套细胞淋巴瘤（Mantle Cell Lymphoma, MCL）是一类罕见的侵袭性B细胞非霍奇金淋巴瘤（B-NHL），而t（11；14）易位及Cyclin D1表达上调是其特征性改变。目前该病的治疗仍主要基于免疫治疗与化疗的联合方案（如R-CHOP等）。近年来，随着新药的开发，以BTK抑制剂Ibrutinib为代表的靶向药物给MCL的治疗打开了新局面。

Prof. Huiqiang Huang：The incidence of Mantle Cell Lymphoma（MCL）is quite low all around the world. It accounts for 3% of NHL patients in China, but the incidence is rising year by year. Generally, MCL patients are typically male and elder, with a median age of onset of 50-60 years.

黄慧强教授：在全球范围内，套细胞淋巴瘤（MCL）的发病率均较低；在中国，MCL发病率约占所有NHL的3%，但呈逐年上升趋势。总体上，MCL为老年性疾病，男性多发，中位发病年龄为50-60岁。

Currently, it's not very difficult to make a diagnosis of MCL, the real challenge is treatment, especially treatment for elder MCL patients. With the aspect of treatment, immunochemotherapy is the most common regimen administered for MCL. However, its clinical effectiveness is not satisfactory for elder MCL patients and the vast majority of them will relapse later, the median overall survival of elder MCL patient is only 1-2 years. Another problem of immunochemotherapy is that the toxicity is frequent and severe. Therefore, more convenient, effective and safer regimen is urgently needed.

目前，MCL的诊断已无明显困难，其主要挑战在于治疗，尤其是老年MCL患者。在MCL治疗方面，免疫治疗+化疗是最常用的治疗方案，但该方案对老年MCL患者的疗效欠佳，且大部分患者于治疗后易复发，老年MCL患者复发后的生存期短，中位生存期仅为1-2年。此外，现有化疗方案毒性较大、不良反应较多。因此，我们需要更简单及安全有效的药物来提高临床疗效。

Prof. Simon Rule: Indeed, the diagnosis of MCL is not difficult nowadays. If you go back to 10-15 years ago, the diagnosis of MCL may not be so reliable. But now, we are quite confident in the diagnosis of MCL, particularly with the application of CyclinD1 staining. However, it's notable that we should avoid missed diagnosis when MCL patients present like Chronic lymphocytic leukemia (CLL)  or Lymphocytosis, which can be diagnosed correctly with flow cytometric analysis.

Simon Rule教授：确实，套细胞淋巴瘤（MCL）的诊断并不困难。在10-15年前，MCL可能缺乏可靠的诊断方法。但现在，我们对于MCL的诊断是极为自信的，尤其是CyclinD1免疫组化的应用。值得注意的是，部分表现为慢性淋巴细胞白血病或淋巴细胞增多的MCL患者应避免漏诊，流式细胞检测可以帮助正确诊断。

With the aspect of treatment, MCL remains incurable condition apart from ASCT. However, patients still facing an ongoing relapsing condition, which is tough to manage. As for elder MCL patients who are intolerant of intensive chemotherapy, novel drugs have a big deal with their treatment.

关于治疗，MCL目前仍是一个除自体移植外无法治愈的疾病，然而即便是移植的患者仍然会面临复发的困境。对于复发的患者，治疗较为棘手，尤其是老年MCL患者。老年患者，尤其是体质虚弱的老年患者无法耐受密集剂量的化疗，因而，新药对于他们的治疗就显得至关重要。

Prof. Won Seog Kim: Recent years, based on the bioscience knowledge we are developing more and more new compounds, among which BTK inhibitor Ibrutinib made a very good success. Another two important compounds are anti-apoptotic drug Venetoclax and immunomodulator Lenalidomide. With these new compounds we can expect longer survival of patients and avoid toxicity of chemotherapy, which means longer and improved quality of life for patients. Especially, Ibrutinib is an oral drug that patients can have it everyday, which improves their quality of life much more and monthly blood test is no longer necessary. The patients can live longer with better life quality.

