Double-expressor Lymphoma Research Articles

The Effect of Bcl-6 Expression on the Prognosis of Newly Treated Double-Expressing Lymphoma Treated with R-CHOP Regimen

To compare the treatment outcome and prognosis of the newly-treated myc+/bcl-2+/bcl-6- lymphoma (bcl-6- double-expression lymphoma, bcl-6- DEL) and myc+/bcl-2+/bcl-6+ co-expression lymphoma (bcl-6+ double-expression lymphoma, bcl-6+ DEL) patients treated by R-CHOP. 152 double-expression lymphoma patients (myc+/bcl-2+) treated in the Oncology Department of the First Affiliated Hospital of Zhengzhou University from September 2016 to June 2020 were selected. The short-term efficacy and long-term survival between the patients with bcl-6- DEL and bcl-6+ DEL was analyzed. The median age of 152 DEL patients was 60.5 years old (15-87 years old). 85 patients (55.9%) were Ann Arbor stage III/IV. There was no significant difference in clinical data between the patients in the two groups. Multivariate Cox regression analysis showed that bcl-6 expression, ECOG score, and stage were the independent prognostic factors for the entire group of DEL patients. There was no statistical difference in ORR between the patients in the two groups (χ2=0.749, P=0.387). Kaplan-Meier survival analysis showed that PFS and OS of the bcl-6+ DEL group were significantly higher than those in bcl-6- DEL group (PFS: χ2=6.095, P=0.014; OS: χ2=5.133, P=0.023). bcl-6+ is a good prognostic factor for DEL. The long-term curative effect of newly-treated bcl-6+ DEL patients treated by R-CHOP regimen is higher than those with bcl-6- DEL patients.

ZCL-082, a boron-containing compound, induces apoptosis of non-Hodgkin's lymphoma via targeting p90 ribosomal S6 kinase 1/NF-κB signaling pathway

IntroductionDespite the rapid progress in the diagnosis and treatment, the prognosis of some types of non-Hodgkin's lymphoma (NHL), especially those with double-hit or double-expressor genotypes, remains poor. Novel targets and compounds are needed to improve the prognosis of NHL. MethodsWe investigated the effect of ZCL-082, a novel boron-containing compound with anti-proliferating activity against ovarian cancer cells, on NHL cells and human peripheral blood mononuclear cells by CCK-8 assay, Annexin V/PI double staining assay, RH123/PI double staining, Western blot, and immunohistochemistry. NF-κB pathway activity was analyzed using luciferase reporter gene assay and RT-PCR. The location of p65 was detected by immunofluorescence and nuclear/cytoplasmic fractionation assay. Immunoprecipitation and chromatin immunoprecipitation assays were used to detect the binding between p65 and p300. CETSA and molecular docking assay were carried out to test the interaction between ZCL-082 and p90 ribosomal S6 kinase 1 (RSK1). Kinase reaction was conducted to examine the inhibition of RSK1 kinase activity by ZCL-082. ResultsWe found that ZCL-082 can induce the apoptosis of various NHL cell lines in vitro and in vivo. ZCL-082 significantly inhibits TNFα- or LPS-induced NF-κB activation without disturbing TNFα-induced IκBα degradation or the nuclear translocation and DNA-binding ability of p65. However, ZCL-082 markedly suppresses the phosphorylation of p65 on Ser536 and the interaction between p65 and p300. The overexpression of the phosphomimetic mutant of p65 at Ser536 partially abrogates ZCL-082-induced cell death. We further found that ZCL-082 directly binds to and inhibits the activity of RSK1. RSK1 can phosphorylate RelA/p65 on Ser536 and its overexpression is associated with the poor prognosis of lymphoma. The overexpression of RSK1 partially rescues ZCL-082-induced cell death. Molecular docking studies show that ZCL-082 fits well with the N-terminal kinase domain of RSK1. Furthermore, the combination of ZCL-082 and BCL-2 inhibitor ABT-199 has a synergistic apoptosis-inducing effect against double-hit lymphoma cell line OCI-Ly10. DiscussionWe found that ZCL-082 is a highly promising anti-lymphoma compound that targets RSK1 and interferes with the RSK1/NF-κB signaling pathway. The combination of ZCL-082 with BCL-2 inhibitor may represent a novel strategy to improve the outcome of double-hit or double-expressor lymphoma.

