弥漫性大B细胞淋巴瘤（DLBCL）作为非霍奇金淋巴瘤中最常见的一种亚型，具有高度异质性，治疗上存在挑战。患者预后受多种因素影响，标准R-CHOP方案虽广泛使用，但对于高风险群体如双重打击淋巴瘤（DHL）患者疗效有限，迫切需要更精准的治疗方案。第12届美国血液肿瘤学会年会（SOHO 2024）于2024年9月4日至7日在美国休斯顿隆重举办，吸引了全球血液肿瘤领域的顶尖专家，在此交流最新的研究成果，共同探讨治疗的新策略。在会议期间，《肿瘤瞭望-血液时讯》特邀梅奥诊所综合癌症中心的Grzegorz S. Nowakowski教授，为我们解析DLBCL治疗的最新进展和未来治疗策略的发展方向，以期为临床医生优化治疗方案和精确治疗选择提供重要指导。
《肿瘤瞭望-血液时讯》目前弥漫大B细胞淋巴瘤的一线治疗有哪些标准方法？近年来有哪些显著的改进？
Grzegorz S. Nowakowski教授：在弥漫性大B细胞淋巴瘤（DLBCL）的治疗领域，R-CHOP（利妥昔单抗、环磷酰胺、多柔比星、长春新碱、泼尼松）化疗方案作为一线治疗的标准方案已有20多年。对于携带MYC和BCL2或MYC和BCL6基因重排的双重打击淋巴瘤（DHL）患者，这类具有高风险特征的人群，临床上倾向于采用更为强化的化学免疫疗法，例如DA-EPOCH-R方案——一种剂量调整的EPOCH方案（依托泊苷、强的松、长春新碱、环磷酰胺、阿霉素联合利妥昔单抗），或其他强化化疗方案，以期提高治疗效果。
近期，DLBCL治疗取得了显著进展，特别是新型抗体药物偶联物（ADC）维泊妥珠单抗（Polatuzumab Vedotin，Pola）的引入。该药物靶向CD79b抗原，并携带有单甲基澳瑞他汀E（Monomethyl auristatin E，MMAE）作为细胞毒性载荷。临床研究结果表明，将维泊妥珠单抗与R-CHOP方案联合使用，与单独使用R-CHOP方案相比，能够提升患者的无进展生存期。然而，目前尚缺乏数据支持其能够显著延长患者的总体生存期。
鉴于此，全球多个医疗团队已调整了其一线治疗策略，将维泊妥珠单抗纳入治疗方案，以期为患者提供更优化的治疗选择。我们中心（梅奥诊所综合癌症中心）亦更新了治疗方案。
Oncology Frontier-Hematology Frontier：What are the standard approaches for frontline treatment of diffuse large B-cell lymphoma? What significant improvements have been made in recent years?
Dr. Grzegorz S. Nowakowski：Diffuse large B cell lymphoma has been treated for years with chemotherapy called R-CHOP, which is a combination of rituximab with CHOP. And that remains the standard therapy for the majority of patients with DLBCL. Patients with double-hit lymphoma, which have translocations of MYC and BCL2 or BCL6, are at particularly high risk, and those patients are often treated with intensified regimens like dose-adjusted EPOCH-R or other intensified chemotherapy regimens.One of the most recent significant advances we have seen is the introduction of a new antibody-drug conjugate called polatuzumab vedotin, which targets CD79b and is linked to a toxin payload. When added to chemotherapy and R-CHOP, it has shown better progression-free survival compared to R-CHOP alone, although it did not show an overall survival advantage.
Many groups around the world have adjusted their frontline treatment approach to use polatuzumab vedotin, and we do as well.
《肿瘤瞭望-血液时讯》在您的演讲中，您讨论了一线DLBCL治疗的最新进展。您能否分享一些具体的最新进展？
Grzegorz S. Nowakowski教授：在DLBCL的治疗中，POLARIS研究(NCT05076097)为我们提供了重要见解。该研究发现，DLBCL患者根据分子亚型的不同，对治疗的反应也有所差异。具体来说，活化B细胞（ABC）型的患者在采用维泊妥珠单抗加强的治疗方案时，显示出了更好的治疗效果，而生发中心B细胞（GCB）型的患者则没有表现出同样的治疗效果。多项回顾性研究显示ABC亚型DLBCL预后较差。
这一发现促使包括梅奥诊所综合癌症中心在内的多家医疗中心调整了治疗策略，对于非GCB或ABC亚型的患者，在R-CHOP方案的基础上增加了维泊妥珠单抗，以期提高治疗效果。而对于GCB亚型的患者，则继续使用标准的R-CHOP方案。这种基于分子亚型的治疗策略调整，体现了个性化医疗在淋巴瘤治疗中的重要性。值得注意的是，尽管维泊妥珠单抗在提高无进展生存期方面展现出潜力，但目前的研究数据尚未证实其能够显著改善患者的总体生存期。因此，对于POLARIS研究中的亚组分析结果，我们应谨慎解读，并期待在即将到来的ASH会议上获得更多更新数据。
Oncology Frontier-Hematology Frontier：In your presentation, you discussed the latest advancements in frontline DLBCL treatment. Could you share some specific key updates?
