中外对话丨Owen O’Connor教授与钱正子教授盘点R/R PTCL治疗现状与最新进展

文摘 2024-10-22 17:16 北京

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第五届天津国际淋巴瘤学术会议作为促进国际学术交流与合作的学术平台，积极发挥了其桥梁作用，促进了国际淋巴瘤领域的深入交流与合作。会议期间，《肿瘤瞭望-血液时讯》特邀美国淋巴瘤联盟主席/弗吉尼亚大学癌症中心Owen O’Connor教授与天津医科大学肿瘤医院钱正子教授展开中外对话，盘点复发/难治性外周 T 细胞淋巴瘤（R/R PTCL）的治疗现状与最新进展。

《肿瘤瞭望-血液时讯》

在开发R/R PTCL新治疗方法方面存在哪些主要挑战，您们认为这些挑战在您们各自的地区如何能够有效解决？

Oncology Frontier-Hematology Frontier：What are the key challenges in developing new treatments for R/R PTCL, and how do you think these can be effectively addressed in both your regions?

Owen O’Connor教授

美国淋巴瘤联盟主席/弗吉尼亚大学癌症中心

外周T细胞淋巴瘤（PTCL）在治疗上面临着诸多的挑战，其中最为突出的挑战当属疾病的异质性或多样性。目前，我们依据国际癌症协作组（ICC）分类和世界卫生组织（WHO）分类这两种不同的分类体系，共识别出了35种不同的T细胞淋巴瘤类型。这些疾病整体发病率极低，据估计，在美国每年新增病例可能仅有1万例。即便是其中最常见的亚型，其年发病数也仅有几千例。这种罕见性加之不同亚型间存在的巨大生物学差异，使得治疗工作变得异常艰巨。

随着新药的不断涌现和众多新数据的积累，我们发现，某些亚型对于特定类别的药物表现出极佳的反应，而其他亚型则不然。因此，这些不同亚型患者的相对比例如何影响临床试验的结果，成为了一个至关重要的问题。同时，这也深刻影响着我们针对这些疾病的药物研发策略。

PTCL的异质性不仅体现在生物学行为上的差异，还体现在遗传学特征以及最终对不同药物的敏感性差异上。这种复杂性使得为所有类型的T细胞淋巴瘤开发一个单一、统一的治疗平台变得极为困难。此外，这也为我们如何为这些疾病争取药物获批带来了前所未有的挑战。

（上下滑动查看英文原文）

Professor Owen O’Connor: So the PTCL had many challenges。Probably the one that is the most significant at the moment relates to the heterogeneity or diversity of the disease。We now have two different classifications schemes，the ICC and the WHO which recognize let's call it 35 different types of T cell lymphoma。As a group，there are awfully rare diseases may be in the United States 10,000 cases per year。And even with the most common sub types，maybe a couple of thousand patients per year。So this makes it very hard because those35 different subtypes are all biologically very different。And as we're seeing in lots of new data sets with new drugs，some sub types respond amazingly well to one class of drugs while other sub types don't and how these relative proportions of patients with these different sub types can then influence the outcome of these trials becomes pretty significant。And it has an impact on how we develop these drugs for those diseases。So I think the notion that there's incredible heterogeneity that heterogeneity is reflected in differences in biologic behavior，differences in genetics and ultimately differences in vulnerability to different drugs。Makes it very difficult to develop a singular unifying platform of care for all types of T cell lymphoma。And it presents a challenge as to how we go about getting drugs approved for the disease。

