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EDITORIALS
Preventing central nervous system spread in diffuse large B-cell lymphoma – novel approaches needed
Mark Roschewski
Lymphoid Malignancies Branch, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA E-mail: MARK ROSCHEWSKI - mark.roschewski@nih.gov
doi:10.3324/haematol.2021.278559
Anumber of retrospective datasets have addressed the controversial topic of chemotherapy as central nerv- ous system (CNS) prophylaxis during frontline man- agement of diffuse large B-cell lymphoma (DLBCL).1-5 Despite the fact that CNS spread is a feared and often termi- nal 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.6-8 The CNS International Prognostic Index (CNS-IPI) is a commonly used risk model that stratifies patients into risk categories;9 combining this model with the
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cell-of-origin phenotype may improve selection of patients.10 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).11 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 ther- apy, but since brain parenchymal sites are the commonest site of CNS relapse, some advocate the use of deeply pene- trant drugs such as high-dose methotrexate.3,12 No random- ized 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.13 In essence, the debate about optimal delivery methods is a “race to the bottom” that compares two strate-
Figure 1. A subset of patients with diffuse large B-cell lymphoma are at high-risk of disease spread to the central nervous system and are often treated with chemotherapy prophylaxis. A critical barrier to effective central nervous system (CNS) prophylaxis is the blood-brain barrier (1) which limits the entry of the chemotherapy agents that are most effective for systemic diffuse large B-cell lymphoma (DLBCL) (2). Current therapeutic options for CNS chemotherapy prophylaxis are systemic chemotherapy (3) or intrathecal chemotherapy (4) which are both limited in efficacy and increase toxicity. Novel small molecule inhibitors that effectively penetrate the blood-brain barrier are being tested in DLBCL involving the CNS and may improve treatment options.
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haematologica | 2021; 106(9)