Nathan Fowler

美国德克萨斯大学 MD 安德森癌症中心

　　《肿瘤瞭望》：以美罗华为首的免疫调节药物在滤泡淋巴瘤中显示独特的优势。一些研究表明，美罗华联合化疗可得到比单药应用美罗华更好的PFS，但两者的OS类似。您如何看待这一研究结果，目前是否可以将细胞毒性药物排除在一线治疗之外？

　　Fowler教授: 在过去的20-30年中，低级别的淋巴瘤患者的总体生存率有明显地升高。事实上当前新诊断的滤泡细胞淋巴瘤的总体生存期已经达到18-20年。此外，已经有一部分病人（大约30%）接受CHOP联合美罗华或者美罗华联合苯达莫司汀方案治疗后可以获得长期缓解而不复发。此类方案已有可能完全治愈该病，所以我认为对于低级别的淋巴瘤患者提出放弃化疗应当万分谨慎。只有当别的治疗方案能够单药获得比化疗更好的治疗效果或者比化疗方案毒性小的时候，我们才有可能将低级别的淋巴瘤化疗方案替代掉。好消息是，目前已经有很多新的治疗方案出现，诸如来那度胺联合美罗华，依鲁替尼联合美罗华，以及其他B细胞检录点抑制剂联合美罗华，似乎在低级别的淋巴瘤中疗效显著，且并没有产生比化疗更加重的毒副作用。而不巧的是，大部分系类药品目前正处于比较早期的临床试验中，所以我们并不能获得非常确切的与化疗相比较的临床效果差异。然而令人兴奋的好消息就是，关于这些药物的临床试验将在未来的3-4年中飞速进展，我们将获得更多的关于此类非化疗药相比于标准化疗方案的疗效差异的数据。所以对于这个问题的解答是，关于于滤泡细胞淋巴瘤目前我们还没有找到可以完全取代化疗的治疗方案，但是我们可以期待这一天在不久的将来会到来。我期待更多的大宗临床试验的结果让我们看到有比传统化疗更加有效且毒性更小的治疗方案出现。

　　Dr Fowler: In the last two or three decades， we have seen the improvement of survival of many patients with low-grade lymphoma. In fact， the expected survival of patients with newly diagnosed follicular lymphoma is probably 18-20 years. In addition， with most chemotherapy combinations like rituximab with CHOP or rituximab and bendamustine， there is probably a percentage of patients (around 30%) who will never relapse with their disease. They are effectively cured of their disease. So I think we have to be very careful when we talk about throwing away chemotherapy for low-grade lymphoma. We should only change chemotherapy for low-grade lymphoma if we have an option that works better than chemotherapy， or is less toxic than chemotherapy. The good news is that a lot of new regimens like lenalidomide and rituximab， potentially ibrutinib and rituximab， and some checkpoint inhibitors with rituximab look very active in low-grade lymphomas and are not associated with a lot of the toxicity of chemotherapy. Unfortunately， a lot of these agents are still in very early clinical trials， so we don’t yet know how they compare with chemotherapy. But the exciting thing is that as we move forward over the next three or four years， we will have more data on how these non-chemotherapy options compare with chemotherapy. The answer to your question is that we are not yet ready to abandon chemotherapy in frontline follicular lymphoma. However， there are many hints that that day will come very soon. I am hopeful that with some of the new larger randomized studies， we will see regimens that are less toxic and maybe more effective than chemotherapy.