First-Line Treatment with R-CHOP Vs Dose-Adjusted R-EPOCH for Double-Expressor Lymphoma: A University of California Hematologic Malignancies Consortium Retrospective Analysis

First-Line Treatment with R-CHOP Vs Dose-Adjusted R-EPOCH for Double-Expressor Lymphoma: A University of California Hematologic Malignancies Consortium Retrospective Analysis

Frequency, Histologic, and Prognostic Significance of CD30 Expression in AIDS-associated Diffuse Large B-Cell Lymphoma

Introduction: AIDS-related Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, with a variable response to chemotherapy depending on, and not limited to, cell of origin, double/triple hit, or MYC/BCL-2 co-expression status. Similar to DLBCL, AIDS-related DLBCL (ARL) with non-germinal center histology or MYC expression reports poorer response to treatment. In the immunocompetent population CD30+ DLBCL defines a histology with improved survival, however, the characteristics and outcomes of ARL expressing CD30 are not well studied.Methods: We assessed 3 cohorts of ARL. The first cohort, consisted of of an immunohistochemistry tissue microarray (TMA) of 30 ARL patients, followed by two validation cohorts. The first validation was a TMA of 80 ARL, from the AIDS Cancer Specimen Resource. Both TMAs were stained for CD10, BCL6, MUM1, CD20, Ki67, EBER, MYC (by IHC) cut off at 40%, BCL2 (by IHC) cut off 50%, and CD30 (considered positive if any CD30 was expressed on the malignant cells). The third validation cohort was from the County Hospital AIDS Malignancy Project (CHAMP), a prospective database of patients with hematological malignancies and HIV. Of the 100 cases with ARL, only 25 cases were found to have CD30 staining performed, thus only those cases were included. In total, 135 patients diagnosed with ARL were assessed. Cell of origin and germinal (GCB) vs. non-germinal center (NGC) was determined by the Hans algorithm. Statistical differences between groups were analyzed by the fisher exact test. Survival data, when available, was estimated using the Kaplan-Meier method and compared using the log-rank test.Results: Of the 135 ARL, 30% (n=41) were CD30+. Ninety-one% of the cohort was male. EBER was 23% positive in the entire cohort (n=29/126). EBER was positive in the CD30+ vs. CD30- population, 59% (N=17) vs 26% (p<0.01). Despite 59% of the CD30+ population being EBER positive, 92% of the population had a NGC phenotype, 2% was germinal, and 5% had a null phenotype (p<0.01). Of the 86 patients that were CD30-, 88% were GC vs. 12% NGC (P<0.01). The CD4+ T-cell count at presentation was higher in the CD30- cohort with a mean CD4+ T-cell count of 234 vs.164 cells/ul (p<0.05), similar to historical studies demonstrating a similar effect in germinal vs. non-germinal center ARL. Ki67 > 80% was also higher in the CD30- vs the CD30+ cohort 75 vs.60%, (p=0.052). Myc, BCL2, and double expressor lymphomas were identified 59 vs. 57%, 59 vs. 57%, and 31 vs. 28%, respectively, in the CD30+ ARL vs. the CD30- population, none were statistically significant. Survival data was only obtained for 56 of the patients. In the patients treated in the combined anti-retroviral era (ART), there was no difference in survival in the CD30+ vs. CD30- population, 74% (n=18) vs. 84% (n=12) at 5 years (p=0.8). In the 15 patients treated in the early ART era, the OS at 5 years was 48% for the CD30+ vs. 52% (p=0.4), the rest were treated in the pre-ART era.Conclusion: CD30+ ARL in this cohort represents 30% of all ARL evaluated, and presents almost exclusively as a non-germinal center phenotype and has a strong correlation with EBV. While no differences in survival were identified in this study, possible due to the small numbers of patients assessed with survival data, historically, NGC ARL have been shown to have poorer outcomes, by 20-30% in studies with da-EPOCH. As such, the need for better therapies, potentially to overcome these poor prognostic factors, should be studied further. [Display omitted] DisclosuresReid: ADC Therapeutics: Other: Serves as Principle Investigator, Research Funding; Aptose Biosciences: Other: Serves as Principle Investigator, Research Funding; Millennium Pharmaceuticals: Other: Serves as Principle Investigator, Research Funding; Xencor: Other: Serves as Principle Investigator.

