Prevention of CNS relapse in diffuse large B‐cell lymphoma: common sense prevails where science fails

Central nervous system (CNS) dissemination is an uncommon event in patients with diffuse large B-cell lymphoma (DLBCL), with an incidence ranging from 2 3% to 12% in the rituximab era. However, prognosis of affected patients is poor, with a two-year overall survival of 20% in routine practice and 45% in prospective trials. Available evidence suggests that the only patients with secondary CNS involvement who can be cured are those who receive myeloablative chemotherapy supported by autologous stem cell transplantation after complete remission of CNS disease. Thus, a compelling strategy should consist of timely identification of patients at high risk of CNS dissemination and delivery of suitable prophylaxis to reduce both CNS recurrences and the necessity of intensified treatments. However, there is no consensus regarding the best criteria to distinguish high-risk patients and, equally important, the best strategy to prevent CNS relapse remains to be defined. In the British Journal of Haematology, Pam McKay and colleagues provide good practice recommendations focused on these important open questions. The authors should be commended for their efforts to draw balanced practical suggestions based on a fragmentary and often confusing literature. Probably, some readers will not agree with certain specific statements, but, in our opinion, with some fine-tunes and clarifications, this is an appropriate document to guide physicians’ decisions, while waiting for high-level studies. CNS involvement is an early event in DLBCL patients, being usually detected before or during first-line chemotherapy. Accordingly, examination of CNS organs at initial lymphoma diagnosis is an important issue, as positive results require consideration of a CNS-directed chemotherapy approach, which is completely different from the R-CHOP combination currently used to treat DLBCL. McKay and colleagues recommend including CNS imaging [contrastenhanced magnetic resonance imaging (MRI) is preferred] and cerebrospinal fluid (CSF) examination as part of staging work-up in patients with clinical features of CNS disease or with lesions in close proximity to the CNS. This is accepted for patients with neurological symptoms, whereas studies addressing the diagnostic sensitivity of brain MRI in asymptomatic patients are lacking. However, discussed recommendations are of good sense as high-risk patients should receive CNS prophylaxis, even when neurological symptoms are absent, and intrathecal chemotherapy delivered by lumbar puncture is the most commonly used strategy, alone or combined with intravenous chemotherapy. A safe lumbar puncture requires that the presence of a brain expansive mass is ruled out by neuroimaging. Therefore, the use of MRI and CSF examination as staging procedures seems a good practice in patients with high-risk DLBCL, at least when intrathecal prophylaxis is indicated. Available CNS prophylaxis strategies are associated with increased risk of neurotoxicity, such as chemical or infective meningitis, as well as haematological, renal and hepatic toxicity in a variable proportion of patients. Thus, we have to limit the use of CNS prophylaxis to patients with higher risk of CNS relapse. Different variables and scores predicting CNS recurrence risk have been proposed, but related studies were retrospective, encompassing different lymphoma entities, and used varied prophylaxis strategies. In the rituximab era, the most consistent scores are based on the variables of the International Prognostic Index (IPI; age, performance status, stage, extranodal sites, serum LDH) and involvement of specific extranodal organs. In their recommendations, authors recognise four features associated with increased risk: a CNS-IPI score ≥ 4, the involvement of ≥ 3 extranodal organs, testicular, renal/adrenal or intravascular involvement and (possibly) breast or uterine involvement. The score termed ‘CNS-IPI’ includes the IPI parameters and renal/adrenal involvement to stratify patients into three different risk groups, with two-year CNS relapse rates of 0 6%, 3 4% and 10 2% respectively. The predictive sensitivity of the CNSIPI is limited by the exclusion of extranodal organs with well-documented propensity to disseminate to the CNS, like testes, breast, paranasal sinus, orbit and skeleton among others. This limitation is highlighted by the retrospective Correspondence: Andr es J. M. Ferreri, Lymphoma Unit, Department of Onco-hematology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy. E-mail: ferreri.andres@hsr.it commentary