<i>TP53</i>, <i>CD36</i> Mutations and <i>CDKN2A</i> Loss Predict Poor Outcome in Mantle Cell Lymphoma: Molecular Analysis of the FIL V-Rbac Phase 2 Trial

INTRODUCTION: The FIL V-RBAC trial (EudraCT: 2017-004628-31) is a phase 2 study which enrolled patients with previously untreated mantle cell lymphoma (MCL), stratifying them at initial diagnosis depending on risk factors. High-risk patients, defined as either Ki67≥30% and/or blastoid variant and/or TP53 mutations and/or 17p deletion, received an abbreviated course of R-BAC followed by consolidation and maintenance with venetoclax. Conversely, standard-risk patients with no risk factors received standard R-BAC. The aim of the project was to evaluate the prognostic role of gene mutations and copy-number analysis (CNV) in patients enrolled in the FIL V-RBAC trial. METHODS: Patients enrolled in the trial with availablegDNA extracted from lymph node biopsy were included in this mutational analysis.A CAPP-Seq assay including 146 genes relevant for MCL pathogenesis was used coupled with a robust and previously validated bioinformatic pipeline. Based on CAPP-Seq data, CNV analysis was performed using CNVkit (version 0.9.10) and GISTIC2.0 was used to identify statistically significant CNVs. The primary endpoint was progression-free survival (PFS) according to molecular lesions. RESULTS: Among the 140 patients enrolled in the V-RBAC trial, 132 were analyzed (53 high-risk and 79 standard-risk). The median age of analyzed patients was 72 years and the median follow-up was 32.0 months. The CAPP-Seq analysis recapitulated the mutational landscape of MCL and identified ATM as the most frequently mutated gene (41.7%, N=55), followed by KMT2D (23.5%, N=31), TP53 (23.5%, N=31), WHSC1 (14.4%, N=19), and BIRC3 (9.8%, N=13). As expected, TP53 mutated patients displayed a significantly inferior PFS compared to TP53 unmutated patients (3-year PFS 30.8% versus 79.9%, p&amp;lt;0.001). Among other genes analyzed, only NOTCH1/2 mutations (10.2%, N=14) and CD36mutations (7.3%, N=7) were associated with significantly inferior PFS. In multivariate analysis adjusted for blastoid variant and Ki67&amp;gt;30%, only CD36 (HR 4.73, 95% CI 1.82-12.28, p=0.001) and TP53 (HR 4.75, 95% CI 2.35-9.60, p&amp;lt;0.001) mutations were independently associated with inferior PFS. Interestingly, CD36 mutations significantly stratified the outcome of standard risk patients (p&amp;lt;0.001), but not of high-risk patients (p=0.348), suggesting that CD36may capture additional high-risk patients that are not currently identified by standard prognostic markers. Regarding CNVs, the most frequently detected were amp3q (36.4%, N=51), del13q (35.0%, N=49), CDKN2A loss (30%, N=42) and del11q (27.9%, N=39). After Bonferroni correction, only CDKN2A loss retained prognostic value (HR 2.47, 95% CI 1.20-5.09, p=0.014), when adjusted for TP53 and CD36 mutations. Finally, non-negative matrix factorization based on gene mutations and CNVs identified 3 different clusters characterized by different molecular composition and with clinical relevance for both PFS (p&amp;lt;0.001) and OS (p=0.0037). Cluster 1 (N=41, 29.3%) was enriched in TP53 and CDKN2A loss and was associated with the worst prognosis (3-year PFS of 39.7% and OS of 50.0%); cluster 2 (N=50, 35.7%) was enriched in ATM mutations and associated with the best prognosis (3-year PFS of 87.5% and OS of 82.0%); cluster 3 (N=35, 25.0%) was enriched in KMT2D mutations and presented an intermediate prognosis (3-year PFS of 77.4% and OS of 76.1%). CONCLUSIONS: Molecular analysis of the FIL V-RBAC trial indicates that, together with TP53 mutations, CD36mutations and CDKN2A loss are associated with adverse outcome in MCL patients treated with chemo-immunotherapy and the BCL2-inhibitor venetoclax.

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Blood
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2024-11-05
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https://doi.org/10.1182/blood-2024-198076
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2
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Lymphoma Diagnosis and Treatment
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article

TP53, CD36 Mutations and CDKN2A Loss Predict Poor Outcome in Mantle Cell Lymphoma: Molecular Analysis of the FIL V-Rbac Phase 2 Trial

Sara Galimberti, Francesca Gaia Rossi, Stefan Hohaus, Federica Melle et al.
2 citations
Blood
Lymphoma Diagnosis and Treatment
0.85
article

TP53, CD36 Mutations and CDKN2A Loss Predict Poor Outcome in Mantle Cell Lymphoma: Molecular Analysis of the FIL V-Rbac Phase 2 Trial

Sara Galimberti, Francesca Gaia Rossi, Stefan Hohaus, Federica Melle, Simone Ferrero, Giovanna Motta, Filippo Ballerini, Monica Tani, Monica Balzarotti, Donatella Talotta, Riccardo Moia, Guido Gini, Maria Chiara Tisi, Vittorio Ruggero Zilioli, Carola Boccomini, Andrea Evangelista, Ilaria Del Giudice, Mohammad Almasri, Alessandro Re, Carlo Visco, Gianluca Gaïdano, Stefano Pileri, Maria Vittoria Sacchi, Benedetta Puccini, Paolo Corradini, Valentina Tabanelli, Francesco Piazza, Riccardo Bruna, Roberta Sciarra, Alice Di Rocco, Francesco Merli, Vincenzo Pavone, Valter Gattei, Marco Ladetto, Gerardo Musuraca, Chiara Cosentino, Claudia Castellino, Annalisa Arcari, Riccardo Bomben, Maria Elena Carazzolo, Stefano Fiori, Federica Cavallo, Mancuso Anna, Luca Cividini
article en
2 citations

