outcomes and prognosis for double-expressor diffuse large B cell lymphoma (DE-DLBCL) in the rituximab era. Zanubrutinib plus R-CHOP (rituximab, cyclophosphamide, doxorubicin/liposomal doxorubicin, vincristine, prednisone; ZR-CHOP) has shown efficacy in untreated non-GCB DLBCL patients with extranodal involvement. However, its efficacy in newly diagnosed DE-DLBCL remains uncertain. Objective This retrospective study sought to assess the efficacy and safety of ZR-CHOP in comparison to R-CHOP in treatment-naïve patients with DE-DLBCL. Method This study assessed 78 patients with newly diagnosed DE-DLBCL who were admitted between June 2017 and January 2024. Among them, 55 patients received the R-CHOP regimen, while 23 patients were treated with the ZR-CHOP regimen. The clinical characteristics were well balanced between the two groups. Results The complete response rates (CRR) were higher in the ZR-CHOP group than the R-CHOP group, regardless of whether patients completed 4 or 6 treatment cycles (P= 0.019; P= 0.025). ORR in the ZR-CHOP group showed a higher trend than that in the R-CHOP group (P= 0.624; P= 0.219). The median follow-up period was 23.3 months, and the predicted median progression free survival (PFS) in the R-CHOP group was 22.8 months, whereas the median PFS in the ZR-CHOP group was not reached. The 1-, 2-, and 3-year PFS rates in the ZR-CHOP group showed a beneficial trend compared with the R-CHOP group, but there was no statistical difference (P= 0.072). However, the PFS of the ZR-CHOP group was longer than that of the R-CHOP group in patients with Ki67 index >75% (P= 0.034) and p53 expression >50% (P= 0.0033). The predicted median overall survival (OS) in the ZR-CHOP and R-CHOP groups were not reached. The 1-, 2- and 3-year OS rates were not significantly different between the two groups (P= 0.29). The most common adverse event in both groups was hematotoxicity, but there was no significant difference in the incidence of all adverse events between the two groups. Conclusion First-line treatment with the ZR-CHOP regimen improved CRR in the untreated patients with DE-DLBCL and prolonged PFS in the Ki67 index >75% subgroup and the p53 expression >50% subgroup.