Clinical Impact of the Cell-of-Origin Classification and the MYC/BCL2 Dual Expresser Status in Diffuse Large B-Cell Lymphoma Treated Within Prospective Clinical Trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group
Annette M. StaigerMarita ZiepertHeike HornDavid W. ScottThomas F.E. BarthHeinz‐Wolfram BerndAlfred C. FellerWolfram KlapperMonika SzczepanowskiMichael HummelHarald SteinDido LenzeMartin‐Leo HansmannSylvia HartmannPeter MöllerSergio CogliattiGeorg LenzLorenz TrümperMarkus LöfflerNorbert SchmitzMichael PfreundschuhAndreas RosenwaldGerman Ott
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Purpose To explore the prognostic impact and interdependence of the cell-of-origin (COO) classification, dual expression (DE) of MYC and BCL2 proteins, and MYC, BCL2, and BCL6 translocations in two prospectively randomized clinical trials of patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods Overall, 452 formalin-fixed paraffin-embedded samples from two prospective, randomized DLBCL trials (RICOVER-60, prospective, randomized study for patients > 60 years, all IPI groups; and R-MegaCHOEP, prospective, randomized study for patients ≤ 60 years with age-adjusted IPI 2,3) of the German High-Grade Non-Hodgkin Lymphoma Study Group were analyzed with the Lymph2Cx assay for COO classification, with immunohistochemistry for MYC and BCL2, and with fluorescent in situ hybridization for MYC, BCL2, and BCL6 rearrangements. Results COO classification was successful in 414 of 452 samples. No significant differences with respect to COO (activated B-cell [ABC]-like DLBCL v germinal center B-cell [GCB]-like DLBCL) were observed in event-free survival, progression-free survival, and overall survival in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the RICOVER-60 trial. Also, no differences with respect to COO were observed in multivariable analyses adjusted for International Prognostic Index factors in event-free survival (hazard ratio [HR] of ABC-like disease v GCB-like disease, 1.0; 95% CI, 0.6 to 1.6; P = .93), progression-free survival (HR, 1.1; 95% CI, 0.6 to 1.8; P = .82), and overall survival (HR, 1.0; 95% CI, 0.6 to 1.8; P = .96). Similar results were observed in the R-MegaCHOEP trial. In patients treated with R-CHOP, DE status was associated with significantly inferior survival compared with nonDE within the GCB, but not within the ABC subgroup. DE status was associated with significantly inferior outcome compared with patients with ABC-like DLBCL without DE (5-year PFS rate, 39% [95% CI,19% to 59%] v 68% [95% CI, 52% to 85%]; P = .03) and compared with patients with GCB-like DLBCL without DE. When data from patients with nonDE were analyzed separately, the outcome of patients in the ABC subgroup was inferior to that of patients in the GCB subgroup (5-year PFS rate, 68% [95% CI, 52% to 85%] v 85% [95% CI, 74% to 96%]; P = .04). Conclusion COO profiling in two prospective randomized DLBCL trials failed to identify prognostic subgroups, whereas dual expression of MYC and BCL2 was predictive of poor survival. Evaluation of prognostic or predictive biomarkers in the management of DLBCL, such as the COO, within prospective clinical trials will be important in the future.Keywords:
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Progression-free survival
Abstract Concomitant deregulation of MYC and BCL2 comprises clinically significant, yet poorly characterized biological high-risk feature in diffuse large B-cell lymphoma (DLBCL). To interrogate these lymphomas, we analyzed translocations and protein expression of BCL2, BCL6, and MYC; correlated the findings with comprehensive mutational, transcriptomic, and clinical data in 181 patients with primary DLBCL; and validated the key findings in independent data sets. Structural variations of BCL2 were subtype-specific and specifically increased BCL2 expression. Molecular dissection of MYC deregulation revealed associations with other lymphoma drivers, including loss of TP53, and distinctive gene expression profiles. Double protein expression (DPE) arose from heterogeneous molecular backgrounds that exhibited subtype-dependent patterns. In the germinal center B-cell (GCB) DLBCL, concurrent alterations of MYC and BCL2 loci gave rise to the majority of DPE DLBCLs, whereas among the activated B-cell (ABC) DLBCLs, concurrent alterations were infrequent. Clinically, DPE DLBCL defined a prognostic entity, which was independent of the International Prognostic Index (IPI) and cell of origin, and together with the loss of TP53 had a synergistic dismal impact on survival. In the DPE DLBCL, the loss of TP53 was associated with a chemorefractory disease, whereas among the other DLBCLs, no correlation with survival was seen. Importantly, BCL6 translocations identified non-GCB lymphomas with favorable BN2/C1-like survival independent of IPI and concurrent DPE status. Taken together, our findings define molecular characteristics of the DPE in DLBCL, and recognize clinically feasible predictors of outcome. Given the emerging taxonomical significance of BCL2, BCL6, MYC, and TP53, our findings provide further depth and validation to the genomic classification of DLBCL.