Practice Patterns Pre-CART for Aggressive B-Cell Lymphomas: Patient Selection and Real World Salvage and Bridging Practices

Practice Patterns Pre-CART for Aggressive B-Cell Lymphomas: Patient Selection and Real World Salvage and Bridging Practices

Significance of Single-cell Level Dual Expression of BCL2 and MYC Determined With Multiplex Immunohistochemistry in Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a fatal heterogenous neoplasm. Recent clinical trials have failed partly due to nebulous criteria for defining high-risk patients. Patients with double-expresser lymphoma (DEL) have a poor prognosis and are resistant to conventional treatment. However, many diagnostic and clinical controversies still surround DEL partly due to the arbitrariness of criteria for the diagnosis of DEL. In this study, we suggest a refined method for diagnosing DEL by evaluating the concurrent expression of BCL2 and MYC at the single-cell level (dual-protein-expressing lymphoma [DUEL]). For the proof of concept, a multiplex immunofluorescence assay for CD20, BCL2, and MYC was performed and quantitatively analyzed using spectral image analysis in patients. The analysis results and clinical applicability were verified by using dual-color immunohistochemistry performed on 353 independent multicenter patients who had been uniformly treated with standard therapy. DUEL showed significantly worse overall survival (OS) and event-free survival (EFS) (P=0.00011 and 0.00035, respectively). DUEL status remained an independent adverse prognostic variable with respect to the International Prognostic Index risk and the cell of origin. Moreover, the advantage of determining DUEL status by dual-color immunohistochemistry was shown by more robust classification and more homogeneous high-risk subgroup patient identification in both training (n=271) (OS: P<0.0001; EFS: P<0.0001) and validation sets (n=82) (OS: P=0.0087; EFS: P<0.0001). This concept of DUEL is more consistent with carcinogenesis and has greater practical utility, hence it may provide a better basis for both basic and clinical research for the development of new therapeutics.

Clinical characteristics and prognosis of 49 newly diagnosed primary central nervous system diffuse large B-cell lymphoma

目的回顾性分析原发中枢神经系统淋巴瘤中弥漫大B细胞淋巴瘤（PCNSL-DLBCL）患者的临床特征及不同治疗方案对患者生存及预后的影响。方法回顾性分析天津医科大学总医院自2014年7月至2020年12月收治的49例PCNSL-DLBCL患者的临床资料，根据治疗方案分为MTX组、R-CDOP组、BTKi-R-MTX组和RLZT组，计算各组中位总生存（OS）与无进展生存（PFS）时间，并进行单因素、多因素预后分析，比较各组患者的生存预后。结果MTX组、R-CDOP组、BTKi-R-MTX组和RLZT组的中位OS时间分别为16.5个月、4.5个月、42个月和未达到（P<0.001），中位PFS时间分别为7个月、1.5个月、20个月和5个月（P＝0.005）。多因素预后分析表明是否双表达、IESLG评分和治疗方案是PCNSL-DLBCL患者的预后影响因素。结论PCNSL-DLBCL患者的生存预后受治疗方案影响，CD20单抗在PCNSL-DLBCL 治疗中的作用尚有争议，含BTKi的治疗方案有巨大潜力，RLZT方案对于高龄、不耐受大剂量化疗及放疗患者有良好前景。

Treatment Outcomes and Clinical Relevance in Patients with Double Expressor DLBCL.

BackgroundDouble-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.MethodsA retrospective study of 291 patients diagnosed with DLBCL during January 2015 – December 2018 was conducted.ResultsOf 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.ConclusionsHigh 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.

Impact of initial chemotherapy regimen on outcomes for patients with double-expressor lymphoma: A multi-center analysis.

Diffuse large B-cell lymphoma featuring overexpression of MYC and B-Cell Lymphoma 2 (double expressor lymphoma, DEL) is associated with poor outcomes. Existing evidence suggesting improved outcomes for DEL with the use of more intensive regimens than R-CHOP is restricted to younger patients and based on limited evidence from low patient numbers. We retrospectively evaluated the impact of intensive frontline regimens versus R-CHOP in a multicenter analysis across 7 academic medical centers in the United States. We collected 90 cases of DEL, 46 out of 90 patients (51%) received R-CHOP and 44/90 (49%) received an intensive regimen, which was predominantly DA-EPOCH-R. Treatment cohorts were evenly balanced for demographics and disease characteristics, though the intensive group had a higher lactate dehydrogenase (LDH, 326 vs. 230 U/L p=0.06) and presence of B-symptoms (50% vs. 22%, p=0.01) compared to the R-CHOP cohort. There was no difference in PFS (median 53 vs. 38 months, p=0.49) or overall survival (67 vs. not reached months, p=0.14) between the R-CHOP and intensive therapy cohorts, respectively. On multivariate analysis, intensive therapy was associated with a hazard ratio of 2.35 (95% CI 0.74-7.41), though this was not statistically significant. Additionally, a subgroup analysis of intermediate high-risk lymphoma defined by IPI ≥3 did not identify a difference in survival outcomes between regimens. We conclude that in our multi-center cohort there is no evidence supporting the use of intensive regimens over R-CHOP, suggesting that R-CHOP remains the standard of care for treating DEL.