　　《肿瘤瞭望》：滤泡淋巴瘤是惰性淋巴瘤，但倾向于反复复发，直至进展为高级别淋巴瘤——通常是弥漫大B细胞淋巴瘤。我们可以预期：早期应用细胞毒性药物有可能影响惰性的肿瘤克隆，筛选出那些高侵袭性的，并使其基因组处于不稳定状态。是否有迹象表明化疗加速后续进展的风险，这是否会影响到治疗决策？

　　Fowler教授:这是一个被反复探讨过多年的问题。据我们目前所知，大概有2-3%的低级别淋巴瘤在治疗过程中会出现侵袭性克隆诸如弥漫大B细胞淋巴瘤。我们现在担心的是是不是早期将病人暴露在化疗中会使的病人更容易转化成大细胞淋巴瘤？幸运的是，目前的一些大宗的回顾性临床研究结果提示病人是否接受化疗似乎并不影响远期转化率。我们并没有看到化疗减低转化率，同时我们也并没有发现化疗本身会增加转化率，具体的原因仍然不清楚。有猜测认为转化的发生有可能是由于滤泡性淋巴瘤患者体内存在一些化疗耐药的亚克隆，而又有报道称病人发生转化时来源的是一个完全不同于初诊任何一个克隆的亚克隆，所以是否使用化疗与发生转化并无关系。至少目前的回顾性研究临床数据显示，诸如CHOP的化疗方案并不会增加患者的转化率。

　　Dr Fowler: This has been a question that we have talked about for many years. We know that around 2-3% of patients with low-grade lymphoma will transform into a more aggressive clone of large cell lymphoma over time. What we worry about is if it is possible that exposing patients to chemotherapy early will increase the risk that they transform to a large cell lymphoma? Luckily， several large retrospective studies have suggested that patients who do and who don’t receive chemotherapy have approximately the same risk of transformation. We have not seen that chemotherapy reduces the risk of transformation， but it doesn’t look like it increases the risk of transformation. We are not sure why that is. It is possible that these subclones that exist in patients with follicular lymphoma are resistant to chemotherapy. There are also some data that when patients transform， they are coming from a completely different subclone so the exposure to chemotherapy is irrelevant. At least with the current data， regimens like CHOP do not appear to increase the risk of transformation based on retrospective data.

　　《肿瘤瞭望》：I/II期滤泡淋巴瘤具有与III/IV期淋巴瘤不同的表现。对于高级别滤泡，我们是否应该强调化疗的优先性？

　　Fowler教授:长期以来研究者认为I/II期滤泡淋巴瘤与高级别滤泡淋巴瘤患者具有不同的生物学表现。目前斯坦福大学研究者完成的数例回顾性临床研究以及一项叫做LymphoCare的大宗队列研究都已经表明低级别淋巴瘤患者无论采取何种治疗方案都会获得比较一个理想的疗效。一些研究者甚至提出对于这类病人取消化疗因为这些病人将不会转化为III/IV级淋巴瘤且他们远期死亡风险也非常的小。而不巧的是，目前并没有关于早期阶段滤泡性淋巴瘤治疗干预或是观察的前瞻性临床研究数据报道，所以我们目前的结论均是基于高级别淋巴瘤患者病历资料。不管怎样，目前的结论仍然倾向于认为对于高级别的淋巴瘤不急于给予化疗治疗似乎并没有威胁到患者生存。对于低肿瘤负荷且并没有临床症状的高级别淋巴瘤患者，观察随访仍然是推荐的治疗方案。我个人认为，局部受累野放疗就可以治愈低级别淋巴瘤患者，所以我通常会建议存在局部受累灶的低级别淋巴瘤患者进行放射治疗。不过不得不承认尽管没有肯定的前瞻性临床研究数据，目前美国以及世界各地的很多内科医生基于这些低级别淋巴瘤生物学特性不同而很少会进展的这一假说，而仅仅建议对这些病人进行随访观察。

　　Dr Fowler: It has long been thought that patients with stage I/II follicular lymphoma have a different biology to patients with advanced stage follicular lymphoma. There have been several retrospective studies done at Stanford University as well as a large cohort study called LymphoCare， that suggest that patients with low-grade lymphoma will do well regardless of their therapy. Some have even advocated that these patients don’t need treatment because they are never going to progress to stage III/IV and the risk of dying is very low. Unfortunately， there are no prospective studies to look at observation versus intervention in early stage follicular lymphoma， so we have to draw conclusions from studies that have looked at advanced stage disease. It does appear that waiting， at least in terms of chemotherapy in advanced stage disease， is not harmful. Observation is still the recommended approach in patients with advanced stage disease with a low tumor burden and the absence of symptoms. In my own practice， I think patients with low-grade disease can be potentially cured with radiotherapy. So I send them to radiation if they have a lesion that we can easily irradiate. But I will freely admit that many physicians in the United States and other parts of the world would recommend observing these patients based upon the hypothesis that the biology of the low-grade disease in its limited stage is different， although that has yet to be shown in any prospective trial.

