Page 146 - Haematologica - Vol. 105 n. 6 - June 2020

Non-Hodgkin Lymphoma
Ferrata Storti Foundation
Haematologica 2020 Volume 105(6):1604-1612
KMT2D mutations and TP53 disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy: a FIL study
Simone Ferrero,1,2* Davide Rossi,3,4* Andrea Rinaldi,4* Alessio Bruscaggin,4 Valeria Spina,4 Christian W. Eskelund,5,6 Andrea Evangelista,7 Riccardo Moia,8 Ivo Kwee,4,9,10 Christina Dahl,11 Alice Di Rocco,12 Vittorio Stefoni,13 Fary Diop,8 Chiara Favini,8 Paola Ghione,1 Abdurraouf Mokhtar Mahmoud,8
Mattia Schipani,8 Arne Kolstad,14 Daniela Barbero,1 Domenico Novero,15 Marco Paulli,16 Alberto Zamò,17,18 Mats Jerkeman,19 Maria Gomes da Silva,20 Armando Santoro,21 Annalia Molinari,22 Andres Ferreri,23 Kirsten Grønbæk,5,6 Andrea Piccin,24 Sergio Cortelazzo,25 Francesco Bertoni,4# Marco Ladetto26# and Gianluca Gaidano8#
1Department of Molecular Biotechnologies and Health Sciences - Hematology Division, Università di Torino, Torino, Italy; 2Hematology Division, AOU Città della Salute e della Scienza di Torino, Torino, Italy; 3Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; 4Universita’ della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland; 5Department of Hematology, Rigshospitalet, Copenhagen, Denmark; 6Biotech Research and Innovation Centre, Copenhagen, Denmark; 7Clinical Epidemiology, Città della Salute e della Scienza and CPO Piemonte, Torino, Italy; 8Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy; 9Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland; 10Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland; 11Danish Cancer Society Research Center, Copenhagen, Denmark; 12Department of Cellular Biotechnologies and Hematology, Policlinico Umberto I, "Sapienza" University of Rome, Roma, Italy; 13Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy; 14Department of Oncology, Oslo University Hospital, Oslo, Norway; 15First Unit of Pathology, AOU Città della Salute e della Scienza di Torino, Torino, Italy; 16Unit of Anatomic Pathology, Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo and Università degli Studi di Pavia, Pavia, Italy; 17Department of Oncology, Università di Torino, Torino, Italy; 18Department of Diagnostics and Public Health, University of Verona, Verona, Italy; 19Department of Oncology, Lund University Hospital, Lund, Sweden; 20Department of Hematology, Instituto Português de Oncologia de Lisboa, Lisboa, Portugal; 21Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy; 22Hematology, Ospedale degli Infermi, Rimini, Italy; 23Lymphoma Unit, Department of Onco-Haematology, IRCCS San Raffaele Scientific Institute, Milano, Italy; 24Department of Hematology, Ospedale Generale, Bolzano, Italy; 25Oncology Unit, Humanitas/Gavazzeni Clinic, Bergamo, Italy and 26SC Ematologia, Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
*SF, DR and AR contributed equally as co-first authors. #FB, ML and GG contributed equally as co-senior authors.
ABSTRACT
In recent years, the outcome of mantle cell lymphoma (MCL) has improved, especially in younger patients, receiving cytarabine-contain- ing chemoimmunotherapy and autologous stem cell transplantation. Nevertheless, a proportion of MCL patients still experience early failure. To identify biomarkers anticipating failure of intensive chemotherapy in MCL, we performed target resequencing and DNA profiling of purified tumor samples collected from patients enrolled in the prospective FIL-MCL0208 phase 3 trial (high-dose chemoimmunotherapy followed by autologous transplantation and randomized lenalidomide maintenance). Mutations of KMT2D and disruption of TP53 by deletion or mutation associated with an increased risk of progression and death, both in univariate and multivariate analysis. By adding KMT2D mutations and TP53 disruption to the MIPI-c backbone, we derived a new prognostic index, the “MIPI-genetic” (“MIPI-
Correspondence:
SIMONE FERRERO
simone.ferrero@unito.it
Received: December 24, 2018. Accepted: September 19, 2019. Pre-published: September 19, 2019.
doi:10.3324/haematol.2018.214056
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