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Advances in risk assessment and prophylaxis for central nervous system relapse in diffuse large B-cell lymphoma
Ferrata Storti Foundation
Haematologica 2019 Volume 104(1):25-34
David Qualls and Jeremy S. Abramson
Center for Lymphoma, Massachusetts General Hospital Cancer Center, Boston, MA, USA
ABSTRACT
Central nervous sytem recurrence of diffuse large B-cell lymphoma is an uncommon but devastating event, making identification of patients at high risk for relapse within the central nervous system essential for clinicians. Modern risk stratification includes both clinical and biological features. A validated clinical risk model employing the five traditional International Prognostic Index risk factors plus renal or adrenal involvement can identify a high-risk patient population with a central nervous system recurrence risk of greater than 10%. Lymphoma involve- ment of certain discrete extranodal sites such as the testis also confers increased risk, even in stage I disease. Adverse biological risk factors for central nervous system relapse include presence of translocations of MYC, BCL2 and/or BCL6, in so-called double- or triple-hit lymphoma. Immunohistochemically detectable co-expression of MYC and BCL2 in the absence of translocations also portends an increased risk of relapse within the central nervous system, particularly in the setting of the acti- vated B-cell-like subtype of diffuse large B-cell lymphoma. The role, method, and timing of prophylactic therapy remain controversial based on the available data. We review both intrathecal and systemic strategies for prophylaxis in high-risk patients. Our preference is for systemic methotrexate in concert with standard chemoimmunotherapy in the majority of cases. Several novel agents have also demonstrated clinical activity in primary and secondary central nervous system lymphoma and warrant future investigation in the prophylactic setting.
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common adult non-Hodgkin lymphoma, accounting for approximately one-third of all newly diagnosed cases in the United States.1,2 The prognosis has improved substantially since the introduction of rituximab nearly 20 years ago, with 5-year overall survival rates of approximately 70% depending on the baseline characteristics of the patients and their disease.3-5
Despite improvements in outcomes, a minority of patients with DLBCL will still suffer relapse within the central nervous system (CNS), which carries nearly univer- sally poor outcomes with a median survival following diagnosis of CNS involvement of only 2-5 months.6-10 Indeed, secondary CNS lymphoma has long represented a great unmet medical need within the field of oncology, a need that has been partic- ularly difficult to address since CNS involvement is usually an exclusion criterion for participation in clinical trials of novel agents. Given the significant morbidity and mortality associated with this event, much attention has been devoted to the identi- fication of high-risk patients, and evaluation of therapies to mitigate the risk of CNS recurrence.
Another important area of investigation involves the diagnosis and treatment of occult leptomeningeal disease: lymphoma detected by cerebrospinal fluid (CSF) cytology or flow cytometry, without overt clinical signs or symptoms of CNS involvement by lymphoma. Occult disease has been shown to be significantly asso-
Correspondence:
jabramson@mgh.harvard.edu
Received: July 25, 2018.
Accepted: November 15, 2018. Pre-published: December 20, 2018.
doi:10.3324/haematol.2018.195834
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/1/25
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