Dr. Grzegorz S. Nowakowski：The update on what is the POLARIS study, which has shown that there are two molecular subtypes of DLBCL: the ABC subtype, which is associated with a worse outcome, and the GCB subtype.What's interesting about the POLARIS study is that when you look at the subgroup analysis, it appears that the ABC subtype is the one that benefits particularly from the addition of polatuzumab vedotin, and not so much the GCB subtype. This raises the question of whether we should use this selection of non-GCB or ABC patients to choose the best therapy for them with polatuzumab vedotin. We actually do this at Mayo Clinic. So if you have a non-GCB or ABC subtype, we tend to add polatuzumab vedotin to R-CHOP. On the other hand, if you have a GCB subtype, we use R-CHOP. Normally, you have to be very careful about interpreting subset analyses like this in studies like POLARIS. But because there was no survival difference, we feel that it is appropriate to extrapolate from this subset analysis based on progression-free survival.
Again, now that the studies show no survival advantage, we'll see the update at this year's ASH meeting for this study.
《肿瘤瞭望-血液时讯》目前有哪些正在进行的临床试验，您认为这些试验可能对DLBCL的一线治疗产生怎样的影响？
Grzegorz S. Nowakowski教授：当前，DLBCL治疗领域正经历着日新月异的发展，众多创新研究不断涌现。这些研究可以根据其研究重点和方法被归纳为几个主要类别。
首先，靶向特定抗体的研究在难治性淋巴瘤治疗中显示出巨大潜力。美国东部肿瘤协作组（ECOG）开展了一项II期随机研究（E1412），对比R2-CHOP（来那度胺+R-CHOP）方案和R-CHOP方案在所有分子亚型的新诊断DLBCL患者中的疗效，这是一种日渐成熟的治疗方法。糖基化修饰的II型抗CD20单克隆抗体奥妥珠单抗（G）在晚期DLBCL患者中与CHOP（G-CHOP）结合使用时，显示出活性和可接受的安全性。正在进行的III期GOYA研究（NCT01287741），比较了G-CHOP和R-CHOP在先前未经治疗的DLBCL患者中的疗效和安全性。同时，该领域还计划开展其他靶向抗体的试验。
小分子药物的研究同样值得关注。卡非佐米作为一种新型的蛋白酶体抑制剂，在DLBCL的治疗中展现出了显著的疗效，尤其是与R-ICE（利妥昔单抗、异环磷酰胺、卡铂、依托铂苷）方案联合使用时。本次SOHO 2024会议上，一项I期研究的初步结果显示，R-ICE与卡非佐米的联合疗法具有非常高的缓解率，令人备受期待。此外，有关该药物的随机对照研究也正在进行中，而针对PI3K抑制剂的研究也在不断成熟。这些研究均属于小分子药物的范畴。
最后，还有一类研究专注于高风险患者，这些研究探讨在不使用标准化疗方案的情况下，如何通过早期巩固治疗作为初始诱导治疗的一部分来改善治疗效果。这些研究的结果同样备受期待。
综上所述，我们有理由相信，在接下来的数年中，DLBCL治疗领域将迎来重大变革。
Oncology Frontier-Hematology Frontier：What are some ongoing clinical trials, and how do you think these trials might impact frontline treatment for DLBCL?
Dr. Grzegorz S. Nowakowski：That's a great question, and it's an area of very rapid development, and we have a number of very interesting studies. I would generally put them into a couple of different categories. One is, do we have a way to target specific antigens? Specific antigen targeting is very active in the refractory setting. We have a study, the ECOGAR study, comparing obinutuzumab with rituximab, which is a mature treatment approach. We also have a study, the GOYA study, comparing polatuzumab vedotin with R-CHOP, which is also ongoing. There are other specific antibody trials planned in this space as well. That's one group of studies that are ongoing. There are also studies of small molecules. For example, carfilzomib is a new generation proteasome inhibitor, which is now being developed in DLBCL in the relapsed setting in combination with R-CHOP and showing nice activity. There's a presentation at this meeting showing a phase 1 study combination of R-CHOP with carfilzomib looks very promising with very high response rates.
There is a randomized study ongoing of this agent, and PI3K inhibitors studies are ongoing and maturing. Those are the categories of small molecules. And finally, we have a category of studies where high-risk patients are treated with consolidation early on as part of initial induction without CAR T cells versus standard chemoimmunotherapy. Those studies will also be very interesting to watch. So I'm confident that over the next several years, the field will change dramatically.
