访加拿大不列颠哥伦比亚大学Randy D. Gascoyne教授

　　《肿瘤瞭望》：滤泡性淋巴瘤和慢性淋巴细胞白血病属惰性B细胞淋巴瘤范畴，以临床前期时间长，一旦治疗开始复发比例高为特征。您能总结一下，最近对该两种疾病的发生率及相关性的研究及肿瘤前细胞在滤泡性淋巴瘤和慢性淋巴细胞白血病发生中的作用机制？

　　Gascoyne教授：在过去的几年里有关单克隆B淋巴细胞增殖做了许多研究工作，结果表明如果患者的家庭成员有人诊断为CLL ，那么这个家庭其它成员的CD5阳性克隆性B细胞会明显增多，但大部分人并不会发展为CLL。那么，哪些人将发展为CLL，哪些人不会发展为CLL，这的确是需要我们进一步研究的重要议题。现有大量的研究数据尝试明确滤泡淋巴瘤的分子遗传学改变，这些改变决定了哪些患者最终会发生滤泡淋巴瘤。60%~70%的普通人群的血液循环中都存在异常细胞，但却不会最终发展为滤泡淋巴瘤。Nadel和Roulland博士一直致力于此项研究，研究方式也多种多样，从大型队列研究（EPIC研究）到分子生物学研究，现在则是小鼠模型研究，这些研究有助于探讨存在哪些生物学异常时会最终发生滤泡淋巴瘤。当然前路漫漫，但我相信会越来越清楚。

　　There has been a lot of work in the last several years with monoclonal B-cell lymphocytosis. There have been many studies now that have shown that if a family member has CLL and you survey the other members of the family， you will find the presence of CD5-positive clonal B-cells in a significant percentage of those people. The majority don’t go on to develop CLL， so trying to understand why the ones that do versus the ones that don’t is an important topic of research. In follicular lymphoma， there is a growing body of data trying to map the molecular genetic changes that determine the patients who do go on to develop follicular lymphoma. If you look at the general population， 60-70% of all of us have those cells in our circulation， but we don’t get follicular lymphoma. So Drs Nadel and Roulland have been working for many years investigating this and have used everything from large cohort studies (the EPIC study)， molecular biology studies and now mouse models， where they can start to understand the biology that determines which people who harbor the abnormalities will then actually go on to get follicular lymphoma. There is still a lot of work to be done but it is becoming clearer.

　　《肿瘤瞭望》：滤泡性淋巴瘤是最常见的惰性非霍奇金淋巴瘤。如何给予个体化治疗以及靶向新药的治疗地位？

　　Gascoyne教授：这是我参加的研讨会的重点内容。大多数人认为，现在已是2015年，通过有效且毒性不是很大的药物的间断性治疗，大部分患者可以更长的生存，80%的患者可以存活很多年，中位生存15~20年。关键是如何鉴定另外20%~25%的患者，这些患者的疾病侵袭性很强，在疾病诊断初始明确疾病的强侵袭性是重点，而不是在观察到疾病表现出强侵袭性后。这些患者应招募进入临床试验进行新药试验，现在有很多新药正在进行临床试验，或是单独使用或是与其它药物联合使用。在不久的将来，对于强侵袭性疾病的患者的研究将会是重点，以阻止患者病情发生转化或进展。目前看来，这些高危患者可能会脱离传统的化学治疗模式，转为毒性很小的生物制剂联合治疗模式。

　　That was the focus of the workshop I was involved in here yesterday. Most people in the world would believe that where we are now in 2015， the majority of patients can live a very long time with that disease with intermittent treatment with effective agents that are not very toxic. For 80% of patients， they will live many years. The current expectation of median survival in those patients is probably 15 or 20 years. The key thing we must do is identify the 20-25% of patients who will behave aggressively but not to make that observation after they have declared their aggressive behavior， but to make it at the time they are first diagnosed. Those are the patients that we can enroll in clinical trials in order to test novel agents. There is a whole list of agents that are entering clinical trials now， alone or in combination， and I see a day in the near future， where that group of patients will be the key focus. They will be the ones in whom we try to prevent transformation and progression. I see them being treated possibly with a combination of biologic agents with very few toxicities， moving away from the traditional model of chemotherapy.

