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Open accessJournal ArticleDOI: 10.1056/NEJMRA2027612

Diffuse Large B-Cell Lymphoma.

04 Mar 2021-The New England Journal of Medicine (Massachusetts Medical Society)-Vol. 384, Iss: 9, pp 842-858
Abstract: Diffuse Large B-Cell Lymphoma DLBCL, an aggressive cancer, accounts for about 30% of all lymphomas. Empirical combination chemotherapy cures about 65% of patients initially, with another 20 to 25% ...

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Topics: Diffuse large B-cell lymphoma (68%), Combination chemotherapy (63%), Lymphoma (54%) ... show more

29 results found

Open accessJournal ArticleDOI: 10.1186/S40164-021-00215-4
Cunte Chen1, Sichu Liu2, Xinmiao Jiang2, Ling Huang2  +6 moreInstitutions (3)
Abstract: Tumor mutation burden (TMB) as estimated by cancer gene panels (CGPs) has been confirmed to be associated with prognosis and is effective in predicting clinical benefit from immune checkpoint blockade (ICB) in solid tumors. However, whether the TMB calculated by CGPs is associated with overall survival (OS) for patients with diffuse large B-cell lymphoma (DLBCL) is worth exploring. The prognostic value of panel-TMB, calculated by a panel of 69 genes (GP69), for 87 DLBCL patients in our clinical center (GDPH dataset) was explored. The results were further validated using 37 DLBCL patients from the Cancer Genome Atlas (TCGA) database (TCGA dataset). Spearman correlation analysis suggested that panel-TMB is positively correlated with the TMB calculated by whole-exome sequencing (wTMB) in the TCGA dataset (R = 0.76, P < 0.0001). Both GDPH and TCGA results demonstrated that higher panel-TMB is significantly associated with a poor OS for DLBCL patients (P < 0.05) where a panel of 13 genes was associated with poor OS, and another panel of 26 genes was correlated with a favorable OS for DLBCL patients. Further subgroup analysis indicated that higher panel-TMB had shorter OS in DLBCL patients with younger than 60 years, elevated LDH, greater than one extranodal involvement, stage III/IV, an IPI score of 3–5, or HBsAg, anti-HBc, or HBV-DNA negativity (P < 0.05). Interestingly, the nomogram model constructed by panel-TMB, stage, and IPI could individually and visually predict the 1-, 2- and 3-year OS rates of DLBCL patients. We established GP69 for the evaluation of OS for Chinese DLBCL patients. panel-TMB might be a potential predictor for prognostic stratification of DLBCL patients.

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3 Citations

Open accessJournal ArticleDOI: 10.1002/JHA2.212
Edward Poynton1, Jessica Okosun1Institutions (1)
12 May 2021-
Abstract: The simultaneous growth in our understanding of lymphoma biology and the burgeoning therapeutic options has come with a renewed drive for precision‐based approaches and how best to incorporate them into contemporary and future patient care. In the hunt for accurate and sensitive biomarkers, liquid biopsies, particularly circulating tumour DNA, have come to the forefront as a promising tool in multiple cancer types including lymphomas, with considerable implications for clinical practice. Liquid biopsy analyses could supplement existing tissue biopsies with distinct advantages including the minimally invasive nature and the ease with which it can be repeated during a patient's clinical journey. Circulating tumour DNA (ctDNA) analyses has been and continues to be evaluated across lymphoma subtypes with potential applications as a diagnostic, disease monitoring and treatment selection tool. To make the leap into the clinic, these assays must demonstrate accuracy, reliability and a quick turnaround to be employed in the real‐time clinical management of lymphoma patients. Here, we review the available ctDNA assays and discuss key practical and technical issues around improving sensitivity. We then focus on their potential roles in several lymphoma subtypes exemplified by recent studies and provide a glimpse of different features that can be analysed beyond ctDNA.

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Topics: Liquid biopsy (63%)

2 Citations

Open accessJournal ArticleDOI: 10.3390/CANCERS13122893
09 Jun 2021-Cancers
Abstract: Lymphoma research is a paradigm of the integration of basic and clinical research within the fields of diagnosis and therapy. Clinical, phenotypic, and genetic data are currently used to predict which patients could benefit from standard treatment. However, alternative therapies for patients at higher risk from refractoriness or relapse are usually empirically proposed, based on trial and error, without considering the genetic complexity of aggressive B-cell lymphomas. This is primarily due to the intricate mosaic of genetic and epigenetic alterations in lymphomas, which are an obstacle to the prediction of which drug will work for any given patient. Matching a patient's genes to drug sensitivity by directly testing live tissues comprises the "precision medicine" concept. However, in the case of lymphomas, this concept should be expanded beyond genomics, eventually providing better treatment options for patients in need of alternative therapeutic approaches. We provide an overview of the most recent findings in diffuse large B-cell lymphomas genomics, from the classic functional models used to study tumor biology and the response to experimental treatments using cell lines and mouse models, to the most recent approaches with spheroid/organoid models. We also discuss their potential relevance and applicability to daily clinical practice.

