Central nervous system dissemination in immunocompetent patients with aggressive lymphomas: incidence, risk factors and therapeutic options

Abstract

Central nervous system (CNS) dissemination is a rare (4-5%) but usually fatal complication of aggressive lymphomas. Prophylaxis modalities to prevent CNS dissemination in aggressive lymphomas cannot be widely applied to every lymphoma patient since it is associated with increased risk of neurotoxicity. Therefore, identification of high-risk patients as the best candidates to receive CNS prophylaxis constitutes a major endpoint in the management of these malignancies. Various risk factors and models for CNS recurrence have been described. Parameters reflecting the extent and proliferation of the disease, like elevated serum lactate dehydrogenase levels, involvement of multiple extranodal sites, advanced stage and high age-adjusted International Prognostic Index (IPI) score, as well as the involvement of specific anatomic sites, like testes, orbit, paranasal sinuses, have been identified and confirmed as important to predict CNS dissemination. Management of this complication in aggressive lymphomas with conventional-dose chemotherapy is associated with disappointing results, while some preliminary but encouraging experiences suggest a potential role of high-dose chemotherapy and stem cell transplantation. The analysis of recent clinical studies could lead to advancement in the prognosis of aggressive lymphomas, but several questions regarding the optimum chemotherapy combination, the best conditioning regimen and the role of radiation therapy and intrathecal chemotherapy remain still unanswered. The purposes of the present review are to critically analyse current data on the risk of CNS dissemination in aggressive lymphomas, the clinical presentation of secondary CNS lymphomas and the efficacy of CNS prophylaxis as well as to discuss the available therapeutic options for this devastating event.

Phase 2 study of intrathecal, long‐acting liposomal cytarabine in the prophylaxis of lymphomatous meningitis in human immunodeficiency virus‐related non‐Hodgkin lymphoma

“…Our recurrence rate (3%) seems to be similar to that reported in previous studies in both HIV-positive 18,21 and HIV-negative patients with aggressive lymphomas. 12 Moreover, in our experience previous to the present study, we used methotrexate in 285 patients with HIV-NHL with comparable side effects and a recurrence rate of 10% (P ¼ .21).…”

“…[1][2][3][4][5][6][7][8][9][10][11] Moreover, the overall incidence of CNS recurrence with or without intrathecal prophylaxis is around 5%. 3,[12][13][14][15] Since the beginning of the acquired immune deficiency syndrome (AIDS) epidemic, a close association between human immunodeficiency virus (HIV) infection and high-grade NHL has been reported. At onset, HIV-NHLs fall within stages III and IV in >70% to 98% of cases with extranodal involvement, mainly the gastrointestinal tract, the bone marrow, and the CNS.…”

Neurological Complications of Non-Hodgkin Lymphoma

“…Control of meningeal disease is necessary to prevent neurological morbidity and preserve quality of life. However, optimal management for LM is unclear, and the prognosis remains poor [35,36]. Reported median overall survival has been in the range of 2.2-19 months, but most often 4-5 months [35].…”

High-Dose Methotrexate and Cytarabine-Based Multi-Agent Chemotherapy (Modified Bonn Protocol) for Systemic Lymphoma with CNS Involvement

“…While these therapies appear to be effective for the treatment of CNS involvement, the main cause of death is the systemic progression of lymphoma [9]. Due to the need to control both the CNS and systemic compartments, the clinical outcomes of systemic lymphoma with CNS involvement are poor compared with PCNSL, and the reported median survival duration is only a few months [1,2]. …”

“…Central nervous system (CNS) involvement of malignant lymphomas is a rare but serious complication, and is related to high mortality [1,2]. CNS involvement of lymphomas has been classified into 4 categories: primary CNS lymphoma (PCNSL) that is limited to a CNS site, systemic lymphoma with CNS involvement at diagnosis, isolated CNS relapse, and CNS involvement with systemic relapse or progression [3].…”