钱正子教授

天津医科大学肿瘤医院

PTCL是一类具有高度侵袭性和异质性的非霍奇金淋巴瘤，其类型繁多，每一亚型均可视为独立疾病。这些亚型在临床表现、发病机制、分子遗传学特征以及预后方面均展现出显著的差异性，无疑为治疗工作带来了极大的挑战。总体而言，绝大多数T细胞淋巴瘤缺乏标准的治疗方案且生存预后普遍不佳，除早期NK/T细胞淋巴瘤和ALK阳性间变大细胞淋巴瘤外，其他类型的5年总生存率（OS）普遍较低，往往不超过30%。值得注意的是，外周T细胞淋巴瘤的发病类型存在明显的地域差异。在国内，NK/T细胞淋巴瘤、外周T细胞淋巴瘤-非特指型以及血管免疫母T细胞淋巴瘤是主要的发病类型；而在欧美国家，则更多以间变大细胞淋巴瘤和皮肤T细胞淋巴瘤为主。

面对PTCL领域的严峻挑战，我国医学界针对不同类型的外周T细胞淋巴瘤展开了大量深入研究。天津医科大学肿瘤医院淋巴瘤科张会来教授团队采用阿扎胞苷联合西达本胺双表观疗法治疗复发难治性PTCL取得了一定成果，并在此基础上开展了一项双表观疗法联合CHOP对比CHOP治疗初治滤泡辅助T细胞表型外周T细胞淋巴瘤的前瞻性、多中心、随机对照III期临床研究。上海交通大学医学院附属瑞金医院赵维莅教授团队在NK/T细胞淋巴瘤领域取得了显著成果，他们对该疾病进行了分型探索，·发现了TSIM、MB、HEA三个亚型，这些亚型对药物的敏感性各不相同。同时，中山大学肿瘤防治中心的黄慧强教授和蔡清清教授也在NK/T细胞淋巴瘤的临床研究上取得了重要突破，他们提出的免疫表观疗法为R/R NK/T细胞淋巴瘤患者带来了显著的疗效，并进一步探索了一线治疗及联合治疗策略。

综上所述，我国在发病率较高的外周T细胞淋巴瘤类型上已取得了深入的研究成果，并有望为全球患者提供更多有效的治疗理念和策略。

（上下滑动查看英文原文）

Professor Zhengzi Qian: PTCL represents a category of highly aggressive and heterogeneous non-Hodgkin lymphomas, characterized by a myriad of subtypes, each regarded as a distinct disease entity. These subtypes exhibit significant differences in clinical manifestations, pathogenesis, molecular genetic profiles, and prognosis, posing considerable challenges for therapeutic interventions. In general, the majority of T-cell lymphomas lack standardized treatment protocols and have poor survival outcomes. Except for early-stage NK/T-cell lymphoma and ALK-positive anaplastic large cell lymphoma, the five-year overall survival rates for other subtypes are generally low, often not exceeding 30%. Notably, there are notable geographical variations in the incidence of peripheral T-cell lymphoma subtypes. In China, NK/T-cell lymphoma, peripheral T-cell lymphoma-not otherwise specified, and angioimmunoblastic T-cell lymphoma are the primary subtypes, whereas in European and American countries, ALCL and cutaneous T-cell lymphoma are more prevalent.

In response to the severe challenges posed by PTCL, the medical community in China has conducted extensive research on various types of peripheral T-cell lymphomas. Professor Zhang Huilai's team at the Lymphoma Department of Tianjin Medical University Affiliated Cancer Hospital has achieved certain results using azacitidine combined with chidamide, a dual epigenetic therapy, for the treatment of relapsed/refractory PTCL. Based on this, they initiated a prospective, multicenter, randomized controlled Phase III clinical study comparing dual epigenetic therapy combined with CHOP versus CHOP alone in the treatment of naive follicular helper T-cell phenotype peripheral T-cell lymphoma. Professor Zhao Weili's team at Ruijin Hospital, has made significant achievements in the field of NK/T-cell lymphoma. They conducted subtype exploration and identified three subtypes: TSIM, MB, and HEA, which differ in their sensitivity to drugs. Meanwhile, Professors Huang Huiqiang and Cai Qingqing at Sun Yat-sen University Cancer Center have also made crucial breakthroughs in clinical research on NK/T-cell lymphoma. Their proposed immune epigenetic therapy has demonstrated remarkable efficacy for patients with relapsed/refractory NK/T-cell lymphoma and further explored first-line and combination treatment strategies.