Dose-adjusted EPOCH and rituximab for the treatment of double expressor and double-hit diffuse large B-cell lymphoma: impact of TP53 mutations on clinical outcome

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.

Interim PET-CT Result Is Not Predictive of Survival in Patients with MYC-Rearranged Non-Burkitt Aggressive B Cell Lymphoma

Abstract Background Patients with a diagnosis of MYC-rearranged non–Burkitt aggressive B-cell lymphoma (MYC-R), including those with double hit lymphoma, are at high risk of developing relapsed/refractory disease, even if treated with intensive front-line immunochemotherapy. It is common in clinical practice and clinical trials to perform an interim positron emission tomography (PET)/computed tomography (CT) scan (iPET) during front-line therapy for diffuse large B-cell lymphoma. However, the utility of the iPET result for MYC-R patients for predicting outcomes is unclear. Patients and Methods We performed a single-center retrospective study with centralized pathologic review and PET/CT image acquisition and interpretation for 28 MYC-R patients. The patients received front-line therapy with R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone) or intensive immunochemotherapy. Results Eight patients had iPET-positive (iPET+) and 20 patients had iPET-negative (iPET−) results using the Deauville visual assessment criteria. At a median follow-up length of 30.4 months, progression-free survival was 65% and overall survival was 76%, neither of which differed significantly between the iPET− and iPET+ patients. The positive predictive value of iPET for progression at 30 months was 25%, and the negative predictive value was 65%. Conclusion Although patients with MYC-R lymphoma have been reported to be at high risk of primary treatment failure, this was not predicted by iPET+ results. Thus, the iPET result should not be used to guide changes in front-line or consolidative therapy for these patients.

Assessment of CD52 Expression in “Double-Hit” and “Double-Expressor” Lymphomas: Implications for Clinical Trial Eligibility

High-grade B-cell lymphomas (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements (i.e. “double/triple-hit lymphomas” [DHL/THL]) and the subset of diffuse large B-cell lymphomas (DLBCL) and HGBCL, not otherwise specified (NOS), with MYC and BCL2 protein over-expression (i.e. “double-expressor lymphomas” [DEL]) represent distinct subsets of mature B-cell lymphomas with aggressive clinical course, poor response to conventional chemotherapy and high relapse rates. Compared with other lymphoma subtypes, DHL exhibits a higher frequency of bone marrow (BM) involvement, which in turn is associated with adverse outcome. The BM microenvironment contributes to this negative prognostic impact by promoting chemoresistance through several mechanisms, including the inhibition of antibody-mediated phagocytosis by BM macrophages.The antibody-refractory nature of the BM microenvironment can be temporarily abrogated through the synergistic effects of high-dose cyclophosphamide (CTX), which inhibits secretion of prostaglandin E2 and induces secretion of IL8, TNFα, VEGF, and CCL4 by leukemic cells, resulting in macrophage recruitment, activation and phagocytosis (Pallasch, Cell 2014). The potential of this therapeutic strategy has recently been extended to human-derived xenografts taken from patients with relapsed/refractory DHL (Lossos, Blood 2016 [Abstract]). The humanized monoclonal antibody alemtuzumab (Campath) targets CD52, a GPI-linked glycoprotein frequently expressed by mature lymphocytes. The success of this agent in the proof-of-principle studies referenced above has provided inspiration for a new phase I clinical trial investigating the use of alemtuzumab and low-dose CTX for the treatment of DHL/THL and DEL (ID: NCT03132584).Previous studies have shown significant heterogeneity in CD52 expression by several of the more aggressive mature B-cell lymphomas (e.g. DLBCL, Burkitt lymphoma), with 25% of cases exhibiting negligible expression by immunohistochemistry (IHC) (Rodig, Clin Cancer Res 2006). As such studies predated our current conception of DHL/THL and DEL, the prevalence of CD52 expression within these newer diagnostic categories has remained speculative. To eliminate this knowledge gap and provide decision support for clinical trial enrollment, we assessed the frequency, intensity and uniformity of CD52 expression within 98 cases of DHL/THL and DEL. Our study included 35 DHL (25 with MYC and BCL2 rearrangements, 10 with MYC and BCL6 rearrangements), 5 THL (with MYC, BCL2 and BCL6 rearrangements), 7 HGBCL, NOS, with double-expressor phenotype, and 51 DLBCL, NOS, with double-expressor phenotype (17 of GCB origin, 34 of ABC origin).The majority of DHL/THL and DEL exhibited convincing cytoplasmic and/or membranous CD52 expression (75% in both groups). There was no significant difference in CD52 intensity (scored from 0-3) or predominant staining pattern (cytoplasmic vs. membranous) between DHL/THL and DEL, however DHL/THL were more likely to show uniform (vs. variable) staining [OR = 4.8; P = 0.0026]. Consistent with their predilection for BM, DHL were more likely to be derived from BM biopsies than DEL [OR = 12.1; P = 0.022], however the frequency of CD52 expression within BM specimens was not significantly different than those from other bodily locations. Assigned morphologic group (blastoid vs. DLBCL vs. DLBCL/BL) and the quantitative results of additional IHC studies (BCL2, MYC, Ki67) were similarly non-predictive of CD52 expression status. Within DHL, the presence of BCL2 versus BCL6 translocation had no bearing on CD52 expression, although there was a trend towards increased CD52 expression in the presence of BCL2 translocation [OR = 3.45; P = 0.099]. Among DLBCL with double-expressor phenotype, the Hans cell-of-origin classification (GCB vs. ABC) had no apparent impact on CD52 expression.In summary, our results indicate that CD52 is expressed by the majority of DHL/THL and DEL, suggesting that alemtuzumab-based therapy may be appropriate for most patients. Target validation must be performed on a case-by-case basis, however, as CD52 expression is not readily predicted by histomorphologic, immunophenotypic or cytogenetic findings. DisclosuresLaCasce:Forty Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Seattle Genetics: Consultancy, Research Funding.

