TP53 Mutations in Mantle Cell Lymphoma: From Backup to Game Changer

Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) whose clinical course is largely shaped by molecular and biological features. Among the most impactful prognostic markers, <i>TP53</i> mutations have emerged as critical determinants of treatment resistance since their first identification in MCL in 1996. Regardless of the detection method, <i>TP53</i> mutations have been consistently associated with primary refractoriness to chemoimmunotherapy and significantly reduced overall survival. In this perspective, we explored recent advances in applying integrated-omics approaches to assess <i>TP53</i> status. Despite its prognostic value, routine testing for <i>TP53</i> at diagnosis remains uncommon, hindered by the lack of standardized protocols and costs for Next-Generation Sequencing (NGS), and the suboptimal reliability of immunohistochemistry (IHC) as a surrogate. This gap between research evidence and clinical practice represents a critical barrier to risk-adapted therapy. The broad implementation of standardized and accessible genomic techniques is essential to identify patients who deserve a personalized therapeutic approach. Several clinical trials have recently explored alternative chemo-free or targeted regimens specifically tailored to <i>TP53</i>-mutated patients (i.e., NCT03824483, NCT03567876), with promising results. This risk-adapted approach reflects a paradigm shift in MCL management, emphasizing the need for early molecular risk assessment to guide treatment decisions. In this scenario, <i>TP53</i> mutations are no longer supporting actors, but a game-changer for the prognosis and treatment of patients with MCL.