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• W3024050325 abstract "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.1-5 However, prognosis of affected patients is poor, with a two-year overall survival of 20% in routine practice6 and 45% in prospective trials.7 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.8 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.9 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.1 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 [contrast-enhanced 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.9 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.2, 10-12 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.11 The predictive sensitivity of the CNS-IPI 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.13 This limitation is highlighted by the retrospective analysis of 1 080 patients with DLBCL enrolled in the UK NCRI R-CHOP14 vs 21 trial,14 in which 81% of CNS relapses have occurred in patients with extranodal disease that usually fell into the low-risk CNS-IPI group because these patients frequently have limited-stage lymphoma and good performance status at presentation. The sensitivity of CNS-IPI might increase to predict 90% of CNS relapses by the addition of some specific extranodal sites;15 however, these figures remain to be confirmed in independent series. Nevertheless, we agree with McKay and colleagues that a higher number of extranodal sites (more than two) is associated with raised CNS risk16 and that available literature does not support undisputedly the use of CNS prophylaxis in patients with double hit lymphoma,14, 17-19 double expresser lymphoma20, 21 or non-germinal-centre B-cell-like phenotype.22 Interestingly, the combined assessment of CNS-IPI and cell of origin seems to be associated with a high predictive sensitivity;20 however, a diffuse use of this strategy to guide CNS prophylaxis indication will require independent confirmatory studies and a wider use of gene-expression profiling in routine practice.23 The proposed UK guidelines raise the importance of a cut-off in the level of estimated CNS risk to distinguish patients who will achieve significant benefit from CNS prophylaxis. Authors pragmatically propose to use prophylaxis in any patient with an estimated CNS relapse rate >10%.9 This is in line with our experience where CNS relapse rate was 12% in DLBCL patients with high CNS risk according to a home-made score.2 However, these findings remain to be confirmed in an independent series, and crude rates should be translated into actuarial rates to avoid the effect of duration of follow-up, which varies widely among reported studies. McKay and colleagues suggest a minimum of two cycles of intravenous methotrexate (MTX) at a dose of ≥ 3 g/m2 by short infusion as CNS prophylaxis in patients with suitable cardiac and renal function.9 Authors suggest administering this drug as early as possible, intercalated with RCHOP-21, leaving intrathecal prophylaxis only for patients with contraindications for high-dose MTX (HD-MTX). When delivered after R-CHOP conclusion, two or three courses of HD-MTX not only have eliminated CNS recurrences in high-risk patients,2 but also have been associated with significantly improved overall survival, with an excellent safety profile.15 When delivered intercalated with standard R-CHOP, three courses of HD-MTX have been associated with transient renal dysfunction and chemotherapy delay in 12% of patients,24 which is an acceptable risk to prevent the discouraging consequences of CNS recurrences.2 The role of intrathecal chemotherapy, alone or combined with intravenous prophylaxis, remains a matter of investigation, but several prospective and retrospective studies failed to demonstrate an association between intrathecal prophylaxis (usually MTX alone) and reduction in CNS relapse rates.4, 14, 25, 26 Something is moving in the study of the role of CNS prophylaxis in DLBCL patients. For instance, some biomarkers, like microRNA (miRNA),27 soluble CD19,28 or circulating tumour DNA,29, 30 assessed preferentially in the CSF, were proposed as useful tools to predict and monitor CNS relapses. From a clinical standpoint, results of a large randomized trial of the Czech Lymphoma Study Group that compares the effect on CNS relapse rate of two courses of intravenous MTX 3 g/m2 or six doses of intrathecal MTX in patients with intermediate/high-risk DLBCL (ClinicalTrials.gov NCT02777736) are expected shortly. Meanwhile, as proposed by McKay and colleagues, guidelines based on common sense and critical analysis of scientific evidence will be valuable tools in decision-making on the use of CNS prophylaxis in everyday practice. TC and AJMF substantially contributed to the acquisition, analysis and interpretation of data, wrote the paper and approved the submitted version of the manuscript. The authors declare to have no potential conflicts of interest regarding the present work." @default.
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• W3024050325 date "2020-05-12" @default.
• W3024050325 modified "2023-10-18" @default.
• W3024050325 title "Prevention of CNS relapse in diffuse large B‐cell lymphoma: common sense prevails where science fails" @default.
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