The treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) has always been a significant challenge and a hot topic in the field of hematologic malignancies. For these patients, treatment options are extremely limited after multiple lines of therapy. Their salvage therapy has a low remission rate and short survival time. Currently, there is an urgent need for new effective treatment regimens to improve patient outcomes. The 12th Annual Meeting of the Society for Hematologic Oncology (SOHO 2024) was held in Houston, USA, from September 4th to 7th, 2024, bringing together top experts in the field of hematologic malignancies worldwide to exchange the latest research findings and discuss new therapeutic strategies. During the conference, Dr. Christopher A. Yasenchak from the Willamette Valley Cancer Institute and Rsearch Center was selected for an oral presentation titled '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' (Abstract Number: ABCL-711). Hematology Frontier specially invited Professor Christopher A. Yasenchak to interpret the efficacy and clinical significance of the BV+R2 (Brentuximab Vedotin combined with Rituximab and Lenalidomide) regimen in the ECHELON-3 study.

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.

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.

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.