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Non-Hodgkin Lymphoma
A B-cell receptor-related gene signature predicts survival in mantle cell lymphoma: results from the Fondazione Italiana Linfomi MCL-0208 trial
Ferrata Storti Foundation
Riccardo Bomben,1* Simone Ferrero,2,3* Tiziana D'Agaro,1 Michele Dal Bo,1 Alessandro Re,4 Andrea Evangelista,5 Angelo Michele Carella,6 Alberto Zamò,7 Umberto Vitolo,8 Paola Omedè,3 Chiara Rusconi,9 Luca Arcaini,10
Luigi Rigacci,11 Stefano Luminari,12,13 Andrea Piccin,14 Delong Liu,15
Adrian Wiestner,15 Gianluca Gaidano,16 Sergio Cortelazzo,17 Marco Ladetto2,18 and Valter Gattei1**
Haematologica 2018 Volume 103(5):849-856
1Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy; 2Department of Molecular Biotechnologies and Health Sciences, Hematology Division 1, University of Torino, Italy; 3Hematology Division 1, AOU “Città della Salute e della Scienza di Torino” University-Hospital, Italy; 4Hematology, AO “Spedali Civili di Brescia”, Italy; 5Unit of Cancer Epidemiology, AOU “Città della Salute e della Scienza di Torino” University-Hospital, Italy; 6Hematology Division 1, IRCCS AOU San Martino IST, Genova, Italy; 7Department of Diagnostics and Public Health, University of Verona, Italy; 8Hematology Division 1, AOU “Città della Salute e della Scienza di Torino” University-Hospital, Italy; 9Hematology Division, “Niguarda Ca’ Granda” Hospital, Milano, Italy; 10Hematology Division, Department of Molecular Medicine, IRCCS Fondazione San Matteo, Pavia, Italy; 11Hematology Division, AOU “Careggi”, University of Firenze, Italy; 12Hematology, Azienda Sanitaria Locale IRCCS, Reggio Emilia, Italy; 13Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Reggio Emilia, Italy; 14Department of Hematology and BMT Unit, Bolzano/Bozen Regional Hospital, Italy; 15Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA; 16Division of Haematology, Department of Translational Medicine –University of Eastern Piedmont, Novara, Italy; 17Hematology, Medical Oncology and Hematology Division, “Istituto Clinico Humanitas Gavazzeni”, Bergamo, Italy and 18SC Ematologia Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
*RB and SF contributed equally to this work as first authors: **ML and VG contributed equally to this work as senior authors
ABSTRACT
Mantle cell lymphoma patients have variable clinical courses, ranging from indolent cases that do not require immediate treat- ment to aggressive, rapidly progressing diseases. Thus, diagnos- tic tools capable of stratifying patients according to their risk of relapse and death are needed. This study included 83 samples from the Fondazione Italiana Linfomi MCL-0208 clinical trial. Through gene expression profiling and quantitative real-time PCR we analyzed 46 peripheral blood and 43 formalin-fixed paraffin-embedded lymph node samples. A prediction model to classify patients was developed. By ana- lyzing the transcriptome of 27 peripheral blood samples, two subgroups characterized by a differential expression of genes from the B-cell recep- tor pathway (B-cell receptorlow and B-cell receptorhigh) were identified. The prediction model based on the quantitative real-time PCR values of six representative genes (AKT3, BCL2, BTK, CD79B, PIK3CD, and SYK), was used to classify the 83 cases (43 B-cell receptorlow and 40 B-cell receptorhigh). The B-cell receptorhigh signature associated with shorter pro- gression-free survival (P=0.0074), selected the mantle cell lymphoma subgroup with the shortest progression-free survival and overall survival (P=0.0014 and P=0.029, respectively) in combination with high (>30%) Ki-67 staining, and was an independent predictor of short progression- free survival along with the Mantle Cell Lymphoma International Prognostic Index-combined score. Moreover, the clinical impact of the 6- gene signature related to the B-cell receptor pathway identified a mantle cell lymphoma subset with shorter progression-free survival intervals also in an external independent mantle cell lymphoma cohort homoge- nously treated with different schedules. In conclusion, this 6-gene signa- ture associates with a poor clinical response in the context of the MCL- 0208 clinical trial. (clinicaltrials.gov identifier: 02354313).
Correspondence:
rbomben@cro.it
Received: November 10, 2017. Accepted: February 14, 2018. Pre-published: February 22, 2018.
doi:10.3324/haematol.2017.184325
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/5/849
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Haematologica | 2018; 103(5)
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