Guidelines for diagnosis, prevention and management of central nervous system involvement in diffuse large B-cell lymphoma patients by the Spanish Lymphoma Group (GELTAMO)

Abstract

Several factors hinder the identification of risk factors for central nervous system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL), including the retrospective nature of most studies, the relatively low frequency of CNS relapse in DLBCL, and the heterogeneity of CNS prophylaxis methods used in these studies. Moreover, the impact of newly developed diagnostic tools (such as multiparameter flow cytometry [FCM]) and new treatments introduced in the last decade, in particular rituximab, has still not been fully clarified.Several studies 4,5,[7][8][9][10] and a recent meta-analysis 1 have described a decrease in rates D iffuse large B-cell lymphoma patients have a 5% overall risk of central nervous system events (relapse or progression), which account for high morbidity and frequently fatal outcomes, 1 and shortened overall survival of <6 months.2 Early diagnosis of central nervous system events is critical for successful treatment and improved prognosis. Identification of patients at risk of central nervous system disease is critical to accurately identify candidates for central nervous system prophylaxis vs. therapy. [3][4][5] This report by the Spanish Lymphoma Group (GELTAMO) aims to provide useful guidelines and recommendations for the prevention, diagnosis, and treatment of central nervous system diffuse large B-cell lymphoma patients with, or at risk of, leptomeningeal and/or brain parenchyma lymphoma relapse. A panel of lymphoma experts working on behalf of GELTAMO reviewed all data published on these topics available in PubMed up to May 2016. Recommendations were classified according to the Grading of Recommendations Assessment Development and Evaluation (GRADE) approach. 6 A practical algorithm based on the proposed recommendations was then developed (Figure 1 have concluded that the incidence of CNS relapse decreased after the introduction of rituximab (Table 1). The identification of risk factors has been the major goal of many studies of CNS involvement. Several large retrospective studies conducted in the pre-rituximab era [12][13][14][15] reported higher rates of CNS relapse in patients with increased serum lactate dehydrogenase (LDH) levels and/or involvement of >1 extranodal site, although these factors failed to predict CNS relapse in more than half of all cases.12 In addition to the involvement of >1 extranodal site and increased LDH, International Prognostic Index (IPI) score was also identified as an independent predictor for CNS relapse in other studies.13,16 A post-rituximab era study of 399 DLBCL patients, randomized to R-CHOP or CHOP chemotherapy, 3 identified an age-adjusted IPI (aaIPI) >1 as the only risk factor for CNS involvement, although a high aaIPI score was recorded for more than 60% of the patients. When aaIPI was excluded from the analysis, elevated LDH and a poor performance status (PS >1) were identified as independent predictive factors for CNS relapse. Similarly, in the randomized RICOVER-60 trial, 4 the combination of increased LDH levels, the involvement of >1 ex...

Extranodal Diffuse Large B Cell Lymphoma: Molecular Features, Prognosis, and Risk of Central Nervous System Recurrence

“…Therefore, some experts offer CNS prophylaxis to all DLBCLs involving high-risk sites like testes, uterus, breast, or epidural bone lesions [42]. British guidelines recommend prophylaxis for those with elevated LDH and >1 extranodal site, or with testicular, breast, or epidural involvement [43], while the Spanish Lymphoma Group recommends it additionally for high CNS-IPI, double-hit lymphoma, and involvement of kidney or adrenal gland [44]. The US National Comprehensive Cancer Network (NCCN) guidelines acknowledge the uncertain efficacy of intrathecal or systemic prophylaxis, suggesting it in high CNS-IPI, HIV-associated, testicular, breast, or double-hit lymphoma [45].…”

“…Common strategies include intrathecal methotrexate (with or without cytarabine and/or hydrocortisone), or intravenous high-dose methotrexate [43]. Because of predominance of intra-parenchymal CNS recurrences, and lack of benefit to intrathecal treatment in several studies [34, 58–60], systemic approaches are increasingly favored [44, 61]. Published data suggest potential efficacy of methotrexate at 3–3.5 g/m 2 administered either concurrently with R-CHOP (on day 15 of cycles 2, 4, and 6) [62], or after its completion [63].…”

Optimization of CSF biological investigations for CNS lymphoma diagnosis

“…Even though clonality analysis is considered as a sensitive method improving the diagnosis of CNS involvement by lymphoid malignancies, it is not recommended so far to use it systematically but rather as a complementary test . Interpretation can be challenging on samples containing low number of B cells, which is typically the case with CSF.…”

Central nervous system involvement in patients with diffuse large B cell lymphoma: analysis of the risk factors and prognostic from a single-center retrospective cohort study

“…Other regimens, such as HD-MTX combined with IV rituximab or IV HD-cytarabine combined with oral temozolomide, may be feasible options 21 . Patients with resistant lymphoma should be candidates for clinical trials or other palliative treatment [17,22]. In our center, we tried to take effective measures to prolong the patients' survival time.…”