Primary thyroid lymphoma with double expression of MYC and B-cell lymphoma-2 Gene

Primary lymphomas of the thyroid (PTLs) are rare entities. We report a case of high-grade B-cell lymphoma double hit (DH) ofthe thyroid gland with dual expression of MYC and BCL-2 gene in a 55-year-old woman. Most PTLs have a good prognosis tocombined modality treatment but identification of DH lymphomas or double-expressor lymphomas is important as these are resistant tochemotherapy and radiotherapy and pose a challenge for the treatment of the same.

Prognostic significance of double expressor lymphoma subtype in patient with diffuse large B-cell lymphoma

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

Clinicopathological features and MYD88 L265P mutation status of intravascular large B cell lymphoma

Objective: To study the clinicopathologic features and MYD88 L265P mutation status of intravascular large B cell lymphoma (IVLBCL). Methods: Fourteen cases of IVLBCLs were diagnosed from March 2014 to December 2019 at the First Affiliated Hospital of Zhengzhou University. The clinicopathologic features and prognosis were analyzed. Epstein-Barr virus encoded RNAs and MYD88 L265P mutation status were detected using in situ hybridization and Sanger sequencing, respectively. The follow-up data were obtained by telephone interview. Results: There were 6 males and 8 females with a median age of 62 years (range: 48-73 years). The involved anatomic locations were demonstrated by positron emission tomography-computed tomography, including adrenal gland (7/14), bone (6/14), central nerve system (4/14), skin (3/14), female reproductive system (3/14), local lymph nodes (3/14), prostate (2/14), liver and spleen (2/14), sphenoid sinus (1/14), penis (1/14), bladder (1/14), and right lung (1/14). Fever was the most common symptom (7/14), followed by neurologic symptoms and lower abdominal pain (2/14 each). The reminder symptoms included rash with edema, legs weakness and numbness, or postmenopausal bleeding (1/14 each). Eleven cases were at Lugano stage Ⅳ. Four cases were associated with the hemophagocytic syndrome, while 6 cases with bone marrow involved. Microscopically, the tumor cells were generally concentrated within the small-to-medium vascular lumens or sinusoids; they had centroblast-like appearance and showed large round or oval nuclei with slightly irregularities, coarse chromatin and 1-3 distinct nucleoli. One exception was the one case with an embryoid nuclei, reminiscent of anaplastic large cell lymphoma. The mitosis was not uncommon. Extravascular neoplastic cells were seen in two cases. The neutrophils could be appreciable in most of the cases (10/14). Immunophenotyping showed that CD20 and CD79α were diffusely and strongly positive in 14 cases; 12 cases were classified as the non-GCB subtype; 6 out of the 11 cases were double expressor lymphoma; 7 out of the 12 cases were CD5-positive. Twelve cases were EBER negative. The MYD88 L265P mutation was detected in 1 case (1/10). The duration of the follow-up ranged from 0.5 to 24.0 months, and 11 patients survived and 3 died. Conclusions: IVLBCL is rare. The most common type of IVLBCL in China is Asian type with scant tumor cells. Combination of clinical and immunohistochemical features can avoid most, if not all, misdiagnoses and missed diagnoses. Some IVLBCL cases may harbor the MYD88 L265P mutation, but the prevalence of MYD88 L265P mutation in the population still warrants additional studies.

