复发/难治性弥漫性大B细胞淋巴瘤（R/R DLBCL）的治疗一直是血液肿瘤领域的重大挑战和热点议题。这部分患者历经多线治疗后，治疗选择极为有限。其挽救治疗的缓解率低，生存时间短。目前，急需新的有效治疗方案以改善患者预后。第12届美国血液肿瘤学会年会（SOHO 2024）于2024年9月4日至7日在美国休斯顿举行，汇聚了全球血液肿瘤领域的顶尖专家，交流最新研究成果，探讨治疗新策略。会议期间，美国Willamette Valley癌症研究所Christopher A. Yasenchak教授入选了题为《Brentuximab Vedotin (BV) in Combination With Lenalidomide (Len) and Rituximab (R) in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL): Results From the Phase 3 ECHELON-3 Study》的口头报告（摘要号：ABCL-711），《肿瘤瞭望-血液时讯》特邀Christopher A. Yasenchak教授为我们解读ECHELON-3研究中，BV+R2（维布妥昔单抗联合利妥昔单抗和来那度胺）方案的疗效和临床意义。
《肿瘤瞭望-血液时讯》：您在ECHELON-3研究中探讨了BV联合R2（R+len）方案的疗效。这种组合疗法在治疗策略上有何创新之处？
Christopher A. Yasenchak教授：我认为来那度胺和抗CD30抗体-药物偶联物（如维布妥昔单抗）之间存在协同作用，这些协同作用的机制尚未被完全阐明。该组合显示出的免疫调节效应可能对淋巴瘤的治疗具有积极影响。已有研究对这一联合疗法进行了探讨，并初步观察到了积极的治疗响应数据。此外，两种药物的毒性作用不出现重叠，这进一步支持了将其作为一种潜在的理想联合治疗策略的观点。
Oncology Frontier-Hematology Frontier：In the ECHELON-3 study, you explored the combination therapy of BV and R2（R+len）. What are the innovative aspects of this therapeutic strategy?
Dr. Christopher A. Yasenchak：I think there's some synergy between lenalidomide and the anti-CD30 agents that have really not been completely understood. So there's definitely some immune modulating effects of this combination that we think can be beneficial in lymphoma therapy, and then there have been previous studies, you know, looking at this combination. And like I said, there have been reasonable response rates, somewhat non overlapping toxicity profile as well. And so if you're able to have some synergy in terms of sort of immune modification, in terms of benefit of response to therapy and non overlapping toxicities, then that would be an ideal combination strategy.
《肿瘤瞭望-血液时讯》您能否分享一些ECHELON-3研究的主要结果，并讨论这些结果如何可能改变R/R DLBCL的治疗？
Christopher A. Yasenchak教授：ECHELON-3(NCT04404283)是一项随机、双盲、安慰剂对照、多中心、3期研究，纳入了既往接受过至少2线全身治疗的复发/难治性弥漫性大B细胞淋巴瘤（R/R DLBCL）患者。之前，这部分患者的治疗反应率相当低，结果不尽人意，总生存期（OS）通常不到一年。本研究将BV+R2与单独R2治疗进行了比较。中期分析的研究结果表明，BV＋R2方案使无进展生存期（PFS）和总生存期获益。BV＋R2组的客观缓解率（ORR）为64.3%，完全缓解率（CR）为40.2%，完全缓解持续时间约为18个月，与R2单药治疗组相比，ORR和CR均较高，且缓解时间更长。
研究结果对三线治疗的DLBCL患者显示出临床意义上的改善，因为这部分患者通常治疗选择有限。大多数患者既往已经接受过造血干细胞移植（HSCT）、CAR-T细胞疗法或双特异性抗体治疗，但未能获得成功。ECHELON-3研究中约有50%-60%的患者有上述治疗失败史。
本研究约30%~40%的患者在治疗中进展，后续接受了额外的治疗。此外，部分患者在入组前被评估为不适合HSCT、CAR-T细胞疗法或双抗治疗，但在接受本研究治疗方案后，再次评估后认为，其符合了HSCT、CAR-T细胞疗法或双抗治疗的条件，因此我们可以认为BV＋R2方案为重度预处理R/R DLBCL患者提供了一种桥接治疗方案，使其有机会在后续接受强化治疗。
Oncology Frontier-Hematology Frontier：Could you share some of the main results from the ECHELON-3 study and discuss how these might change the treatment of R/R DLBCL?
