Concurrent TP53 and CDKN2A Gene Aberrations in Newly Diagnosed Mantle Cell Lymphoma Correlate with Chemoresistance and Call for Innovative Upfront Therapy

Mantle cell lymphoma (MCL) is a subtype of B-cell lymphoma with a large number of recurrent cytogenetic/molecular aberrations. Approximately 5-10% of patients do not respond to frontline immunochemotherapy. Despite many useful prognostic indexes, a reliable marker of chemoresistance is not available. We evaluated the prognostic impact of seven recurrent gene aberrations including tumor suppressor protein P53 (TP53) and cyclin dependent kinase inhibitor 2A (CDKN2A) in the cohort of 126 newly diagnosed consecutive MCL patients with bone marrow involvement >= 5% using fluorescent in-situ hybridization (FISH) and next-generation sequencing (NGS). In contrast toTP53, no pathologic mutations ofCDKN2Awere detected by NGS.CDKN2Adeletions were found exclusively in the context of other gene aberrations suggesting it represents a later event (after translocation t(11;14) and aberrations ofTP53,or ataxia telangiectasia mutated (ATM)). Concurrent deletion ofCDKN2Aand aberration ofTP53(deletion and/or mutation) represented the most significant predictor of short EFS (median 3 months) and OS (median 10 months). Concurrent aberration ofTP53andCDKN2Ais a new, simple, and relevant index of chemoresistance in MCL. Patients with concurrent aberration ofTP53andCDKN2Ashould be offered innovative anti-lymphoma therapy and upfront consolidation with allogeneic stem cell transplantation.