In summary, China has achieved in-depth research results in the types of peripheral T-cell lymphomas with high incidence rates and holds promise for providing more effective treatment concepts and strategies for patients worldwide.

《肿瘤瞭望-血液时讯》

影响R/R PTCL治疗选择的关键因素有哪些，您们如何在临床决策中平衡这些因素？

Oncology Frontier-Hematology Frontier：What are the key factors that influence the selection of treatment options for R/R PTCL, and how do you balance these factors in clinical decision-making?

Owen O’Connor教授

淋巴瘤联盟主席/弗吉尼亚大学癌症中心

当前，治疗标准普遍涵盖了化疗。然而，在选择化疗类型时，通常参考的是治疗B细胞淋巴瘤的方法。因此，在探讨联合化疗方案时，确实缺乏强有力的数据来明确哪种方案在复发或难治性患者中表现最佳。实际上，大多数化疗药物的疗效并不理想。对现有数据的分析表明，既往数据大部分源自回顾性研究，而缺乏前瞻性随机研究。

尽管如此，相关数据仍提示尽早使用新药可能会取得更好的效果，例如，我们团队已发表的普拉曲沙相关研究、组蛋白去乙酰化酶抑制剂和其他药物的研究数据。在使用这些新药方面，美国进展显得相对缓慢。目前中国拥有众多美国尚未拥有的新药，构成了巨大的优势。此外，据悉还有两种新药可能即将问世，包括PI3K抑制剂和EZH2抑制剂，同时中国也已经拥有了其他获批的治疗药物。根据我的临床经验，建议尽早使用这些新型药物。因为研究表明，早期治疗可以对疗效产生重大影响。以普拉曲沙为例，在严谨的病例匹配对照分析中，早期使用该药物已展现出对总生存期的积极影响。随着更多新药的不断研发，这一积极趋势预计将持续显现。

同时，探索药物的联合使用也显得极为重要。应优先考虑新药之间的联合应用，而非仅仅局限于与化疗药物的联合。为了更深入地了解如何开发针对复发难治性的有效疗法，应尽快推动患者参与相关临床试验。通过临床研究与实践的积累，将不断推动医学领域的进步，为患者提供更加高效、安全的治疗方案。

（上下滑动查看英文原文）

Professor Owen O’Connor: the current standards of care typically involve some form of chemotherapy。And the type of chemotherapy folks pick is usually modeled after how they treat B cell lymphoma a radically different disease。And so when it comes to combination chemotherapy，we really don't have that much great data to say what combination chemotherapy works best in the relapsed or refractory setting，I think is a general statement that's true。Most chemotherapy in the relapse to refractory setting is not effective。I believe if you look at the data and most of it is retrospective，we don't have prospective randomized studies。It would suggest that new drugs using them earlier will work better。And there's data that we've published with pralatrexate。There's lots of data with histone deacetylase inhibitors and other drugs。It's my very strong opinion。We wait too long to start these new drugs。here in China，you're extraordinarily fortunate。You have a lot of new drugs that we don't have in the United States。You've got two new ones potentially pending，including the PI3K inhibitor, the EZH2 inhibitor。And you already have other approved agents。And I would suggest because I do it in my own practice that we use those novel drugs as early as possible because what the data suggests is they can have a big impact。And in the case of pralatrexateusing the drug earlier has been shown to have impacts on overall survival in very strong robust case match control analyses。I think that paradigm is going to hold true as we begin to develop these other drugs。And secondarily I think clinical trials I think we need to start studying these drugs in combination new drugs。We need to prioritize studying those new drugs in combination with each other over chemotherapy and really try to get patients into those clinical trials as efficiently and fast rapidly as possible。So we can better understand how to develop what the next relapse refractory setting therapies might be。

