Diffuse large B-cell lymphoma (DLBCL), as the most common subtype of non-Hodgkin lymphoma, is highly heterogeneous and poses challenges in treatment. Patient prognosis is influenced by various factors, and while the standard R-CHOP regimen is widely used, its efficacy is limited for high-risk groups such as patients with double-hit lymphoma (DHL), necessitating more precise treatment plans. The 12th Annual Meeting of the Society for Hematologic Oncology (SOHO 2024) took place from September 4th to 7th, 2024, in Houston, USA, attracting top experts in the field of hematologic malignancies from around the world to exchange the latest research findings and discuss new strategies for treatment. During the conference, "Hematology Frontier" specially invited Dr. Grzegorz S. Nowakowski from the Mayo Clinic Comprehensive Cancer Center to analyze the latest advances in the treatment of DLBCL and the future direction of treatment strategies, aiming to provide important guidance for clinicians in optimizing treatment plans and making precise therapeutic choices.

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.

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.

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.