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Double-hit B-cell lymphoma is a common designation for a group of tumors characterized by concurrent translocations of MYC and BCL2, BCL6, or other genes. The prognosis of concurrent MYC and BCL6 translocations is not well known. In this study, we assessed rearrangements and expression of MYC, BCL2 and BCL6 in 898 patients with de novo diffuse large B-cell lymphoma treated with standard chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab). Neither BCL6 translocation alone (more frequent in activated B-cell like diffuse large B-cell lymphoma) nor in combination with MYC translocation (observed in 2.0% of diffuse large B-cell lymphoma) predicted poorer survival in diffuse large B-cell lymphoma patients. Diffuse large B-cell lymphoma patients with MYC/BCL6 co-expression did have significantly poorer survival, however, MYC/BCL6 co-expression had no effect on prognosis in the absence of MYC/BCL2 co-expression, and had no additive impact in MYC+/BCL2+ cases. The isolated MYC+/BCL6+/BCL2- subset, more frequent in germinal center B-cell like diffuse large B-cell lymphoma, had significantly better survival compared with the isolated MYC+/BCL2+/BCL6- subset (more frequent in activated B-cell like diffuse large B-cell lymphoma). In summary, diffuse large B-cell lymphoma patients with either MYC/BCL6 rearrangements or MYC/BCL6 co-expression did not always have poorer prognosis; MYC expression levels should be evaluated simultaneously; and double-hit B-cell lymphoma needs to be refined based on the specific genetic abnormalities present in these tumors.
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L'impact de l'expression combinée de MYC, BCL2 et BCL6 sur la survie des patients atteints de lymphome diffus à grandes cellules BIntroduction.C-MYC est l'un des facteurs de transcription essentiels qui jouent un rôle dans diverses fonctions cellulaires.Le réarrangement MYC est associé à une faible survie globale et une faible survie sans progression, un risque accru de rechute du système nerveux central chez les patients diagnostiqués avec un lymphome diffus à grandes cellules B (DLBCL) et traités par R-CHOP.En outre, l'amplification c-MYC est un facteur pronostique défavorable, amplifié par les réarrangements BCL2 et BCL6, respectivement, désignant les lymphomes de haut degré selon la révision de 2016 de l'OMS.Objectifs.Nous recherchons les corrélations de l'expression double ou triple des marqueurs c-MYC et ABSTRACT Introduction.C-MYC is one of the essential transcription factors that play a role in various cellular functions.The MYC rearrangement is associated with low overall survival and low progression-free survival, increased risk of central nervous system disease relapse in patients diagnosed with diffuse large B cell lymphoma (DLBCL) and treated with R-CHOP.Also, c-MYC amplification is an unfavorable prognostic factor, amplified by BCL2 and BCL6 rearrangements, respectively, designating lymphomas as high grade according to the WHO 2016 revision.Objectives.We search the correlations of the double or triple expression of C-MYC and BCL2 and/or BCL6 markers, with clinical survival data.Methods.A cohort of 80 patients with DLBCL was examined for MYC, BCL2 and BCL6 immunohistochemical expression.
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The International Prognostic Index (IPI) has been the basis for determining prognosis in patients with diffuse large B-cell lymphoma (DLBCL) for the past 20 years. The utility of the IPI must be reassessed in the era of immunochemotherapy. Seven risk factors at diagnosis were identified, and a maximum of 7 points were assigned to each patient. Four risk groups were created: low (0-1), low-intermediate (2-3), high-intermediate (4), and high (5-7). Using MYC and BCL-2 clinical data from the Drum Tower Hospital collected during the rituximab era, we performed a retrospective analysis of patients with DLBCL treated with R-CHOP and built an biological markers adjusted IPI with the goal of improving risk stratification.Clinical features from 60 adults with de novo DLBCL diagnosed from 2008-2013 were assessed for their prognostic significance. The IPI remains predictive, but it cannot identify the high-risk subgroup. Compared with the IPI, the MYC and BCL-2 adjusted-IPI (A-IPI) better discriminated patients in the high-risk subgroup (4-year overall survival [OS]: 33.3%) than did the IPI (4 year OS: 48.0%). In the era of R-CHOP treatment, MYC and BCL-2 adjusted-IPI is more powerful than the IPI for helping guide treatment planning and interpretation of clinical trials.