钱正子教授

天津医科大学肿瘤医院

在治疗R/R PTCL的过程中，针对中国患者的治疗考量显得尤为复杂。首先，需要细致分析患者的具体病理类型，鉴于不同病理类型展现出独特的发病机制与分子遗传学特性，这些特性为医生制定更具针对性的治疗方案提供了关键依据。

此外，在为中国患者制定治疗方案时，还需全面考量其体质状况、功能状态、经济承受能力以及个人治疗意愿。值得注意的是，复发难治的患者往往已历经多种治疗方案及药物治疗，故在制定后续治疗方案时，需要详尽回顾其过往治疗方案、评估疗效及副作用情况。

因此，为每位患者定制治疗方案时，需综合权衡多种因素，力求在疗效和毒性之间找到一个最佳的平衡点。正如Owen教授所指出，当前国内存在众多临床试验项目，为复发难治的患者提供了多样化的治疗选择。对于那些历经多线治疗而疗效欠佳或经济负担较重的患者而言，参加临床试验不失为一个值得考虑的选择。

（上下滑动查看英文原文）

Professor Zhengzi Qian: In the treatment of relapsed/refractory peripheral T-cell lymphoma (R/R PTCL), the therapeutic considerations for Chinese patients are particularly complex. Firstly, a detailed analysis of the patient's specific pathological type is required, as different pathological types exhibit unique pathogenesis and molecular genetic characteristics, which provide critical evidence for doctors to develop more targeted therapeutic strategies.

Furthermore, when devising treatment plans for Chinese patients, it is necessary to comprehensively consider their physical constitution, functional status, economic capacity, and personal treatment preferences. It is noteworthy that patients with relapsed/refractory disease have often undergone multiple treatment regimens and drug therapies. Therefore, when formulating subsequent treatment plans, it is crucial to thoroughly review their past treatment regimens, assess treatment efficacy, and consider side effects.

Hence, when customizing treatment plans for individual patients, multiple factors must be comprehensively weighed to strive for an optimal balance between efficacy and toxicity. As Professor Owen has pointed out, there are numerous clinical trial projects currently ongoing in China, providing diverse treatment options for patients with relapsed/refractory disease. For those patients who have undergone multiple lines of treatment with suboptimal efficacy or significant economic burdens, participating in clinical trials may be a worthwhile consideration.

《肿瘤瞭望-血液时讯》

最近有哪些重要的R/R PTCL新治疗方法的临床试验结果，这些结果如何影响临床实践？

Oncology Frontier-Hematology Frontier：What are the most significant clinical trial results for new treatments of R/R PTCL that have emerged recently, and how do these results impact clinical practice?

Owen O’Connor教授

淋巴瘤联盟主席/弗吉尼亚大学癌症中心

在我看来，最具影响力的临床试验往往聚焦于那些在治疗T细胞淋巴瘤中反复出现且至关重要的机制。这些机制涉及多种药物靶点，包括PI3K、JAK1以及表观遗传学机制，同时还包括全局性影响DNA合成的药物普拉曲沙。

近期，有两方面的进展显得尤为重要。首先，新型药物的联合研究展现出了显著的潜力。在诸多研究团队中，组蛋白去乙酰化酶抑制剂与去甲基化药物的联合应用已取得了令人瞩目的成效。对于复发患者而言，罗米地辛与阿扎胞苷的联合方案可能是迄今为止所有已研究药物组合中效果最优的一种，充分验证了科学驱动的新型联合用药方案的益处，也进一步强调了加大此类研究力度的必要性。

