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A 3-gene signature in DLBCL
analysis on the impact of bortezomib in the MBN-high subgroup of the Sha cohort27 (from the REMoDL-B trial) seems to confirm a potential druggability of the MBN sig- nature: in fact treatment with RB-CHOP (R-CHOP plus bortezomib) was associated with a significantly prolonged PFS which translated in increased OS rates in the MBN-high subgroup, as compared to standard R-CHOP (Figure 5E and F). Proteasome inhibitors, BET inhibitors and selective BCL-2 inhibitors could be the basis for rationally-designed combinations for the MBN-Sig high DLBCL subgroup. Alternative strategies to target NF-kB include lenalidomide and B-cell receptor signaling inhibitors, all of which are under clinical investigation in DLBCL. Three COO-based phase III trials testing R- CHOP + Ibrutinib (Phoenix trial16) or Lenalidomide (ROBUST trial17) or bortezomib (REMoDL-B trial18) did not meet their primary endpoints. Although several fac- tors concurred to these negative results, the development of alternative and druggable molecular signatures repre- sents an unmet need and could be of primary importance for the design of future precision medicine clinical trials.
The results of our study indicate that a simple and cost- effective three-gene assay (MBN signature) could refine current prognostic stratification algorithms providing the rationale for the implementation of precision medicine tri- als in the MBN-Sig high subset.
Disclosures
ACe and NC are employees and shareholders of NanoString technology; ED has received research funding from TG- Therapeutics, ADC-Therapeutics, Takeda and sits on the Advisory Board for Gilead; ES has received support from Novartis and Eusapharma for educational events; ACh sit on the Advisory Boards with Celgene, Gilead-Kite, Janssen, Iqone, Takeda and has received honoraria for lectures from Celgene, Gilead-Kite, Janssen, Roche, Servier; UV has a consulting or advisory role for Celgene, Gilead and Janssen and is part of the speakers’ bureau with Roche, Celgene, Janssen, Gilead
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Contributions
ED and SP designed the study, interpreted the data and wrote the manuscrip; SM and MF performed bioinformatics and statis- tical analyes, and SM helped with manuscript writing; FM and GM performed T-GEP experiments; VT, SF, CA and ACa per- formed immunohistochemistry; SP, ES, VT, SF and CA evaluat- ed immunohistochemistry data; CC and SR performed FISH analyses; ACe and NC helped designing T-GEP experiments and helped with data interpretation; RB helped with data collec- tion; ACab, GP, CT, AMG, PLZ, AR, PC, UV and ACh helped with data collection and interpretation. All authors critically reviewed the draft and approved the manuscript.
Aknowledgments
The authors wish to thank Pier Luigi Antoniotti, Sebastiano Spagnolo, Marco Giuffrida and Virginia Maltoni for technical assistance.
Funding
This study was funded by the AIRC 5x1000 grant to SP (n. 21198) and Italian Ministry of Health with Ricerca Corrente.
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