Haematologica | 2021
Preventing central nervous system spread in diffuse large B-cell lymphoma – novel approaches needed
Abstract
Anumber of retrospective datasets have addressed the controversial topic of chemotherapy as central nervous system (CNS) prophylaxis during frontline management of diffuse large B-cell lymphoma (DLBCL). Despite the fact that CNS spread is a feared and often terminal complication of DLBCL, there is not a broad consensus regarding which patients should receive CNS prophylaxis or the most effective method of delivery. Overall, the incidence of CNS relapse across all subsets of DLBCL is only about 5%, but some clinical risk factors, including the involvement of specific anatomic sites, are associated with a significantly higher rate of CNS spread. Furthermore, we are beginning to uncover the biological basis for DLBCL involving the CNS as specific genetic subtypes demonstrate an inherently higher rate of CNS tropism. The CNS International Prognostic Index (CNS-IPI) is a commonly used risk model that stratifies patients into risk categories; combining this model with the cell-of-origin phenotype may improve selection of patients. However, even the most robust predictive models cannot overcome the fundamental problem that the chemotherapy agents most effective for the cure of systemic DLBCL do not reliably penetrate the blood-brain barrier (Figure 1). Conversely, methotrexate, which reliably penetrates the CNS, is not highly effective for DLBCL. The most commonly used prophylactic strategy is repeated intrathecal injections of chemotherapy such as methotrexate during frontline therapy, but since brain parenchymal sites are the commonest site of CNS relapse, some advocate the use of deeply penetrant drugs such as high-dose methotrexate. No randomized prospective study has directly addressed this specific issue and, as a result, practice patterns rely on consensus guidelines and vary widely across institutions and individual providers. In essence, the debate about optimal delivery methods is a “race to the bottom” that compares two strate-