　　《肿瘤瞭望》：在您的一篇文章中，您提出针对无细胞毒性药物治疗，我们已经有了“原料”，但还需要“菜谱”。那么，您认为那些药物在新药时代更具优势，我们应该如何联用？

　　Fowler教授:目前对于低级别的淋巴瘤出现了很多极具前景的治疗药物，许多药物单药治疗都能获得30%-60%的治疗反应率，所以我认为对于下一代的联合治疗，我们已经有了“原料”。而不幸的是，目前很多研究的努力均没有找到最优化的治疗方案。我们看到目前将idelalisib加来那度胺联合美罗华的方案产生了极大的治疗毒副反应甚至对于一些病人出现了致命的反应；idelalisib加Sky抑制剂GS9903联合美罗华同样出现了包括致命毒性的毒副反应；而依鲁替尼联合美罗华和雷利度胺方案虽然并没有报道像之前一样的致命性毒性反应，不断增加的皮疹似乎也是困扰研究者的问题。所以很多新药在联合应用时出现了非常严重的毒副反应，而这些副作用在单药应用时并没有显示出来。所以目前临床医生对于联合应用新药上变得非常谨慎。对于目前大部分极具前景的新药，我对于B细胞检录点的抑制剂诸如派姆单抗以及nivolumab的治疗应用非常兴奋因为我看到它们在不同的恶性肿瘤中的应用。低级别的淋巴瘤治疗总体反应率仅有30%左右，而靶向CD19的单克隆抗体以及靶向CD20的新药诸如obinutuzumab似乎在低级别淋巴瘤中治疗应用前景瞩目。在此次会议中我们了解到了对于多次复发的低级别淋巴瘤患者，CAR-T细胞治疗缓解率可高达80%，且大约半数患者可获得长期缓解。所以我非常的看好目前大部分的新型治疗药物，免疫调节药物对于低级别的淋巴瘤可能会起到很好的疗效，同时我认为雷利度胺联合美罗华是使得几乎100%患者获得治疗反应的最佳双药联合典范。

　　Dr Fowler: There are a lot of promising agents for low-grade lymphoma. Many of these agents have single-drug response rates from 30% to 60%， so I do think we have the ingredients for the next combination therapy. Unfortunately， most of the efforts so far have failed to identify the next best regimen. We have looked at the combination of idelalisib plus lenalidomide and rituximab and it was extremely toxic including fatal in some patients. We have looked at combinations with idelalisib， a Syk inhibitor called GS9903 with rituximab， which as also very toxic including fatal toxicities. And we have looked at ibrutinib with rituximab and revlimid. The jury is still out on that but it appears that there is increased rash. So some of these novel drugs that may not be toxic as single agents， when they are in combination， there is very significant toxicity. Right now， we are moving forward very cautiously when combining some of these novel drugs. With regard to the most promising novel agents， I think that the checkpoint inhibitors like pembrolizumab and nivolumab are very exciting across different types of malignancies. Low-grade lymphoma response rates are not quite as high， around 30%. We see monoclonal antibodies targeting CD19， and novel drugs targeting CD20 like obinutuzumab， which look very active in low-grade lymphoma. We have also seen data at this meeting about CAR T-cells， which look very active in patients with multiple relapsed low-grade lymphomas with response rates above 80% and long-term remission in around half the patients. So I think there are a lot of very exciting novel regimens. The immunomodulatory drugs are very active in low-grade lymphoma and I think revlimid and rituximabis the most exciting doublet with responses in almost 100% of patients.