CNS prophylaxis in diffuse large B-cell lymphoma: If, when, how and for whom?

Central nervous system (CNS) relapse is an uncommon devastating complication of diffuse large B-cell lymphoma (DLBCL) that usually occurs within 2 years from initial diagnosis. Its pathophysiology is poorly understood and there is no consensus on the definition of high-risk patients for CNS relapse. Consequently, an empirical and highly variable practice of chemoprophylaxis is employed. In this review we critically appraise the available literature in order to address issues related to ineffectiveness of current paradigms of chemoprophylaxis. The commonly used prophylaxis is derived from past experience with childhood acute leukemia where most early CNS relapses are leptomeningeal. In contrast, CNS involvement in DLBCL affects brain parenchyma in almost 60% of cases and thus intrathecal prophylaxis remains ineffective. We propose that CNS relapse in DLBCL is sometimes related to occult malignant cells present in the CNS at diagnosis. In others, CNS relapse is likely due to a later acquisition of CNS-penetrating subtypes of malignant clones. With lack of evidence for occult CNS involvement no strong indication currently exist that any form of chemoprophylaxis is beneficial. Future directions for evaluation and treatment of CNS disease are outlined. This complex and intriguing topic should be ideally investigated by prospective trials.