A retrospective analysis of clinicopathological and genetic features of synchronous CNS and systemic DLBCL at diagnosis.

Synchronous central nervous system (CNS) and systemic diffuse large B-cell lymphoma (synDLBCL) is a rare, aggressive entity with poor prognosis and limited data guiding optimal management. We retrospectively analyzed 25 patients with synDLBCL treated at our institution between 2012 and 2021. Among the 20 patients undergoing curative-intent treatment, most received less-intensive CNS-directed therapies, including R-CHOP with intrathecal chemotherapy or high-dose methotrexate. The 3-year progression-free survival rate was 33%, with CNS progression as the predominant site of treatment failure. Genetic profiling in 12 patients revealed a high prevalence (83%) of the MCD subtype, characterized by frequent MYD88 and CD79B mutations, irrespective of immunohistochemical cell-of-origin classification. These findings align with the genetic landscape of primary CNS lymphoma, underscoring the limitations of less-intensive CNS-directed therapies in achieving durable CNS control in synDLBCL. Our findings highlight the need for CNS-penetrant, intensified frontline strategies and support the investigation of Bruton's tyrosine kinase inhibitor-containing regimens in this population. Multicenter collaborative studies with standardized diagnostic and treatment approaches are essential to improve outcomes in synDLBCL.