　　《肿瘤瞭望》：淋巴瘤中的中枢神经系统受累是一种相关并发症，通常预后差。如何判定患者发生中枢侵犯的高危因素，并从预防治疗中受益？

　　Dr Gascoyne: 就拿最常见的弥漫大B细胞淋巴瘤来说吧，虽然患有强侵袭性疾病的风险不是很高（大约3%~4%），但只要表现为强侵袭性，那么这将是灾难性的，因为这种强侵袭性疾病的治疗非常困难。德国工作组公布了一组鉴定强侵袭性疾病的临床标准，在一定程度上有效。我们正在尝试对活检标本进行一些指标检测，以预测这种不良结果，现在观察到一些患者如果表达某些蛋白（MYC和 BCL-2），CNS进展风险就会特别高。识别这一点很重要，但并不意味着要采用预防性CNS治疗，而是要首先考虑采用不同的治疗方法阻止CNS进展。如果患者出现了CNS受累，应给予相应的治疗，但如果能够发现预测CNS复发或进展的因素，那么思考方式将会完全不同，应考虑其它的治疗模式，不仅仅是CNS预防，而是要采用不同的治疗策略阻止CNS侵犯结果的出现。

　　If we focus on the most common disease， diffuse large B-cell lymphoma， then there is a risk. It is not very high (about 3-4%) but when it happens it is devastating in terms of progression because it is very hard to treat. We are starting to put together an idea of the factors in the diagnostic biopsy that predict for that outcome. There is a set of clinical criteria that have been developed by a German group that seems to work to a degree. My colleagues and I in Vancouver have made the observation that the patients who show expression of a couple of proteins in their diagnostic biopsy (MYC and BCL-2) have a pretty significant heightened risk of CNS progression. To recognize that is important but you wouldn’t prophylactically treat those patients. What you would do is consider the possibility of treating them in a different way upfront to prevent that as an outcome. If the patient has CNS involvement， then that would be treated， but in those where you find eventual predictors of relapse or progression in the CNS， that is a different consideration and needs to be approached in a different way. Not through CNS prophylaxis， but by treating them differently upfront to prevent the eventual clinical outcome.

　　《肿瘤瞭望》：复发难治的非霍奇金淋巴瘤淋巴瘤总体预后差，复发后治疗有效时间短。新的治疗手段可以改善这类患者的预后。您能讨论一下最近出现并欣欣发展的生物治疗手段吗？

　　Dr Gascoyne: 还是用弥漫大B细胞淋巴瘤作为例子，全球标准治疗是利妥昔单抗联合CHOP（R-CHOP），60%的患者可以长期治愈，但仍有35%~40%的患者不能治愈。问题的关键不是发展新的治疗方法处理复发/难治患者，而是要确定哪些因素使得这些淋巴瘤变得侵袭性更强，导致治疗失败，这种判断应该在诊断初就明确，那么这类患者就会接受新的治疗方法。

　　除了R-CHOP能改善治疗结果，这个领域的研究正在不断进展，现在正在验证依鲁替尼和雷那度胺的治疗作用，还有许多新药处于III期临床试验，我们不得不耐心等待结果。理想化的情况是在诊断之初就可以将治疗反应差、疾病侵袭性强的患者分选出来，给予这类患者恰当的治疗，以阻止疾病复发或是进展。

　　Focusing again on diffuse large B-cell lymphoma as the commonest example， the standard of care globally is still the combination of rituximab and CHOP (R-CHOP). That will cure long-term 60% of patients. The problem is that 35-40% are not cured through that approach. The key is not to develop novel therapies to be used in the relapsed/refractory setting， but to determine what the factors are that make those patients the ones to behave aggressively and fail and to determine that at the outset. If we can determine who they are at the very beginning， they can be offered these new therapies. The field has been moving towards what in addition to R-CHOP will improve outcomes. This is where ibrutinib and lenalidomide are being tested. There are a number of new agents now in phase III clinical trials. We will have to wait for the results of those before we can make decisions， but in an ideal world， if we can pick the bad responders at the point of initial diagnosis， we can offer them appropriate treatments if we know they are going to behave aggressively to prevent relapse or progression.