KMT2D mutations and TP53 disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy:a FIL study
| Autor: | Abdurraouf Mokhtar Mahmoud, Chiara Favini, Kirsten Grønbæk, Domenico Novero, Armando Santoro, Davide Rossi, Arne Kolstad, Andrea Rinaldi, Andrés J.M. Ferreri, Valeria Spina, Christian Winther Eskelund, Simone Ferrero, Paola Ghione, Daniela Barbero, Sergio Cortelazzo, Andrea Evangelista, Marco Ladetto, Vittorio Stefoni, Mattia Schipani, Alice Di Rocco, Fary Diop, Mats Jerkeman, Riccardo Moia, Francesco Bertoni, A. L. Molinari, Andrea Piccin, Gianluca Gaidano, Alberto Zamo, Christina Dahl, Alessio Bruscaggin, Marco Paulli, Ivo Kwee, Maria Gomes da Silva |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Oncology
medicine.medical_specialty Non-Hodgkin Lymphoma Population Aggressive Non-Hodgkin's Lymphoma Gene mutation 03 medical and health sciences 0302 clinical medicine Autologous stem-cell transplantation Chemoimmunotherapy Internal medicine Medicine Autologous transplantation Molecular predictors Progression-free survival education Cytogenetics and Molecular Genetics Laboratory Hematology Mantle cell lymphoma education.field_of_study business.industry Articles Hematology medicine.disease Transplantation business 030215 immunology |
| Zdroj: | Ferrero, S, Rossi, D, Rinaldi, A, Bruscaggin, A, Spina, V, Eskelund, C W, Evangelista, A, Moia, R, Kwee, I, Dahl, C, Di Rocco, A, Stefoni, V, Diop, F, Favini, C, Ghione, P, Mahmoud, A M, Schipani, M, Kolstad, A, Barbero, D, Novero, D, Paulli, M, Zamò, A, Jerkeman, M, Gomez Da Silva, M, Santoro, A, Molinari, A, Ferreri, A, Grønbæk, K, Piccin, A, Cortelazzo, S, Bertoni, F, Ladetto, M & Gaidano, G 2020, ' KMT2D mutations and TP53 disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy : a FIL study ', Haematologica, vol. 105, no. 6, pp. 1604-1612 . https://doi.org/10.3324/haematol.2018.214056 Haematologica |
| Popis: | In recent years, the outcome of mantle cell lymphoma (MCL) has improved, especially in younger patients, receiving cytarabine-containing 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- g”). The “MIPI-g” improved the model discrimination ability compared to the MIPI-c alone, defining three risk groups: i) low-risk patients (4-year progression free survival and overall survival of 72.0% and 94.5%); ii) inter-mediate-risk patients (4-year progression free survival and overall survival of 42.2% and 65.8%) and iii) high-risk patients (4-year progression free survival and overall survival of 11.5% and 44.9%). Our results: i) confirm that TP53 disruption identifies a high-risk population characterized by poor sensitivity to conventional or intensified chemotherapy; ii) provide the pivotal evidence that patients harboring KMT2D mutations share the same poor outcome as patients harboring TP53 disruption; and iii) allow to develop a tool for the identification of high-risk MCL patients for whom novel therapeutic strategies need to be investigated. (Trial registered at clinicaltrials.gov identifier: NCT02354313). |
| Databáze: | OpenAIRE |
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