Won Seog Kim教授：近年来，MCL领域的新药不断涌现，BTK抑制剂伊布替尼是其中非常成功的一种药物，此外还有抗凋亡药物Venetoclax和免疫调节剂来那度胺。这些新药显著延长了MCL患者的生存期，同时提升了患者的生活质量。其中，伊布替尼具有口服的便利性，对患者生活质量的提高尤为显著：患者可以每日服用，无需每月来医院治疗和进行血常规化验。患者可以活得更长且生活质量更高。

Prof. Simon Rule: I agree with that, these new drugs are much more valuable for elder patients. We tend to treat elder patients with chemotherapy that do not work well but comes along with side effects. These new drugs have the potential to change that. In UK, we are carrying out a randomized clinical trial, which compares the efficacy of Ibrutinib+ Rituximab as first-line treatment for elder patients against chemotherapy. Hopefully, this triall will show that these new drugs are better than chemotherapy. Even if the efficacy shows no difference, we are confident that these new drugs will be better in side effects. I think we are in a whole new era of treatment for MCL patients.

Simon Rule教授：我赞同Kim教授的观点。新药对于老年患者尤为重要。过去我们用化疗治疗老年患者效果欠佳且毒副作用明显。新药的应用将会改变这一情况。在英国，我们正进行一项随机临床试验，旨在比较伊布替尼+利妥昔单抗对比化疗作为MCL患者一线治疗的疗效差异。我们希望伊布替尼较之化疗能显示出更佳的疗效。当然，即便其疗效相似，我们相信新药在副反应方面是有显著优势的。我们处在一个全新的疾病治疗时代。

Simon Rule教授：随着伊布替尼在MCL患者中得到广泛应用，我们越来越认识到它的卓越之处：超过70%的MCL患者对伊布替尼有反应，具有口服便利性，不良反应轻微。

The earlier, the better

As we got more experience of using it, we started to realize that the best benefits come from using it at earlier stage. So we published some data late last year, looking at elder MCL patients that have been in Ibrutinib clinical trials about the benefits based on when they were treated. It is quite clear that the earlier patients start using Ibrutinib the better outcomes they get. If MCL patients use Ibrutinib at first relapse, the duration of response (DOR) is 3 times longer than use Ibrutinib later and three-year PFS also enhanced. So we should use Ibrutinib early. Another advantage of early use is when relapsing happens, it will be easier to retreat the patient than late use.

随着应用经验的增多，我们认识到使患者从伊布替尼中获得最佳受益的方法就是尽早应用。去年年底我们发表了关于Ibrutinib药物临床中老年MCL患者应用时机的相关数据显示：1）越早应用伊布替尼MCL患者的临床结局越佳；2）首次复发即应用伊布替尼，其治疗反应持续时间是后期复发时应用伊布替尼的3倍，且3年无进展生存率（PFS）亦得到提升；3）早期应用可使复发后的治疗更简单。综上，我们认为在MCL的治疗中宜尽早应用伊布替尼。

About first line use

So if it is better the earlier patients use Ibrutinib, then obviously, the following question should be whether it is better to use Ibrutinib as first-line treatment. A triall is going on in the UK right now, using Ibrutinib at first line compare to chemotherapy among elder patients who are not transplantable. It is an important study and 400 patients will be enrolled within years.

既然越早应用伊布替尼患者获益越大，那么伊布替尼是否可以用于一线治疗呢？对于老年MCL患者，目前英国正开展一项重要的临床试验，计划入组400例老年MCL患者，旨在比较伊布替尼vs化疗作为不适合移植老年MCL患者一线治疗的疗效差异。

As top expert worldwide who participated in phase II/ III clinical trials of Ibrutinib( MCL)  and is very experienced in side effect management about using Ibrutinib, professor Simon shared the side effect managenent experience thoroughly, which is a must-see and quite useful for clinical practice.Here it comes:

作为世界顶尖的淋巴瘤专家，Simon教授参与了伊布替尼II/III期临床研究（MCL）并且在副反应管理方面非常有经验，他在采访中对副反应的管理做了系统分享。以下内容对临床实践非常有帮助，必看！

Prof. Simon Rule: I have been using Ibrutinib for like seven years( including clinical trials). Another thing we know now is the longer the patients use Ibrutinib the fewer side effects they get. Side effects happen at early stage and there are very few side effects, which means Ibrutinib is a safe drug. I have never stopped using Ibrutinib because of toxicity.