Upregulation of fatty acid synthase in MYC and BCL-2 double-expressor lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common and heterogeneous lymphoid malignancy. The subtype with MYC and BCL-2 double-expressor lymphoma (DEL) was defined by its aggressive nature and poor survival outcome. Therefore, the development of effective therapies for the DEL subtype is imperative. Fatty acid synthase (FASN) activity is associated with altered lipid metabolism and aberrant protein translation in DLBCL. However, the inter-regulation of these key processes is not fully determined in DEL. In the present study, the clinical and biological impact of FASN was investigated in the DEL subtype. Initially, FASN expression levels were analyzed from a patient cohort and the data indicated that the highest FASN expression was noted in DEL tissues compared with that noted in the DLBCL and reactive lymphoid hyperplasia tissues. Patients with DEL with combined high-FASN expression indicated poorer EFS outcomes than the rest of the patients. In vitro data indicated that FASN was overexpressed in SU-DHL-2 and U2932 cells. Silencing FASN decreased cell growth and promoted cell apoptosis by modulating the pERK/BCL-2 signaling pathway. In conclusion, the present study indicated that FASN was overexpressed in DEL and that its expression was associated with poor survival outcomes. Furthermore, the data demonstrated that FASN regulated the biological function via the pERK/BCL-2 signaling pathway. FASN serves a critical role in the progression of DEL and its expression may be associated with the development to a more aggressive phenotype of DLBCL. Therefore, it may be considered a potential therapeutic target for DLBCL.

Prognostic value of lymphocyte-to-monocyte ratio and histone methyltransferase G9a histone methyltransferase in patients with double expression lymphoma: A retrospective observational study.

In patients with diffuse large B-cell lymphoma, MYC combined with Bcl2 and/or Bcl6-based protein expression is called double expression lymphoma (DEL). R-DA-EPOCH program chemotherapy is typically recommended because these patients often have a poor prognosis. Although numerous factors affect survival of patients with DEL, the roles of the tumor biomarker histone methyltransferase G9a (G9a) and the lymphocyte-to-monocyte ratio (LMR) are unknown.We performed a retrospective analysis of data from 51 patients. These patients were newly diagnosed with DEL and treated with R-DA-EPOCH at Taizhou People’ s Hospital and Northern Jiangsu People's Hospital between June 2014 and December 2019. Receiver operator characteristic curve results were used to calculate the LMR cutoff value. We used an immunohistochemical analysis to examine G9a expression in DEL tissues. The Kaplan–Meier method was used to determine progression-free survival (PFS) and overall survival (OS) characteristics. Cox proportional-hazards models were constructed for univariate and multivariate analyses to examine the prognostic values of LMRs and G9a in patients with DEL.The cutoff value for LMR was 2.18. The 5-year PFS rate was 35.3%, and the 5-year OS rate was 39.2%. Patients with DEL with lower LMRs and who were G9a-positive predicted inferior PFS and OS. Univariate analysis revealed that patients with elevated LDH levels, high National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) scores, LMRs ≤2.18, and G9a-positive results had relatively poorer PFS and OS. The multivariate analysis revealed that LMRs ≤2.18 and a G9a-positive result were independent prognostic factors for PFS and OS in patients with DEL treated with R-DA-EPOCH.The study results suggested that peripheral blood LMRs were an important marker for evaluation of prognosis in patients with DEL. High expression of G9a was associated with worse outcomes, indicating that G9a may serve as a prognostic biomarker for patients with DEL who undergo R-DA-EPOCH program chemotherapy.

