Drs Locke and Gordon explain how outcomes for patients with DLBCL have improved as treatments continue to evolve.
Grzegorz S. Nowakowski, MD: R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone] has been there for 20 years. Fred, do you think that outcomes are improving with frontline therapy? Because if you look at the initial studies that were published, the survival curves and progression-free survival [PFS] curves were somewhat lower than we see in the modern studies. Do you think it’s due to patient selection for the studies? Or are we better at supportive care and what we do in patient selection, where patients are doing better overall with frontline therapy?
Frederick Locke, MD: That’s a great question. For full disclosure, I’m a transplanter and a CAR [chimeric antigen receptor] T guy, so I don’t give the frontline therapy until we’re going to talk about CAR T maybe as a frontline treatment. But I see that as well, and we, at ASH [American Society of Hematology Annual Meeting] this year, had the POLARIX data showing that adding polatuzumab to a CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone]–like regimen could improve PFS, but it’s a very small difference with a lot of patients. We’re making incremental small changes.
The part I don’t fully grasp is that yes, we have these ways of looking at patients and knowing who’s likely to need dose-adjusted EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin] or the more intensive hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone]–like regimen, but it isn’t clear to me that those are defining features that tell us that these patients are going to do much worse—like so bad that we need to do CAR T-cell therapy for those patients. We need to do more to figure out how we can stratify those patients in the frontline setting, because if we’re curing 60% or 70% of patients with R-CHOP or by adding other agents, who do we need to give CAR T-cell therapy to in the frontline, at least in the clinical trial setting? Obviously, it would be a clinical trial.
Leo Gordon, MD: Sattva S. Neelapu, MD, at The University of Texas MD Anderson Cancer Center, published some data that addressed that as part of the ZUMA studies, where they looked at 2 cycles in a high-risk group getting dose-adjusted EPOCH and then a PET [positron emission tomography] scan, and if that wasn’t satisfactory, they went to CAR T. It’s almost first-line.
Frederick Locke, MD: That’s the ZUMA-12 study. It was published in Nature Medicine. They call it frontline, but to me, it isn’t frontline if you gave 2 cycles of chemotherapy, did a PET, and saw that there’s still PET-positive tumor there. That’s a viable strategy, though. But the question is, how do you pick those patients at the front end and do that?
Leo Gordon, MD: That’s a great question. That’s the question.
Caron Jacobson, MD: Some interesting data out of that study, though, are the high and durable complete response rate and attractive T-cell population that was recovered from the patient in order to make the CAR T cells. It may even be that finding patients who are in partial response with 2 cycles of chemotherapy may lend them to do better. Maybe frontline isn’t the way to do it. Maybe it’s to do 1 or 2 cycles, catch them in response, and then take them to CAR T. It will be interesting to see. We’ll get some data.
Frederick Locke, MD: Yes, I like that strategy, and it changes the way we interact with our community colleagues if that ultimately does become a strategy. It requires another trial to show that, not just ZUMA-12. But I agree, those response rates are impressive, better than anything we have seen with axicabtagene ciloleucel.
Matthew Lunning, DO, FACP: It’s going to be interesting. If those data and that situation are going to go forward clinically in the real world outside of a clinical trial, how are we going to do it? Because we all know that CAR T-cell clinical trials aren’t anywhere comparable with when we commercialize or use a commercial product from that gap in time between apheresis manufacturing and in some cases the preapheresis therapies that are needed for these patients.
Preapheresis chemotherapy and how that affects the T cells is an underexplored area in cellular therapy. This lends to a discussion about preapheresis in a newly diagnosed large-cell lymphoma population, like can we identify who we should be doing apheresis for at the time of diagnosis? We all have robust apheresis groups now. Can we identify and enrich for [them], and is that the best T cell that you’re going to get? Whether or not it’s using it as first-line Deauville 4-5 or if it’s in the second line based on TRANSFORM and ZUMA-7? We’re going to get there, but how do we change the architecture of our cellular therapy algorithm?
Leo Gordon, MD: One thing this brings to mind actually what Caron suggested and what the Nature Medicine paper did was when you go back to the origins of autologous stem cell transplant and diffuse large b-cell lymphoma was a paper by Thierry Lamy. Their group looked at people who weren’t getting an adequate response—based on CT scan—to their initial chemotherapy, which was CHOP, for the most part. They were randomized to either continue the same therapy or go to autologous transplant. It isn’t a big difference.
I’ll remind everybody that it isn’t a huge difference, but that’s what we base autologous stem cell transplant on: that initial observation. This is similar. It's the same question. If people aren’t getting a good response, would you go to CAR T? I agree with Matt that I’d like to have T cells available that we’ve collected early. Anecdotally, there’s a patient whose couldn’t be collected, but we had previously collected stem cells a year before that we froze. To remind everyone, there are about 20% T cells in the usual 5-million bag. CAR T cells were able to be manufactured from that, saving them, hopefully. We’ll see what the response is. The issue of having some stem cells around [is important]. Convincing insurance companies that’s a good idea is a whole different story.
Frederick Locke, MD: Was that on a trial?
Leo Gordon, MD: It was on a trial with an exception. Out of spec.
Frederick Locke, MD: But to this discussion about how we operate in collecting cells, can we collect them earlier? Will it make better T cells for CAR T? We also have to keep in mind that there’s a cost to collecting and doing apheresis and holding on to cells. That cost to hold on to it isn’t necessarily covered by the insurer.
Grzegorz S. Nowakowski, MD: And the majority of the patients will never need it.
Leo Gordon, MD: There’s a cost, and there isn’t enough room in our freezers for all the cells.
Frederick Locke, MD: Maybe there’s a business opportunity. Maybe we should sign a CDA [confidentiality and disclosure agreement] and start a company where we collect and store these things. But there have to be changes in the way business is done to make that sort of thing happen. To the point of 2 cycles of chemotherapy and whether we could roll in the CAR T, we have to interact with our colleagues in the community. If they’re giving R-CHOP or whatever in the frontline setting, seeing that, we have to be able to get that patient in quickly. We have to work closely with our friends in the community in order to get that patient CAR T if that’s what we’re going to do. We also need trials to verify that’s the way to go.
Grzegorz S. Nowakowski, MD: All of us have seen the POLARIX data, and there was some improvement in progression-free survival. So far, there’s no overall survival difference. There are some other exciting studies going in this space. We have bispecific antibodies added to R-CHOP, and other targeted agents: tafasitamab plus R2-CHOP [rituximab, lenalidomide, cyclophosphamide, doxorubicin, vincristine, prednisolone]. Those are all interesting studies, and hopefully they’ll move the bar.
Transcript edited for clarity.