Molecular Correlates of Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma

Introduction:Central nervous system (CNS) relapse is a rare phenomenon in diffuse large B-cell lymphoma (DLBCL), occurring in less than 5% of all patients, but is associated with disproportionate morbidity and mortality. Indeed, the median survival of patients diagnosed with CNS relapse is as low as 2-4 months. Individual risk factors for CNS relapse are well established, and include clinical parameters such as stage, number/type of extranodal sites and elevated lactate dehydrogenase. These and other clinical risk factors have been integrated into a risk score that is reproducible and easy to calculate (CNS International Prognostic Index). Moreover, molecular attributes such as double-hit translocation status, MYC/BCL2 dual protein expression and the activated B-cell-like subtype have been associated with a higher risk of CNS relapse. However, while experts recommend prophylactic interventions for high-risk patients, the major shortcoming of available risk tools is their limited sensitivity. Herein, we evaluated whether gene expression and/or mutational profiles can identify those patients that will ultimately experience CNS relapse, and whether intratumoral heterogeneity impedes accurate prognostication.