Programmed cell death-1 inhibitor combined with rituximab in refractory or relapsed diffuse large B-cell lymphoma: a preliminary efficacy and safety analysis

Objective: To investigate the efficacy and safety of programmed cell death protein-1 (PD-1) inhibitor combined with rituximab in the treatment of refractory or relapsed diffuse large B-cell lymphoma (rrDLBCL) patients. Methods: The efficacy and safety of rrDLBCL patients treated with PD-1 inhibitor combined with rituximab as salvage therapeutic regimen after initially treated with rituximab, cyclophosphamide, anthracycline, vincristine and prednisone (R-CHOP) regimen in Cancer Hospital, Chinese Academy of Medical Science & Peking Union Medical College from October 2018 to Janurary 2020 were retrospectively analyzed.Patient who received at least one dose of PD-1 inhibitor combined with rituximab treatment and obtained the efficacy and safety evaluation were included. Results: A total of 22 patients were enrolled in this study. The median age was 51.5 years and the median number of prior treatment regimen was 2. The median time to progression (TTP) for the initial R-CHOP treatment was 9.3 months and the median interval time of rituximab administrations between the previous and the research regimen was 5.5 months. Patients were classified as germinal center B cell (GCB) origin (n=8), non-GCB origin (n=9) and primary mediastinal large B cell lymphoma (PMBCL, n=5). Four patients were double-expression lymphoma, one patient were triple-hit lymphoma. Nine patients had PD-L1 immunohistochemical staining and the proportion of PD-L1 positive tumor cells were 1%-90% for eight patients and negative for one patient.The objective response rate (ORR) and complete response rate (CR) were 72.7% (16/22) and 13.6% (3/22), respectively. The median progression free survival (PFS) was 8.0 (95%CI: 7.0-14.5) months, and overall survival (OS) was not reached. For the 17 patients of non-specific DLBCL, the ORR was 64.7% (11/17), the estimated median PFS was 4.0 (95%CI: 0-8.8) months, the 1-year PFS and OS rates were 39.2% (95%CI: 19.4%-43.4%)and 81.3% (95%CI: 71.4%-91.1%), respectively. All of 5 PMBCL cases achieved ORR, among them, one case was CR and 4 cases were partial responase (PR), and their PFS were 16.4, 9.3, 8.3, 7.9and 3.0 months, respectively. One patient had National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 grade 3 hypophysitis and one patient had NCI CTCAE grade 3 interstitial pneumonia. Conclusion: For rrDLBCL patients who have underwent rituximab treatment previously, PD-1 inhibitor combined with rituximab regimen shows a promising efficacy and tolerability, which can be a potential treatment option.

Dose-Adjusted R-EPOCH Therapy for Aggressive Lymphoma: A single center experience

Objective: When we look at diffuse large B-cell lymphomas, 5-7% are double hit lymphoma, 30-40% are double expressor lymphoma and 5-10% are triple hit lymphomas and they have an aggressive course. In our study, the efficacy of the dose-adjusted-R-EPOCH treatment regimen in the treatment of double hit lymphoma, double expressor lymphoma, triple hit lymphoma; triple expressor lymphoma and primary large B cell lymphomas of the mediastinum are presented.&#x0D; Materials and Methods: Thirty-six patients diagnosed with B-cell lymphoma who received dose-adjusted R-EPOCH treatment were included in the study. The patients were grouped cytogenetically according to the Bcl-2 and Bcl-6 rearrangement by MYC translocation. Response assessment with PET-CT was performed in patients whose planned therapy reached the number of cycles.&#x0D; Results: At the end of the treatment, 61% of the patients had a complete response, 3% had a partial response, and 8% had no response. During the follow-up, 9 of the patients died and while the treatment of 2 patients was still ongoing, the treatment regimen of 1 patient was changed. When the patients were evaluated, 2 had double hit lymphoma (complete response in 2 patients), 9 had double expressive lymphoma (5 patients had complete response, 2 patients had progressed disease, 1 patient died and 1 patient had a change in treatment), and 8 had triple expressor lymphoma (Complete response in 5 patients, death in 2 patients, and progressive disease in 1 patient).&#x0D; Conclusion: The dose-adjusted-R-EPOCH treatment regimen can also provide a high response rate in patients with lymphoma with a triple expressor cytogenetic subtype.

Evaluation of Dose-Adjusted EPOCH-R Compared with R-CHOP for the Treatment of High-Risk, Aggressive B-Cell Lymphomas: A Single-Center Experience