Dr. Christopher A. Yasenchak：This was in relapse refractory patients. And these patients who were in this study had to have received at least two prior lines of therapy.
Historically, response rates to treatment are pretty low and the outcomes are more. Survival is typically less than a year. So what the study did was in a randomized, blinded fashion compared lenalidomide and rituximab with placebo to lenalidomide and rituximab and vibutuximab in adult. The results of the study showed at the interim analysis is that there was overall survival advantage to the approach. Not only was the overall survival advantage, but there was progression free survival advantage. The duration of response was superior, the response rate was higher, and the CR rate was higher. So the response rate to the to the combination with vibutuximab was 60% with about a 40% complete response rate. Durability of that CR was about 18 months.
And so for third line beyond therapy and large cell lymphoma, we would do that as being a clinically meaningful improvement for these patients who have very few treatment options available.
If you look at the landscape of relapse large cell lymphoma, we also have to realize that these patients had either failed auto transplant，CAR T or bispecific therapy, which was about 50% to 60% of the patients on the study or they were ineligible to receive it. And so in terms of looking in our toolbox, what else is available? It's getting a little empty. So this may fit into a treatment plan, again, once these agents have either failed or in patients who are ineligible to receive them. And the other interesting thing as well is that one's patients progressed on this therapy. About 30% to 40% of those patients did go on to receive additional therapies. Some of those patients, and I don't know exact numbers, but that's being looked at right now. Some of those patients weren't unable to receive CAR T，bispecific therapy，antibody drug conjugates, which they previously weren't felt to be eligible for. And so may potentially this regimen be a bridge for those sicker patients to potentially then allow them to have more intensive therapies down the lines.
《肿瘤瞭望-血液时讯》在设计ECHELON-3这样的3期临床试验时，您认为最关键的要素是什么？
Christopher A. Yasenchak教授：刚才提到，R/R DLBCL患者有巨大的未满足需求，他们既往接受过至少2线的全身治疗，既往全身治疗线中位数为3，因此他们的治疗选择极其有限。
此项研究希望寻求HSCT、CAR-T细胞疗法或双抗治疗失败后可以使用的治疗方案，或者不适合接受上述治疗的患者可以使用的方案。
本研究根据CD30状态（≥1% vs. <1%）、起源细胞（生发中心B细胞[GCB] vs. 非GCB）、既往CAR-T细胞治疗（是 vs. 否）和既往干细胞移植（是 vs. 否）进行分层。
结果显示，无论CD30表达情况如何，在GCB亚型、ABC亚型及既往接受过CAR-T细胞疗法或干细胞移植的患者中均获得缓解，且有OS获益。这一结果令人瞩目。
Oncology Frontier-Hematology Frontier：When designing a Phase 3 clinical trial like ECHELON-3, what do you consider to be the most critical elements?
Dr. Christopher A. Yasenchak：I think this population has a huge unmet need, So at least two prior lines of therapy, median number of prior therapies was three for this patient population. There's not a lot of treatment options left. And so it's a huge unmet need. The primary purpose of this was to find some treatment regimen which can be utilized following transplant ，CAR-T，bispecifics or in those patients who were ineligible for that.
It's also interesting that the randomization did stratify. It's CD30 status. And we saw responses irrespective of CD30 expression for cell of origin activated B cell versus germinal center B-cell-like lymphoma, a large cell lymphoma and for previous CAR T， auto transplant. And it was overall survival benefit irrespective of many of those some groups, which is fairly significant and impressive in my opinion.