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LYMPHOID NEOPLASIA| JANUARY 20, 2022 CNS prophylaxis in DLBCL: time to say goodbye? 是到了与弥漫大B细胞淋巴瘤的中枢神经系统预防说拜拜的时候了吗？ Norbert Schmitz, Fabian Frontzek
In this issue of Blood, Orellana-Noia et al report that central nervous system (CNS) relapse rates following either intrathecal (IT) or systemic (IV) administration of methotrexate (MTX) are not significantly different, shedding doubt on the overall efficacy of both approaches.1
For patients with diffuse large B-cell lymphoma (DLBCL), the overall incidence of relapse or progression in the CNS has been estimated at 5% with percentages varying from 1% to >15% in different risk groups. Current guidelines recommend CNS prophylaxis with IT or IV MTX for patients with high CNS–international prognostic index (IPI).2 In a large retrospective study, Orellana-Noia et al now compare CNS relapses occurring after single-route IT or IV MTX. Do their findings suggest that both routes of administration are comparably effective, or ineffective? What are the clinical implications? 弥漫大B细胞淋巴瘤出现CNS复发或进展的总的发生率是5%，对不同风险分层的患者来说，这个比例是从1%到大于15%。目前指南建议采用鞘注或MTX静脉滴注对CNS-IPI高评分患者来做预防。在一项大样本的回顾性研究中，Orellana-Noia等人比较了单途径的鞘注或MTX静脉滴注后的CNS复发率。他们的研究结果，是提示两种办法同样有效，还是同样无效？对临床的指导意义又是什么？
Because the overall incidence of CNS disease in DLBCL is ∼5%, not all patients are deemed high-risk candidates requiring prophylaxis. The CNS-IPI identifies a high-risk group carrying a 10% rate of CNS disease.3 Because this rate was not considered high enough to justify CNS prophylaxis in every high-risk patient, the search for alternative predictors continued. Indeed, more recently, combinations of CNS-IPI and molecular characteristics (activated B-cell subtype, double-hit lymphoma, distinct genetic signatures) were reported to increase the risk of CNS relapse.4,5 Disappointingly, however, a very high-risk group unequivocally warranting aggressive CNS prophylaxis in any patient carrying these characteristics has not been identified so far. 由于大B的CNS复发率总体上是5%，因此并不是每一位患者都是高危患者因而需要做预防。CNS-IPI评分可以确认哪些是风险超过10%的高危患者。由于这个比例还没有高到必须对每一位患者都做CNS预防，因此，还在寻找其它的预测因子。确实，最近据报告CNS-IPI与分子学特征（活化B细胞亚型，双重打击，独特的遗传性特征）结合起来会增加CNS复发的风险。令人失望的是，仍未能确定哪些患者，如果存在这些不良因素，是必须要做预防的极高危患者。
As early as 2009, we and others started to report that IT MTX was not effective in preventing CNS relapse in the rituximab era.6 Similarly, studies investigating the systemic administration of MTX also gave equivocal results. Thus, although studies on prophylaxis with IT or IV MTX became increasingly controversial, guidelines and most clinicians continue to recommend MTX for prophylaxis to prevent secondary CNS involvement (see table). 早在2009年，我们和其他一些人开始报告鞘注MTX在利妥昔单抗的时代对CNS预防没有效果。相似的是，那些系统性MTX的研究，也未能得出确切结论。因此，尽管鞘注和静脉MTX的争议越来越大，但指南和大多数临床医生继续推荐用MTX来预防继发性的CNS疾病（表略）。
The study by Orellana-Noia et al adds to our doubts on the current practice of prophylactically administering IV or IT MTX to patients with DLBCL. The authors report that CNS relapse rates do not significantly differ between patients receiving IT or IV MTX (5.4% vs 6.8%, P = .4) and, importantly, differences in CNS relapse rates by route of administration failed to show significant differences also when patient groups were stratified by CNS-IPI, National Comprehensive Cancer Network–IPI, and double-hit status. Interpretation of the data and arriving at appropriate recommendations are not easy. One extreme would be to completely abandon CNS