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Non Hodgkin Lymphoma
A three-gene signature based on MYC, BCL-2 and NFKBIA improves risk stratification in diffuse large B-cell lymphoma
Enrico Derenzini,1,2 Saveria Mazzara,3 Federica Melle,3 Giovanna Motta,3 Marco Fabbri,3 Riccardo Bruna,1 Claudio Agostinelli,4 Alessandra Cesano,5 Chiara Antonia Corsini,6 Ning Chen,5 Simona Righi,4 Elena Sabattini,4 Annalisa Chiappella,7 Angelica Calleri,3 Stefano Fiori,3 Valentina Tabanelli,3 Antonello Cabras,8 Giancarlo Pruneri,8 Umberto Vitolo,9 Alessandro Massimo Gianni,1 Alessandro Rambaldi,10 Paolo Corradini,7 Pier Luigi Zinzani,11 Corrado Tarella1,2 and Stefano Pileri3
1Onco-Hematology Division, IEO European Institute of Oncology IRCCS, Milan and European Institute of Oncology IRCCS, Milan, Italy; 2Department of Health Sciences, University of Milan, Milan, Italy; 3Division of Diagnostic Hematopathology, IEO European Institute of Oncology IRCCS, Milan and European Institute of Oncology IRCCS, Milan, Italy; 4Hematopathology Unit, Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy; 5NanoString Technologies Inc, Seattle, WA, USA; 6Laboratory of Hematology-Oncology, IEO European Institute of Oncology IRCCS, Milan and European Institute of Oncology IRCCS, Milan, Italy; 7Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, University of Milan, Milan, Italy; 8Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; 9Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy; 10Hematology and Bone Marrow Transplant Unit, ASST-Papa Giovanni XXIII, Bergamo, Italy and 11Institute of Hematology and Medical Oncology “L. e A. Seragnoli”, Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy
ABSTRACT
Recent randomized trials focused on gene expression-based deter- mination of the cell of origin in diffuse large B-cell lymphoma could not show significant improvements by adding novel agents to standard chemoimmunotherapy. The aim of this study was the iden- tification of a gene signature able to refine current prognostication algo- rithms and applicable to clinical practice. Here we used a targeted gene expression profiling panel combining the Lymph2Cx signature for cell of origin classification with additional targets including MYC, BCL-2 and NFKBIA, in 186 patients from two randomized trials (discovery cohort) (clinicaltrials gov. Identifier: NCT00355199 and NCT00499018). Data were validated in three independent series (two large public datasets and a real-life cohort). By integrating the cell of origin, MYC/BCL-2 double expressor status and NFKBIA expression, we defined a three-gene signa- ture combining MYC, BCL-2 and NFKBIA (MBN-signature), which out- performed the MYC/BCL-2 double expressor status in multivariate analysis, and allowed further risk stratification within the germinal cen- ter B-cell/unclassified subset. The high-risk (MBN Sig-high) subgroup identified the vast majority of double hit cases and a significant fraction of activated B-cell-derived diffuse large B-cell lymphomas. These results were validated in three independent series including a cohort from the REMoDL-B trial, where, in an exploratory ad hoc analysis, the addition of bortezomib in the MBN Sig-high subgroup provided a progression free survival advantage compared with standard chemoimmunotherapy. These data indicate that a simple three-gene signature based on MYC, BCL-2 and NFKBIA could refine the prognostic stratification in diffuse large B-cell lymphoma, and might be the basis for future precision-ther- apy approaches.
Ferrata Storti Foundation
Haematologica 2021 Volume 106(9):2405-2416
Correspondence:
ENRICO DERENZINI
enrico.derenzini@ieo.it
STEFANO PILERI
stefano.pileri@ieo.it
Received: August 25, 2019. Accepted: August 3, 2020. Pre-published: August 13, 2020.
https://doi.org/10.3324/haematol.2019.236455 ©2021 Ferrata Storti Foundation
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