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

abstractThis study comprehensively dissects the molecular landscape of older patients with mantle cell lymphoma (MCL) enrolled in the phase 2 FIL V-RBAC trial of the Fondazione Italiana Linfomi (FIL). Of the 140 patients enrolled, 132 had available genomic DNA extracted from lymph node biopsies or bone marrow aspirates and were included in the analysis. A cancer personalized profiling by deep sequencing assay targeting 146 genes relevant to MCL pathogenesis was used 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%), whereas CDKN2A loss was observed in 29 (22%). Beyond TP53 mutations, 3 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, whereas CD36 mutations were associated with adverse survival. Both findings represent previously unrecognized aberrations in this cohort that were independently and inversely associated with survival. The 4 variables were integrated into a 4-factor molecular prognostic model internally validated using a bootstrapping approach, which identified 4 distinct patient subgroups with significantly different outcomes. These findings support the importance of (1) molecular profiling in MCL, (2) risk-adapted trials such as FIL V-RBAC, and (3) the integration of other biological markers with TP53 mutations for a more precise risk assessment in MCL. This trial was registered at www.clinicaltrials.gov as NCT03567876.