prophylaxis because increasing numbers of studies failed to demonstrate a benefit of MTX administration regardless of the route (see table). A more cautious approach would possibly return to IT MTX because, if not more effective, it is undoubtedly less toxic than IV MTX. Both conclusions seem premature because all studies have limitations (eg, patients in the current study receiving IT MTX were mostly treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) while patients given IV MTX mostly received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Although the key message remained unchanged after this imbalance had been taken care of by statistical modeling, the retrospective nature of this and other studies does not definitely exclude that the results were influenced by known and unknown confounding factors. Orellana-Noia等人的研究让我们对目前的做法产生了更多的疑问。作者报告两种方法的CNS复发率没有什么区别（5.4% vs 6.8，P=.4），而且，当把患者按照CNS-IPI，NCCN-IPI以及双重打击来分组的时候，两种途径的MTX在CNS复发率上也没有显著区别。解读数据并得出合适结论并不容易。极端做法是完全放弃CNS预防，因为多项研究都未能证明有用，不管是哪种途径的MTX。更为审慎的做法是回到鞘注上去，毕竟，即使效果不佳，毒性显然要比静脉滴注小的多。两种做法，都不成熟，因为所有的研究都有局限性（例如，目前研究中接受鞘注的大多采用DA-EPOCH-R方案，而静脉滴注的通常与R-CHOP联合）。尽管通过数据模型的调整可以摈除这种因素并维持原来的结论，但是回顾性研究的性质决定了这样的结果是无法完全排除已知或未知因素影响的。
The comparison of CNS relapses occurring after CHOP vs cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (CHOEP) or R-CHOP vs CHOP was an early demonstration that not only the prophylactic regimen but also first-line therapy may influence the incidence of CNS relapses.7,8 We recently reported that rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone (R-ACVBP) including 4 IT injections of MTX followed by consolidative CNS prophylaxis with IV MTX, rituximab, ifosfamide, etoposide, and cytosine arabinoside resulted in very low CNS relapses. Patients with age-adjusted International Prognostic Index (aaIPI) 2 or 3 experienced a 3-year cumulative incidence of CNS relapse of 1.6% treated with R-ACVBP vs 4% following R-CHOP, R-CHOEP, or dose-escalated R-CHOEP (R-MegaCHOEP).9 Although the difference was not significant, the low rate of CNS relapse after R-ACVBP may suggest that the combination of aggressive first-line therapy, IT MTX, and systemic administration of multiple drugs crossing the blood-brain barrier may reduce the incidence of CNS relapse. Although patients with low or intermediate CNS-IPI can be spared CNS prophylaxis because of the low relapse rates reported, CNS imaging and fluorescence-activated cell sorter analysis of the cerebrospinal fluid will identify CNS involvement at diagnosis in some patients with high CNS-IPI. Patients with high CNS-IPI but no evidence of CNS involvement by modern screening technologies remain prime candidates for CNS prophylaxis. In light of the devastating prognosis of CNS relapse, and before results of studies involving alternative molecules (lenalidomide, Bruton tyrosine kinase, or BCL2 inhibitors) become available, this small group of patients (<<10% of DLBCL patients) may benefit from the combination of aggressive first-line therapy, IT MTX, and systemic administration of multiple drugs crossing the blood-brain barrier.
不仅CNS预防的方法可以影响到CNS复发率，而且一线方案的选择也对CNS复发率有影响。我们最近报告了R-ACVBOP方案加上四次MTX鞘注，然后在加上MTX滴注，利妥昔单抗、异环磷酰胺、依托泊苷和阿糖胞苷巩固获得了非常低的CNS复发率（1.6%）。这提示更强的一线方案，联合鞘注和系统性多药穿透血脑屏障可能可以降低CNS复发率。CNS-IPI高评分但未有CNS侵犯迹象的患者是做CNS预防的主要人选。考虑到CNS侵犯预后极差，在其它相关研究（来那度胺，BTK或BCL-2抑制剂）的结果出来之前，这一小批患者（不到10%），可能会从高强度一线化疗，加鞘注，加系统性的能穿透血脑屏障的多药滴注中获益。
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