其次，临床试验中不断涌现的系列新药同样引人注目。这些新药包括PI3K抑制剂林普利塞、EZH2抑制剂SHR2554、另一种EZH1/2抑制剂伐美妥司他（Valemetostat），以及近期获批的JAK1抑制剂戈利昔替尼等。这些临床试验无疑正在深刻改变当今的临床实践，并预示着这些药物具有巨大的潜力，但目前其潜力还远未被充分挖掘。当前，这些药物主要作为单一药物使用，尚未通过探索和理解正确的药物组合来充分发挥其全部功效。因此，新型药物的早期联合研究显得尤为重要。同时，针对PI3K、EZH2、JAK1等反复出现的小分子药物的研究也将继续改变临床实践。随着医学界逐渐摒弃化疗组合的旧范式，转向更多无化疗治疗理念，这些新药及其组合方案无疑将在未来发挥更加重要的作用。

（上下滑动查看英文原文）

Professor Owen O’Connor: the most impactfull clinical trials are those that are zeroing in mechanisms that seem to be recurring and important in treating T cell lymphoma。Those mechanisms include drugs targeting PI3K mechanisms targeting JAK1 mechanisms targeting the epigenetic biology， Pralatrexate which globally affects DNA synthesis。And so what I believe is important of late has been two things。One is combination studies of those novel drugs。And in our hands，at least for my group，the combinations of histone de acetylase inhibitors and hypomethylating agents。Romidepsin and azacitidine have to date produced the most compelling maybe the best outcomes for patients with relapse disease of any drug combination that's been studied so far。I think it's a testament to the benefit of these novel scientifically driven combinations。And I think we gotta do much more of that。the other in compelling data that's coming from clinical trials pertains to the emergence of all these promising new drugs like we talked about earlier with the PI3K inhibitor Linperlisib，the EZH2 inhibitor SHR2554, another EZH1/2 inhibitor valemetostat，I think and the recent approval of gold to sit nib the JAK1 inhibitor，and the recent approval of Golidocitinib the JAK1 inhibitor.I think those clinical trials there's no doubt are changing practice today。I think we are only scratching the surface and the potential of those drugs to change practice because they are being used as single agents。We're not really optimizing their full capability by exploring and understanding the right combination。So I think that combinations early combination studies of novel drugs are the most compelling and the vast recurring array of smaller single agent studies like the PI3K, EZH2, JAK1 are all going to change practice and they're going to continue to change practice as we move away from these paradigms of chemotherapy combinations and move towards more of a chemotherapy free idea about treating these diseases。

钱正子教授

天津医科大学肿瘤医院

R/R PTCL的最新研究主要聚焦于新型小分子靶向药物的研发以及免疫检查点抑制剂的创新。近年来，在PI3K抑制剂、EZH1/2抑制剂、JAK1抑制剂、免疫检查点抑制剂以及HDAC抑制剂等领域，我们见证了显著的疗效提升。然而，值得注意的是，尽管这些小分子靶向药物展现出一定的治疗潜力，其单药治疗的总体有效率普遍局限于30%至60%之间，这对于患者的治疗选择构成了显著的限制。因此，多药联合的治疗策略成为了当前及未来探索的重点方向。

在制定联合治疗方案时，需综合考量药物的疗效、副作用以及它们之间是否存在协同作用。此外，一些新兴的治疗方案也展现出了令人瞩目的疗效。例如，维布妥昔单抗联合苯达莫司汀（BBV）的方案，其客观缓解率（ORR）高达71%，完全缓解率（CRR）接近50%。这一成果不仅为我们提供了治疗上的新选择，也预示着在复发/难治性疾病的治疗中，免疫靶向治疗的地位可能会日益凸显，尤其是在疾病后期化疗效果逐渐减弱的情况下。同时，全口服方案如西达本胺联合强的松、环磷酰胺和沙利度胺（CPCT方案）也取得了良好的疗效，且在安全性和耐受性方面表现出色。这些成果进一步证实了新药在R/R PTCL治疗中的重要作用，并预示着未来多药联合治疗方案将成为主流趋势。

然而，在追求疗效的同时，我们也必须高度关注联合用药可能带来的不良反应。因此，在制定治疗方案时，应充分考虑患者的个体差异、药物间的相互作用以及潜在的不良反应风险，以确保治疗的安全性和有效性。