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Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma worldwide, and represents a clinically, pathologically and biologicaly very heterogeneous group of tumours. Recent studies have subdivided diffuse large B cell lymphomas into morphological variants, molecular and immunophenotypical subgroups and distinct entities. An immunophenotypical subdivision of DLBCL, into germinal centre-like (GCB) and non-germinal centre-like (non-GCB) subgroups, using a combination of antibodies to CD10, BCL6 and MUM1, does not correlate exactly with gene expression profile of GCB and activated peripheral B-cells (ABC). Some studies reported that combination of CD10, BCL6 and MUM1 expression could subdivide DLBCL patients into long- and short-time survivors. The WHO classification of 2008. recognizes a group of aggressive B-cell lymphomas that are not readily classified as either Burkitt lymphoma (BL) or DLBCL, and provisional category of B-cell neoplasms with features intermediate between DLBCL and classical Hodgkin lymphoma. Furthermore, the new classification recognizes the patient age, site-specific categories, and clinical factors in defining variants of DLBCL. The WHO classification of 2008. is the result of successful international collaboration among pathologists, biologists and clinicians, but heterogeneous group of DLBCL will be the subject of further investigation.
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Objective:To investigate the influence of Bcl2 expression on clinicopathological features and prognosis of diffuse large B cell lymphoma(DLBCL)developed from different cell origins.Methods:Tissues of 42 cases of DLBCL were screened from 180 cases of B cell non-Hodgkin lymphoma.Sections were stained with routine HE method,and immunophenotypes of neoplastic cell,such as CD20,CD3,CD10,Bcl6,Bcl2 and MUM1,were examined with immunohistochemistry(IHC)stained sections.The clinical and pathological data of all cases were collected.Some patients were followed up.Statistical analysis was done.Results:The expression of Bcl2 was found in 31 out of 42 case of DLBCL(73.8%).There was no statistically significant difference of Bcl2 expression between GBC-like(14/17)and ABC-like(17/25)DLBCL.The relation of Bcl2 expression with age,sex,site of DLBCL was not found,but it was associated with clinical staging of the disease.The stages of Bcl2-positive DLBCL cases were later than those of Bcl2-negative DLBCL cases(P0.05).Most of the DLBCL cases that originated outside nodes showed positive expression of Bcl2(5/6).There was a tendency that the survival status of Bcl2-positive cases was worse than that of Bcl2-negative cases(P=0.06).Conclusions:The expression of Bcl2 in DLBCL doesn't associate with the gene expression spectra obviously,but it affects the clinical course and prognosis of DLBCL.Bcl2 may be one of predictive factors for prognosis of DLBCL.
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Gene expression profiling studies have distinguished diffuse large B-cell lymphomas (DLBCLs) by cell of origin, with distinct pathogenetic mechanisms and prognosis. We attempted to identify DLBCL molecular subtypes in an epidemiologic study of 214 DLBCL patients diagnosed during 1998-2000 with archival tissues to investigate etiology. Immunohistochemical staining for CD10, BCL6, LMO2, MUM1/IRF4, and BCL2 and fluorescence in situ hybridization for t(14;18) were conducted, with ≥93% blinded duplicate agreement. CD10, LMO2, and BCL2 expression was similar to previous reports (32%, 44%, and 44% of DLBCLs, respectively), but BCL6 and MUM1/IRF4 expression was lower than expected (29% and 5%, respectively). We classified 112/214 (52%) cases as germinal center B-cell-like DLBCL (GCB-DLBCL; Hans et al., Blood 2004; CD10+ or CD10-/BCL6+/MUM1-), with no difference in prognosis compared with non-GCB-DLBCL (Cox regression, P=0.48). Comparing other GCB correlates, LMO2 expression and t(14;18) were more common but not exclusive to GCB-DLBCL as defined in our study, whereas BCL2 expression did not differ between DLBCL molecular subtypes. We could not confidently identify patients with GCB-DLBCL using these immunohistochemistry-based markers on archival tissues.
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The Hans algorithm categorizes the diffuse large B-cell lymphoma (DLBCL) into two major subtypes: the germinal center B-cell-like (GCB) DLBCL and the non-GCB DLBCL. This classification is based on three immunohistochemical markers: CD10, BCL6, and MUM1. The non-GCB subtype is associated with lower overall survival (OS) and progression-free survival (PFS) rates compared to the GCB. DLBCL without positive staining for these three markers (CD10–, BCL6–, MUM1–), also called a triple negative or TN, are classified as the non-GCB subtype. However, they show different clinical characteristics and better prognosis than others assigned to the same cell-of-origin group. Herein, we report a case of a TN non-GCB DLBCL with a complete response after R-CHOP therapy. Together with previous reports of TN non-GCB DLBCLs, our case might depreciate the prognostic value of the Hans algorithm, which was already controversial in the literature, especially in the chemoimmunotherapy era.
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<div>Abstract<p>Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease and response to therapy is difficult to predict. An algorithm to sort DLBCL cases using a series of five immunohistochemical markers (GCET1, CD10, BCL6, MUM1, FOXP1) accurately predicts survival in patients treated with current chemotherapeutic regimens. (Clin Cancer Res 2009;15(17):5291–3)</p></div>
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