Introduction High-risk subtypes of DLBCL, including high-grade B-cell lymphomas (HGBCL) with rearrangements of c-MYC (MYC-R), BCL2 and/or BCL6 [or double hit and triple hit lymphomas (DHL/THL)], double expressor lymphoma (DEL), and patients with International Prognostic Index (IPI) scores of 3-5 have a poor prognosis with standard R-CHOP chemotherapy. Treatment intensification with DA-EPOCH-R did not improve outcomes when compared to R-CHOP in the CALGB 50303 trial (Bartlett et al JCO 2019). However, high-risk patients were underrepresented as 36% of patients had IPI scores of 3-5, 0.61% of patients had DHL or THL, 2.6% of patients had MYC-R, and 8.6% of patients had DEL (Bartlett et al JCO 2019). Our purpose was to retrospectively compare DA-EPOCH-R to R-CHOP in the treatment of high-risk DLBCL. Methods Patients ≥ 18 years old who received either DA-EPOCH-R or R-CHOP at Moffitt Cancer Center between 1/2010 - 9/2019 were included. Patients with a diagnosis of DLBCL with IPI score of 3-5, DHL/THL, and/or DEL were included. Patients with primary mediastinal B-cell lymphoma (PMBCL), DLBCL with testicular or central nervous system (CNS) involvement, grade 3b follicular lymphoma, Richter's transformation or IPI score &amp;lt; 2 were excluded. The primary endpoint was complete response (CR) rate and secondary endpoints included progression-free survival (PFS), overall survival (OS), CNS relapse rate, and adverse events (AE). PFS and OS were estimated using Kaplan-Meier curves and differences were established using the log-rank test. Statistically significant difference was considered if p &amp;lt; 0.05. Results The study included 128 patients: DA-EPOCH-R (n=36) and R-CHOP (n=92). General characteristics were similar between groups and included: median age = 66 years (33-85), stage III/IV = 89%, IPI score 3-5 = 87.6%, non-germinal center B-cell (GCB) = 32.8%, DEL = 26.6%, and DHL/THL = 18%. Of note, more patients in the DA-EPOCH-R group were &amp;lt; 60 years old, had MYC-R, and/or were DHL/THL or HGBCL, NOS cases. The CR rates for DA-EPOCH-R and R-CHOP were 72.2% (95% CI: 54.8, 85.8) vs. 68.5% (95% CI: 57.8,78.0), respectively (p=0.831). In a pre-planned subgroup analysis, the CR rates across subgroups, including IPI score 3-5, DEL, and DHL/THL, were not different. There was no difference in PFS between DA-EPOCH-R and R-CHOP (p= 0.33; Figure 1). The 1-year (y) PFS for DA-EPOCH-R and R-CHOP was 69% (95% CI: 56.0, 86.0) and 62% (95% CI: 52.0, 73.0), respectively. The 3 y PFS for DA-EPOCH-R and R-CHOP was 66% (95% CI: 53.0, 84.0) and 46% (95% CI: 35.0, 59.0), respectively. PFS was higher in the DA-EPOCH-R arm for patients with MYC-R (p=0.0224) and DHL/THL (p=0.045). There was no difference in OS between DA-EPOCH-R and R-CHOP (p=0.83). The 1 y OS was 77% (95% CI: 65.0, 92.0) for the DA-EPOCH-R group compared with 81% (95% CI: 73.0, 90.0) for the R-CHOP group. The 3 y OS was 71% and 65% for the DA-EPOCH-R and R-CHOP groups, respectively. The CNS relapse rate was 6.2% in the DA-EPOCH-R group and 2.4% in the R-CHOP group (p=0.301). Of the 4 patients with CNS relapse, 3 were DHL, THL or DEL. There were more grade ≥ 3 AEs in DA-EPOCH-R vs. R-CHOP (97.2% vs. 77.2%; p=0.003). There was significantly more grade ≥ 3 hematologic toxicity in the DA-EPOCH-R group regarding neutropenia (DA-EPOCH-R 91.7% vs. R-CHOP 69.6%; p=0.017) and thrombocytopenia (DA-EPOCH-R 50% vs. R-CHOP 16.3%; p=0.0003). Neuropathy and mucositis were significantly more common in the DA-EPOCH-R arm. Conclusions R-CHOP remains standard of care for high-risk DLBCL subgroups when compared to DA-EPOCH-R (such as non-GCB DLBCL, DEL, and patients with IPI score &amp;gt; 3). Patients with DHL/THL or MYC-R had greater benefit from DA-EPOCH-R compared to R-CHOP. DA-EPOCH-R was associated with increased rates of AEs, including significantly more hematologic toxicity. Disclosures Chavez: AstraZeneca: Speakers Bureau; Celgene: Consultancy; Bayer: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Novartis: Consultancy; Merck: Research Funding; Morphosys: Consultancy, Speakers Bureau; BeiGene: Speakers Bureau; Karyopharm: Consultancy; Genentech: Speakers Bureau; AbbVie: Consultancy; Verastem: Consultancy; Pfizer: Consultancy; Epizyme: Speakers Bureau; Gilead: Consultancy.