In recent years, the outcome of mantle cell lymphoma has improved, especially in younger patients, receiving cytarabine-containing chemoimmunotherapy and autologous stem cell transplantation. Nevertheless, a proportion of mantle cell lymphoma patients still experience early failure. To identify biomarkers anticipating failure of intensive chemotherapy in mantle cell lymphoma, we performed target resequencing and DNA profiling of purified tumor samples collected from patients enrolled in the prospective FIL-MCL0208 phase III 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. The MIPI-g improved the model discrimination ability compared to the MIPI-c alone, defining three risk groups: i) low-risk patients (4-years progression free survival and overall survival of 72.0% and 94.5%); ii) intermediate-risk patients (4-years progression free survival and overall survival of 42.2% and 65.8%) and iii) high-risk patients (4-years 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 mantle cell lymphoma patients for whom novel therapeutic strategies need to be investigated. (Trial registered at clinicaltrials.gov identifier: NCT02354313).