Abstract

INTRODUCTION: The FIL V-RBAC trial (EudraCT: 2017-004628-31) is a phase 2 study which enrolled patients with previously untreated mantle cell lymphoma (MCL), stratifying them at initial diagnosis depending on risk factors. High-risk patients, defined as either Ki67≥30% and/or blastoid variant and/or TP53 mutations and/or 17p deletion, received an abbreviated course of R-BAC followed by consolidation and maintenance with venetoclax. Conversely, standard-risk patients with no risk factors received standard R-BAC. The aim of the project was to evaluate the prognostic role of gene mutations and copy-number analysis (CNV) in patients enrolled in the FIL V-RBAC trial. METHODS: Patients enrolled in the trial with availablegDNA extracted from lymph node biopsy were included in this mutational analysis.A CAPP-Seq assay including 146 genes relevant for MCL pathogenesis was used coupled with a robust and previously validated bioinformatic pipeline. Based on CAPP-Seq data, CNV analysis was performed using CNVkit (version 0.9.10) and GISTIC2.0 was used to identify statistically significant CNVs. The primary endpoint was progression-free survival (PFS) according to molecular lesions. RESULTS: Among the 140 patients enrolled in the V-RBAC trial, 132 were analyzed (53 high-risk and 79 standard-risk). The median age of analyzed patients was 72 years and the median follow-up was 32.0 months. The CAPP-Seq analysis recapitulated the mutational landscape of MCL and identified ATM as the most frequently mutated gene (41.7%, N=55), followed by KMT2D (23.5%, N=31), TP53 (23.5%, N=31), WHSC1 (14.4%, N=19), and BIRC3 (9.8%, N=13). As expected, TP53 mutated patients displayed a significantly inferior PFS compared to TP53 unmutated patients (3-year PFS 30.8% versus 79.9%, p&amp;lt;0.001). Among other genes analyzed, only NOTCH1/2 mutations (10.2%, N=14) and CD36mutations (7.3%, N=7) were associated with significantly inferior PFS. In multivariate analysis adjusted for blastoid variant and Ki67&amp;gt;30%, only CD36 (HR 4.73, 95% CI 1.82-12.28, p=0.001) and TP53 (HR 4.75, 95% CI 2.35-9.60, p&amp;lt;0.001) mutations were independently associated with inferior PFS. Interestingly, CD36 mutations significantly stratified the outcome of standard risk patients (p&amp;lt;0.001), but not of high-risk patients (p=0.348), suggesting that CD36may capture additional high-risk patients that are not currently identified by standard prognostic markers. Regarding CNVs, the most frequently detected were amp3q (36.4%, N=51), del13q (35.0%, N=49), CDKN2A loss (30%, N=42) and del11q (27.9%, N=39). After Bonferroni correction, only CDKN2A loss retained prognostic value (HR 2.47, 95% CI 1.20-5.09, p=0.014), when adjusted for TP53 and CD36 mutations. Finally, non-negative matrix factorization based on gene mutations and CNVs identified 3 different clusters characterized by different molecular composition and with clinical relevance for both PFS (p&amp;lt;0.001) and OS (p=0.0037). Cluster 1 (N=41, 29.3%) was enriched in TP53 and CDKN2A loss and was associated with the worst prognosis (3-year PFS of 39.7% and OS of 50.0%); cluster 2 (N=50, 35.7%) was enriched in ATM mutations and associated with the best prognosis (3-year PFS of 87.5% and OS of 82.0%); cluster 3 (N=35, 25.0%) was enriched in KMT2D mutations and presented an intermediate prognosis (3-year PFS of 77.4% and OS of 76.1%). CONCLUSIONS: Molecular analysis of the FIL V-RBAC trial indicates that, together with TP53 mutations, CD36mutations and CDKN2A loss are associated with adverse outcome in MCL patients treated with chemo-immunotherapy and the BCL2-inhibitor venetoclax.

BloodVol. 144(Supplement 1)
University of Pisa (IT), University of Verona (IT), Marche Polytechnic University (IT), Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), University of Padua (IT), University of Milan (IT), Agostino Gemelli University Polyclinic (IT), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Ospedale degli Infermi (IT), Ospedale "Santa Maria delle Croci" di Ravenna (IT), Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IT), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), Azienda Ospedaliero-Universitaria Careggi (IT), Azienda USL di Bologna (IT), Fondazione Intergruppo Italiano Linfomi Onlus (IT), Centro di Riferimento Oncologico (IT), Guglielmo da Saliceto Hospital (IT), Ospedale Policlinico San Martino (IT), Piedmont Reference Center for Epidemiology and Cancer Prevention (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), Piedmont University (US), Gruppo Italiano per il Trapianto di Midollo Osseo (IT), IRCCS Humanitas Research Hospital (IT), University of Turin (IT), European Institute of Oncology (IT), Sapienza University of Rome (IT)
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Lymphoma Diagnosis and Treatment
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