Simon Rule教授：我们的另外一个经验所得是：随着伊布替尼使用时间的延长，副反应会越来越少。伊布替尼副反应较少，大多发生在用药初期。其安全性是很好的。在我使用伊布替尼的临床经验中，从未因毒性反应而停药。

患者担心的问题之一是瘀斑和出血，约有50%的患者会发生淤斑，常表现为手背上的小瘀斑。作为医生，我们需要让患者知晓这是可能发生的，并且50%的人都会发生，如此在发生的时候他们就不会过于焦虑。使用伊布替尼出现瘀斑与老年人使用阿司匹林会出现瘀斑是类似的。值得注意的是，在进行任何手术前需要停用伊布替尼，因为淤斑可能会进展为出血。

The other thing people worry about is atrial fibrillation, which occurs 6-8 percent. Again, I don’t stop Ibrutinib when atrial fibrillation happens. Just get AF in control and use anticoagulation. It is fine to use anticoagulation plus Ibrutinib.（This refers to the New Oral Anticoagulant Combination (NOAC), such as Rivaroxaban and Apperoxaban.）

患者担心的另外一个问题是房颤，这发生在6%-8%的患者身上，但即便发生房颤，我也并未停药，只要控制好房颤、使用抗凝药即可继续使用伊布替尼，伊布替尼与抗凝药一起使用并无不妥。(此处指联合新型口服抗凝药（NOAC），如利伐沙班、阿哌沙班）

Also, some people may worry about diarrhea problem. Diarrhea problem may happen when stop using the drug, but it will go away a couple of weeks. It is reported in some country that diarrhea occurs to patients and evanished by reducing the dose. In my opinion, diarrhea will go away any way, so there is no need to stop Ibrutinib.

患者还有可能会担心腹泻问题，如停药后可能出现的腹泻，也有国家报道用药中患者出现腹泻，减少剂量后即消失。腹泻是一个完全不必担心的问题，它是一定会消失的，无需停药。

Prof. Huiqiang Huang: Ibrutinib was approved in China last year. Actually, we have involved in global clinical trials of Ibrutinib for several years; therefore, we have our own clinical experience about it. We found that immunotherapy plus Ibrutinib didn’t increase toxicity for newly diagnosed MCL, the safety of Ibrutinib is quite excellent and reliable.

黄慧强教授：伊布替尼于去年在中国上市，但实际上我们参与其临床研究多年，对该药物亦有自己的体会。我们在免疫化疗基础上加用伊布替尼，发现其毒性并无明显增加，因此伊布替尼的安全性很好。

After approval, we treat relapsed and refractory MCL with Ibrutinib single agent and no serious adverse events ever happened in MCL patients. What’s more, Ibrutinib shows effectiveness to MCL patients who are resistant to anti CD20 antibody, immunochemotherapy, Lenalidomide and so on. Also Ibrutinib is fast onset.

伊布替尼上市后，我们应用伊布替尼单药治疗复发/难治套细胞淋巴瘤的过程中有如下经验：1）未发生因毒性或不良事件停药的情况；2）并无明显影响生活质量的不良事件发生；3）对抗CD20单抗、多线化疗、来那度胺等药物耐药的MCL患者，采用伊布替尼治疗仍然有效；4）伊布替尼起效很快。

We used to accept a 70-year-old female MCL patient who had received four line therapies and not suitable for transplantation. However, when treated with Ibrutinib for one month, the tumor shrank dramatically, and then complete remission (CR) was achieved after two month. It is a very impressive case.All in all, Ibrutinib is a very good choice for RR-MCL treatment. Hopefully, it will benefit more Chinese patients. 

我们收治过一例70岁的老太太，已使用过四线治疗并且不适合移植，其治疗相当棘手，但应用伊布替尼1个月后发现患者的肿块明显缩小，2个月便达CR。这是一个很有趣的病例。因此，我认为伊布替尼给复发/难治的套细胞淋巴瘤带来了很好的治疗选择，希望它能更多的造福我们中国的患者。

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