综上所述，随着新药的不断涌现和联合治疗方案的不断优化，R/R PTCL患者的治疗前景将更加广阔。未来，我们将继续探索更加有效、安全且耐受性良好的治疗方案，以期为患者带来更好的治疗效果和生活质量。

（上下滑动查看英文原文）

Professor Zhengzi Qian:The latest research on relapsed/refractory primary cutaneous T-cell lymphoma has primarily focused on the development of novel small-molecule targeted therapies and innovations in immune checkpoint inhibitors. In recent years, we have witnessed significant improvements in efficacy in the fields of PI3K inhibitors, EZH1/2 inhibitors,JAK1 inhibitors, immune checkpoint inhibitors, and Histone Deacetylase Inhibitors. However, it is noteworthy that despite demonstrating certain therapeutic potential, the overall response rates of these small-molecule targeted therapies as monotherapy are generally limited to between 30% and 60%, posing significant constraints on treatment options for patients. Consequently, the strategy of multidrug combination therapy has become a key area of exploration both currently and in the future.

When formulating combination therapy regimens, it is essential to comprehensively consider the efficacy, side effects of the drugs, and whether there is a synergistic effect between them. Additionally, some emerging therapeutic regimens have demonstrated remarkable efficacy. For instance, the regimen combining brentuximab vedotin with bendamustine has achieved an objective response rate of up to 71% and a complete response rate close to 50%. This outcome not only provides us with a new treatment option but also indicates that immune-targeted therapy may increasingly play a prominent role in the treatment of relapsed/refractory diseases, especially when the effectiveness of chemotherapy gradually diminishes in later stages of the disease. Meanwhile, oral-only regimens such as chidamide in combination with prednisone, cyclophosphamide, and thalidomide (CPCT regimen) have also shown good efficacy and exhibited excellent safety and tolerability profiles. These results further confirm the significant role of new drugs in the treatment of R/R PTCL and suggest that multidrug combination therapy regimens will become a mainstream trend in the future.

However, while pursuing efficacy, we must also pay close attention to the potential adverse reactions associated with combination therapy. Therefore, when devising treatment plans, it is crucial to fully consider individual patient differences, drug-drug interactions, and potential risks of adverse reactions to ensure the safety and effectiveness of treatment.

In summary, with the continuous emergence of new drugs and the ongoing optimization of combination therapy regimens, the treatment prospects for R/R PTCL patients are becoming broader. In the future, we will continue to explore more effective, safe, and well-tolerated treatment regimens, aiming to provide patients with better therapeutic outcomes and quality of life.

专家简介

Owen O’Connor 教授

美国哥伦比亚大学医学中心主席

美国淋巴瘤联盟主席

哥伦比亚大学医学中心Herbert Irving综合癌症中心淋巴发展和恶性肿瘤项目的联合项目主任

淋巴恶性肿瘤中心主任在管理霍奇金淋巴瘤和非霍奇金淋巴瘤以及开发治疗这些疾病的新药物方面具有国际权威

专注于发现和开发治疗淋巴瘤的新药，目前已率先开发了三种被批准用于治疗淋巴瘤的新药，并已发表200多篇关于淋巴瘤治疗的文章、书籍章节和评论等

专家简介

钱正子教授

天津医科大学肿瘤医院淋巴瘤科

肿瘤学博士

天津市整合医学学会淋巴瘤专业委员会副主委

天津市抗癌协会淋巴瘤专业委员会常委

天津市抗癌协会肿瘤临床化疗专委会委员

天津市抗癌协会肿瘤治疗不良反应救治专委会委员

CSCO中国自体造血干细胞移植工作组委员

CSCO头颈肿瘤专业委员会委员

《白血病-淋巴瘤》杂志编委

2008年赴美国德州大学M.D.Anderson肿瘤中心访问学习

在国内外期刊发表论文数篇

承担及参与多项国家级课题

（来源：《肿瘤瞭望–血液时讯》编辑部）

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