Search

BACKGROUND: Biologically distinct subtypes of diffuse large B-cell lymphoma can be identified using gene-expression analysis to determine their cell of origin, corresponding to germinal centre or activated B cell. We aimed to investigate whether adding bortezomib to standard therapy could improve outcomes in patients with these subtypes. METHODS: In a randomised evaluation of molecular guided therapy for diffuse large B-cell lymphoma with bortezomib (REMoDL-B), an open-label, adaptive, randomised controlled, phase 3 superiority trial, participants were recruited from 107 cancer centres in the UK (n=94) and Switzerland (n=13). Eligible patients had previously untreated, histologically confirmed diffuse large B-cell lymphoma with sufficient diagnostic material from initial biopsies for gene-expression profiling and pathology review; were aged 18 years or older; had ECOG performance status of 2 or less; had bulky stage I or stage II–IV disease requiring full-course chemotherapy; had measurable disease; and had cardiac, lung, renal, and liver function sufficient to tolerate chemotherapy. Patients initially received one 21-day cycle of standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP; rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1·4 mg/m(2) [to a maximum of 2 mg total dose] intravenously on day 1 of the cycle, and prednisolone 100 mg orally once daily on days 1–5). During this time, we did gene-expression profiling using whole genome cDNA-mediated annealing, selection, extension, and ligation assay of tissue from routine diagnostic biopsy samples to determine the cell-of-origin subtype of each participant (germinal centre B cell, activated B cell, or unclassified). Patients were then centrally randomly assigned (1:1) via a web-based system, with block randomisation stratified by international prognostic index score and cell-of-origin subtype, to continue R-CHOP alone (R-CHOP group; control), or with bortezomib (RB-CHOP group; experimental; 1·3 mg/m(2) intravenously or 1·6 mg/m(2) subcutaneously) on days 1 and 8 for cycles two to six. If RNA extracted from the diagnostic tissues was of insufficient quality or quantity, participants were given R-CHOP as per the control group. The primary endpoint was 30-month progression-free survival, for the germinal centre and activated B-cell population. The primary analysis was on the modified intention-to-treat population of activated and germinal centre B-cell population. Safety was assessed in all participants who were given at least one dose of study drug. We report the progression-free survival and safety outcomes for patients in the follow-up phase after the required number of events occurred. This study was registered at ClinicalTrials.gov, number NCT01324596, and recruitment and treatment has completed for all participants, with long-term follow-up ongoing. FINDINGS: Between June 2, 2011, and June 10, 2015, 1128 eligible patients were registered, of whom 918 (81%) were randomly assigned to receive treatment (n=459 to R-CHOP, n=459 to RB-CHOP), comprising 244 (26·6%) with activated B-cell disease, 475 (51·7%) with germinal centre B cell disease, and 199 (21·7%) with unclassified disease. At a median follow-up of 29·7 months (95% CI 29·0–32·0), we saw no evidence for a difference in progression-free survival in the combined germinal centre and activated B-cell population between R-CHOP and RB-CHOP (30-month progression-free survival 70·1%, 95% CI 65·0–74·7 vs 74·3%, 69·3–78·7; hazard ratio 0·86, 95% CI 0·65–1·13; p=0·28). The most common grade 3 or worse adverse event was haematological toxicity, reported in 178 (39·8%) of 447 patients given R-CHOP and 187 (42·1%) of 444 given RB-CHOP. However, RB-CHOP was not associated with increased haematological toxicity and 398 [87·1%] of 459 participants assigned to receive RB-CHOP completed six cycles of treatment. Grade 3 or worse neuropathy occurred in 17 (3·8%) patients given RB-CHOP versus eight (1·8%) given R-CHOP. Serious adverse events occurred in 190 (42·5%) patients given R-CHOP, including five treatment-related deaths, and 223 (50·2%) given RB-CHOP, including four treatment-related deaths. INTERPRETATION: This is the first large-scale study in diffuse large B-cell lymphoma to use real-time molecular characterisation for prospective stratification, randomisation, and subsequent analysis of biologically distinct subgroups of patients. The addition of bortezomib did not improve progression-free survival. FUNDING: Janssen-Cilag, Bloodwise, and Cancer Research UK.

The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities (n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ-related or not; n = 65 837) revealed four major clusters of cases sharing homologous (‘public’) heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non-malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A20, encoded by TNFAIP3, is a molecular “brake” of the canonical NF-κB activation pathway and attenuates the NF-κB activity triggered by a number of surface receptors.1,2 A20 contains an N-terminal OTU domain that possesses deubiquitinating activity, and 7 zinc finger (ZF) domains in its C-terminus that confers the E3 ubiquitin ligase activity.3 Through removing the K63-linked ubiquitin chain, catalysing the K48-linked polyubiquitination, and also direct binding to the linear polyubiquitin chain of its targets, A20 can inactivate a number of NF-κB positive regulators, including RIP1/2, TRAF6, Ubc13 and NEMO, thus negatively regulating the signalling of several surface receptors, including BCR, TNFR, TLR and IL1βR.1,2,4 A20 itself is a transcriptional target of NF-κB, and its transcriptional activation by NF-κB thus serves as an auto-negative feedback to attenuate NF-κB activities triggered by these receptor signallings.1,2

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) invariably arises from a background of chronic microbial infection and/or autoimmune disorder at diverse mucosal sites. The prolonged chronic infection and/or autoimmunity generate active immune and inflammatory responses that provide a setting for evolution and development of autoreactive B-cells, their expansion and eventual malignant transformation following acquisition of genetic changes. The immune responses also play a critical role in sustaining the growth and survival of the transformed cells as shown by complete regression of a high proportion of MALT lymphoma of the stomach, ocular adnexa and skin following anti-microbial treatment. B-cell receptor engagement by auto-antigen as well as T-cell help including both cognate interaction and bystander help via soluble ligands such as CD40L and BAFF are thought to underpin the immunological drive in the lymphoma development through activation of the canonical and non-canonical NF-κB pathway respectively. Similarly, the three MALT lymphoma associated chromosome translocations, namely t(1;14)(p22;q32)/$\small \textit{BCL10-IGH}$, t(14;18)(q32;q21)/$\small \textit{IGH-MALT1}$, and t(11;18)(q21;q21)/$\small \textit{BIRC3}$ ($\small \textit{API2}$)$\small \textit{-MALT1}$, are also capable of activating both canonical and non-canonical NF-κB pathways. Furthermore, $\small \textit{TNFAIP3}$ (A20) inactivation by deletion and/or mutation abolishes the auto-negative feedback to several signalling including BCR and TLR, which connect to the canonical NF-κB activation pathway. Thus, there is a considerable overlap in the molecular pathways dysregulated by immunological drive and somatic genetic changes, strongly arguing for their oncogenic cooperation in the development of MALT lymphoma.

The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at ∈ European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better fu treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine ‘sections’ in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients. © 2016 Ferrata Storti Foundation.

The t(11;14) (q13;q32) between the BCL-1 and immunoglobulin heavy chain gene (Ig-H) loci in mantle cell lymphomy (MCL) are believed to be mediated by the mechanism of V(D)J recombination similar to the t(14;18) in follicular lymphoma. We have recently shown that the t(14;18) event creates staggered double-strand breaks in the BC-2 locus, and that the t(14;18) junctions contain templated nucleotide insertions (T-nucleotides)...