Molecular biomarkers as key determinants of outcome in mantle cell lymphoma: results from the FIL V-RBAC trial

The present study comprehensively dissects the molecular landscape of elderly mantle cell lymphoma (MCL) patients enrolled in the phase II V-RBAC trial of the Fondazione Italiana Linfomi. Of the 140 patients enrolled in the trial, 132 had available gDNA extracted from lymph node biopsies or bone marrow aspirates and were included in the analysis. A CAPP-Seq assay targeting 146 genes relevant to MCL pathogenesis was employed to identify gene mutations and copy number variations. ATM was the most frequently mutated gene, detected in 55 patients (41.7%), followed by TP53 and KMT2D in 31 patients (23.5%). ATM deletion was observed in 32 patients (24%), while CDKN2A loss in 29 (22%). Beyond TP53 mutations, three other molecular lesions, including CDKN2A loss, CD36 mutations and single-hit ATM abnormalities (either mutation or deletion) were independently associated with progression-free survival after adjustment for high-risk trial-defining features, namely Ki-67 >30% and blastoid variant. Notably, patients harboring single-hit ATM alterations without any additional risk factors achieved durable long-term remission, while CD36 mutations were associated with adverse survival. Both findings represent previously unrecognized aberrations that in this cohort independently and inversely associated with survival. The four variables were integrated into a 4-factor molecular prognostic model internally validated using a bootstrapping approach, which identified four distinct patient subgroups with significantly different outcomes. These findings support the importance of i) molecular profiling in MCL, ii) risk-adapted trials like V-RBAC, and iii) the integration of other biological markers with TP53 mutations for a more precise risk assessment in MCL. (NCT03567876).

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Journal
Blood Advances
Published
2026-07-24
DOI
https://doi.org/10.1182/bloodadvances.2026020780
Primary Topic
Lymphoma Diagnosis and Treatment
Type
article
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article

Molecular biomarkers as key determinants of outcome in mantle cell lymphoma: results from the FIL V-RBAC trial

Stefan Hohaus, A. Mokhtar Mahmoud, Federica Melle, Simone Ferrero et al.
Blood Advances
Lymphoma Diagnosis and Treatment
article

Molecular biomarkers as key determinants of outcome in mantle cell lymphoma: results from the FIL V-RBAC trial

Stefan Hohaus, A. Mokhtar Mahmoud, Federica Melle, Simone Ferrero, Filippo Ballerini, Alessia Castellino, Monica Balzarotti, Riccardo Moia, Marcello Riva, Maria Chiara Tisi, Vittorio Ruggero Zilioli, Andrea Evangelista, Nawar Maher, Mohammad Almasri, Lucia Farina, Alessandro Re, Carlo Visco, Gianluca Gaïdano, Alessia Moioli, Stefano Pileri, Benedetta Puccini, Paolo Corradini, Andrea Bernardelli, Elisa Genuardi, Chiara Cosentino, Sara Veronica Usai, Daniela Drandi, Valentina Tabanelli, Francesco Piazza, Roberta Sciarra, Giacomo Loseto, Alice Di Rocco, Jacopo Olivieri, A Merli, Caterina Patti, Francesca Maria Quaglia, Piero Maria Stefani, Gerardo Musuraca, Cristina Muzi, Claudia Castellino, Andrés J.M. Ferreri, Riccardo Bruna, Riccardo Bomben, Pier Luigi Zinzani, Matteo Bellia, Maria Elena Carazzolo, Benedetta Bianchi, Stefano Fiori, Federica Cavallo, Luca Cividini, Francesca Gaia Rossi Dardanoni, Caterina Stelitano, Michele Spina, Francesco Di Rotondo, Marco Ladetto
article en

Abstract

The present study comprehensively dissects the molecular landscape of elderly mantle cell lymphoma (MCL) patients enrolled in the phase II V-RBAC trial of the Fondazione Italiana Linfomi. Of the 140 patients enrolled in the trial, 132 had available gDNA extracted from lymph node biopsies or bone marrow aspirates and were included in the analysis. A CAPP-Seq assay targeting 146 genes relevant to MCL pathogenesis was employed to identify gene mutations and copy number variations. ATM was the most frequently mutated gene, detected in 55 patients (41.7%), followed by TP53 and KMT2D in 31 patients (23.5%). ATM deletion was observed in 32 patients (24%), while CDKN2A loss in 29 (22%). Beyond TP53 mutations, three other molecular lesions, including CDKN2A loss, CD36 mutations and single-hit ATM abnormalities (either mutation or deletion) were independently associated with progression-free survival after adjustment for high-risk trial-defining features, namely Ki-67 >30% and blastoid variant. Notably, patients harboring single-hit ATM alterations without any additional risk factors achieved durable long-term remission, while CD36 mutations were associated with adverse survival. Both findings represent previously unrecognized aberrations that in this cohort independently and inversely associated with survival. The four variables were integrated into a 4-factor molecular prognostic model internally validated using a bootstrapping approach, which identified four distinct patient subgroups with significantly different outcomes. These findings support the importance of i) molecular profiling in MCL, ii) risk-adapted trials like V-RBAC, and iii) the integration of other biological markers with TP53 mutations for a more precise risk assessment in MCL. (NCT03567876).

Blood Advances
University of Verona (IT), Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), Humanitas University (IT), University of Padua (IT), Vita-Salute San Raffaele University (IT), University of Milan (IT), Agostino Gemelli University Polyclinic (IT), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), San Raffaele University of Rome (IT), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), Azienda Ospedaliera Universitaria Integrata Verona (IT), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IT), Azienda ospedaliera "Bianchi-Melacrino-Morelli" (IT), Ospedale Vincenzo Cervello (IT), Azienda Ospedaliero-Universitaria Careggi (IT), Azienda USL di Bologna (IT), Ospedale Santa Maria della Misericordia di Udine (IT), Ospedale di Circolo di Busto Arsizio (IT), Centro di Riferimento Oncologico (IT), Ospedale Infermi di Rimini (IT), Istituto Tumori Bari (IT), Azienda Sanitaria Ospedaliera S.Croce e Carle Cuneo (IT), Ca' Foncello Hospital (IT), Ospedale Policlinico San Martino (IT), Azienda Ospedale - Università Padova (IT), Policlinico San Matteo Fondazione (IT), Ospedale San Bortolo (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Fondazione IRCCS Istituto Nazionale dei Tumori (IT), Azienda Ospedaliera Carlo Poma (IT), University of Turin (IT), European Institute of Oncology (IT)
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Lymphoma Diagnosis and Treatment
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