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Topics: B-cell lymphoma (51%), Precision medicine (51%)

1 Citations

Open accessJournal Article
Abstract: Post-transplant lymphoproliferative disorders (PTLD) are among the most serious complications after solid organ transplantation (SOT). Monomorphic diffuse large B-cell lymphoma (DLBCL) is the most common subtype of PTLD. Historically, outcomes of PTLD have been poor with high mortality rates and allograft loss, although this has improved in the last 10 years. Most of our understanding about PTLD DLBCL is extrapolated from studies in non-PTLD DLBCL, and while several clinical factors have been identified and validated for predicting non-PTLD DLBCL outcomes, the molecular profile of PTLD DLBCL has not yet been characterized. Compartment-specific metabolic reprograming has been described in non-PTLD DLBCL with a lactate uptake metabolic phenotype with high monocarboxylate transporter 1 (MCT1) expression associated with worse outcomes. The aim of our study was to compare the outcomes of PTLD in our transplant center to historic cohorts, as well as study a subgroup of our PTLD DLBCL tumors and compare metabolic profiles with non-PTLD DLBCL. We performed a retrospective single institution study of all adult patients who underwent a SOT between the years 1992-2018, who were later diagnosed with PTLD. All available clinical information was extracted from the patients' medical records. Tumor metabolic markers were studied in a subgroup of PTLD DLBCL and compared to a group of non-PTLD DLBCL. Thirty patients were diagnosed with PTLD following SOT in our center. Median time from SOT to PTLD diagnosis was 62.8 months (IQR 7.6; 134.4), with 37% of patients diagnosed with early PTLD, and 63% with late PTLD. The most common PTLD subtype was DLBCL. Most patients were treated with reduction of their immunosuppression (RIS) including a group who were switched from calcineurin inhibitor (CNI) to mTOR inhibitor based IS, in conjunction with standard anti-lymphoma chemoimmunotherapy. Progression free survival of the PTLD DLBCL cohort was calculated at 86% at 1 year, and 77% at 3 and 5-years, with overall survival of 86% at 1 and 3-years, and 75% at 5 years. Death censored allograft survival in the kidney cohort was 100% at 1 year, and 93% at 3, 5 and 10 years. MCT1 H scores were significantly higher in a subset of the non-PTLD DLBCL patients than in a PTLD DLBCL cohort. Our data is concordant with improved PTLD outcomes in the last 10 years. mTOR inhibitors could be an alternative to CNI as a RIS strategy. Finally, PTLD DLBCL may have a distinct metabolic profile with reduced MCT1 expression compared to non-PTLD DLBCL, but further studies are needed to corroborate our limited cohort findings and to determine if a specific metabolic profile is associated with outcomes.

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Open accessJournal ArticleDOI: 10.3390/CANCERS13184683
18 Sep 2021-Cancers
Abstract: Besides a recognized role of PD-1/PD-L1 checkpoint in anti-tumour immune evasion, there is accumulating evidence that PD-1/PD-L1 interactions between B and T cells also play an important role in normal germinal center (GC) reactions. Even when smaller in number, T follicular helper cells (TFH) and regulatory T (TFR) or B (Breg) cells are involved in positive selection of GC B cells and may result critical in the lymphoma microenvironment. Here, we discuss a role of PD-1/PD-L1 during tumour evolution in diffuse large B cell lymphoma (DLBCL), a paradigm of GC-derived lymphomagenesis. We depict a progression model, in two phases, where malignant B cells take advantage of positive selection signals derived from correct antigen-presentation and PD-1/PD-L1 inter-cellular crosstalks to survive and initiate tumour expansion. Later, a constant pressure for the accumulation of genetic/epigenetic alterations facilitates that DLBCL cells exhibit higher PD-L1 levels and capacity to secrete IL-10, resembling Breg-like features. As a result, a complex immunosuppressive microenvironment is established where DLBCL cells sustain proliferation and survival by impairing regulatory control of TFR cells and limiting IL-21-mediated anti-tumour functions of TFH cells and maximize the use of PD-1/PD-L1 signaling to escape from CD8+ cytotoxic activity. Integration of these molecular and cellular addictions into a framework may contribute to the better understanding of the lymphoma microenvironment and contribute to the rationale for novel PD-1/PD-L1-based combinational immunotherapies in DLBCL.

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Topics: Germinal center (64%), B cell (59%), Diffuse large B-cell lymphoma (59%) ... show more


81 results found

Journal ArticleDOI: 10.1056/NEJMOA011795
Abstract: Background The standard treatment for patients with diffuse large-B-cell lymphoma is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Rituximab, a chimeric monoclonal antibody against the CD20 B-cell antigen, has therapeutic activity in diffuse large-B-cell lymphoma. We conducted a randomized trial to compare CHOP chemotherapy plus rituximab with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. Methods Previously untreated patients with diffuse large-B-cell lymphoma, 60 to 80 years old, were randomly assigned to receive either eight cycles of CHOP every three weeks (197 patients) or eight cycles of CHOP plus rituximab given on day 1 of each cycle (202 patients). Results The rate of complete response was significantly higher in the group that received CHOP plus rituximab than in the group that received CHOP alone (76 percent vs. 63 percent, P=0.005). With a median follow-up of two years, event-free and overall survival times were significantly higher in the CHOP-plus-rit...

