A three-gene signature based on MYC, BCL-2 and NFKBIA improves risk stratification in diffuse large B-cell lymphoma

• Published in: Haematologica (Roma) 2021-09, Vol.106 (9), p.2405-2416
• Main Authors: Derenzini, Enrico, Mazzara, Saveria, Melle, Federica, Motta, Giovanna, Fabbri, Marco, Bruna, Riccardo, Agostinelli, Claudio, Cesano, Alessandra, Corsini, Chiara Antonia, Chen, Ning, Righi, Simona, Sabattini, Elena, Chiappella, Annalisa, Calleri, Angelica, Fiori, Stefano, Tabanelli, Valentina, Cabras, Antonello, Pruneri, Giancarlo, Vitolo, Umberto, Gianni, Alessandro Massimo, Rambaldi, Alessandro, Corradini, Paolo, Zinzani, Pier Luigi, Tarella, Corrado, Pileri, Stefano
• Format: Article
• Language: English
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2019.236455

Recent randomized trials focused on gene expression-based determination 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 identification of a gene signature able to refine current prognostication algorithms 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 2 randomized trials (discovery cohort) (NCT00355199 and NCT00499018). Data were validated in 3 independent series (2 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 3-gene signature combining MYC, BCL-2 and NFKBIA (MBN-signature), which outperformed the MYC/BCL-2 double expressor status in multivariate analysis, and allowed further risk stratification within the germinal center 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 3 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 3-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-therapy approaches.