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Topics: CHOP (72%), International Prognostic Index (61%), Diffuse large B-cell lymphoma (59%) ... show more

4,493 Citations

Open accessJournal Article
Abstract: BACKGROUND\nAlthough many patients with intermediate-grade or high-grade (aggressive) non-Hodgkin's lymphoma are cured by combination chemotherapy, the remainder are not cured and ultimately die of their disease. The Ann Arbor classification, used to determine the stage of this disease, does not consistently distinguish between patients with different long-term prognoses. This project was undertaken to develop a model for predicting outcome in patients with aggressive non-Hodgkin's lymphoma on the basis of the patients' clinical characteristics before treatment.\n\n\nMETHODS\nAdults with aggressive non-Hodgkin's lymphoma from 16 institutions and cooperative groups in the United States, Europe, and Canada who were treated between 1982 and 1987 with combination-chemotherapy regimens containing doxorubicin were evaluated for clinical features predictive of overall survival and relapse-free survival. Features that remained independently significant in step-down regression analyses of survival were incorporated into models that identified groups of patients of all ages and groups of patients no more than 60 years old with different risks of death.\n\n\nRESULTS\nIn 2031 patients of all ages, our model, based on age, tumor stage, serum lactate dehydrogenase concentration, performance status, and number of extranodal disease sites, identified four risk groups with predicted five-year survival rates of 73 percent, 51 percent, 43 percent, and 26 percent. In 1274 patients 60 or younger, an age-adjusted model based on tumor stage, lactate dehydrogenase level, and performance status identified four risk groups with predicted five-year survival rates of 83 percent, 69 percent, 46 percent, and 32 percent. In both models, the increased risk of death was due to both a lower rate of complete responses and a higher rate of relapse from complete response. These two indexes, called the international index and the age-adjusted international index, were significantly more accurate than the Ann Arbor classification in predicting long-term survival.\n\n\nCONCLUSIONS\nThe international index and the age-adjusted international index should be used in the design of future therapeutic trials in patients with aggressive non-Hodgkin's lymphoma and in the selection of appropriate therapeutic approaches for individual patients.

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Topics: Aggressive Non-Hodgkin Lymphoma (78%), Non-Hodgkin's lymphoma (72%), Aggressive lymphoma (70%) ... show more

4,132 Citations

Journal ArticleDOI: 10.1056/NEJMOA012914
Andreas Rosenwald1, George E. Wright, Wing C. Chan2, Wing C. Chan1  +37 moreInstitutions (9)
Abstract: Background The survival of patients with diffuse large-B-cell lymphoma after chemotherapy is influenced by molecular features of the tumors. We used the gene-expression profiles of these lymphomas to develop a molecular predictor of survival. Methods Biopsy samples of diffuse large-B-cell lymphoma from 240 patients were examined for gene expression with the use of DNA microarrays and analyzed for genomic abnormalities. Subgroups with distinctive gene-expression profiles were defined on the basis of hierarchical clustering. A molecular predictor of risk was constructed with the use of genes with expression patterns that were associated with survival in a preliminary group of 160 patients and was then tested in a validation group of 80 patients. The accuracy of this predictor was compared with that of the international prognostic index. Results Three gene-expression subgroups — germinal-center B-cell–like, activated B-cell–like, and type 3 diffuse large-B-cell lymphoma — were identified. Two common oncogeni...

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Topics: Diffuse large B-cell lymphoma (63%), International Prognostic Index (57.99%), Lymphoma (53%) ... show more

3,321 Citations

Open accessJournal ArticleDOI: 10.1200/JCO.2013.54.8800
Abstract: The purpose of this work was to modernize recommendations for evaluation, staging, and response assessment of patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). A workshop was held at the 11th International Conference on Malignant Lymphoma in Lugano, Switzerland, in June 2011, that included leading hematologists, oncologists, radiation oncologists, pathologists, radiologists, and nuclear medicine physicians, representing major international lymphoma clinical trials groups and cancer centers. Clinical and imaging subcommittees presented their conclusions at a subsequent workshop at the 12th International Conference on Malignant Lymphoma, leading to revised criteria for staging and of the International Working Group Guidelines of 2007 for response. As a result, fluorodeoxyglucose (FDG) positron emission tomography (PET)–computed tomography (CT) was formally incorporated into standard staging for FDG-avid lymphomas. A modification of the Ann Arbor descriptive terminology will be used for ana...

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2,294 Citations

Open accessJournal ArticleDOI: 10.1056/NEJMOA1707447
Abstract: BackgroundIn a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy. MethodsIn this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments. ResultsAmong the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%)....

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Topics: Refractory Diffuse Large B-Cell Lymphoma (64%), B-cell lymphoma (61%), Follicular lymphoma (56.99%) ... show more

2,088 Citations

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