Recommendations for Second-Line Therapy in DLBCL

John Leonard, MD: Loretta, the approach to second-line therapy really comes down to transplant typically now eligible defined by ability to tolerate treatment and at some level, chemo responsiveness. And then the transplant ineligible group. I’m going to ask you in a second how we break them up. I just want to highlight to our audience that as we record here today there have been some interesting press release data suggesting that CAR T [chimeric antigen receptor T-cell therapy] might have a role in second-line therapy. We don’t know what that is yet and hopefully we’ll see that in an upcoming meeting. This may evolve and we’re all interested. But as of today, we don’t have that data and we don’t have that availability, although I just want to highlight for people that might potentially change. As of now it seems like we’re really heading toward transplants if we’re lucky or we’re not, and those are 2 paths. Loretta, how do you approach those 2 groups of patients?

Loretta Nastoupil, MD: I think it’s an important thing to highlight that what we describe today may be different even in the next year. I think the other important thing to recognize is that there are a number of these patients that are treated in community centers and so the determination about how intensive you should be with that second-line approach may be different depending on where the patient is being treated. But in general, I do think that at first relapse we’re deciding is this a patient that is going to be appropriate for an intensive salvage approach and if they have chemo-sensitive disease, consolidated with high-dose therapy autologous stem cell transplant I think most places will agree on characteristics according to the patient and the depth of response in terms of whether or not they’re appropriate for consolidation. I do think that may be more of a moving target if we move CAR T therapy into second line. I will note one controversy in that all of the 3 randomized studies looking at CAR T versus salvage and high-dose therapy in second line enroll transplant eligible patients. I feel that we are pretty good at deciding based off of comorbidities, not agent isolation, but fitness who would be appropriate for instances of therapy and based off of that the response proceeding with high-dose therapy auto [autologous] transplant. Some of the controversies in the past year reported at ASH [American Society of Hematology] last year as how do we manage those PET PRs [partial responses] that fail to achieve a PET CR [complete response] in the area of CAR T at third line. I think there are some controversies in the depth of response. One interpretation of a PET whether it’s 99% improvement versus 51%. There are some selection biases that factor into some of those analysis from CIBMTR [The Center for International Blood & Marrow Transplant Research] but I do think that these are the dilemmas we currently face. We decide that a patient is an appropriate candidate for intensive salvage. We pursue that salvage. Most of the time it is RISE. It might be a gemcitabine [Gemzar] approach or gap in combination with a CD20. We get a PET after 2 cycles and if a patient is in a complete response move on to transplant. There is some interesting data reported at ASCO [American Society of Clinical Oncology] this year looking at a nontraditional approach in second line and you will hear, Greg, I’m sure take us into a deeper dive. Looking at tafasitamab, the CD19 naked antibody, in combination with lenalidomide [Revlimid] in the second-line non-transplant candidate space. Most of these patients were deemed to be not appropriate for candidate I think mostly based off age, median age, and the L9 study with 72 because they otherwise had to qualify for the study. Maybe marginal performance status. But what’s intriguing about the L9 data if you look at the outcomes according to second line versus third line, which is what they went into at ASCO this year, must better PFS [progression-free survival] in the second-line patients versus third-line patients. I will take a step back and say it’s even a very more select patient population in that they excluded patients with double hit [lymphoma]. They excluded those with primary care refractory disease, and they could only have had 1 to 3 prior lines of therapy. The majority of patients had only 1 prior line of therapy. But it does make me rethink. Do you need an intensive salvage chemotherapy if some of the outcomes are that good with a nonchemo approach, albeit in a selective patient population? And now just as you’ve heard as CAR T, particularly CD19 autologous CAR, moves into second line, how does that then disrupt the treatment landscape?

John Leonard, MD: We’ve gone from very few options in really a chemotherapy approach to now several different options. I want to come back particularly to the transplant ineligible patients because we have lots of choices. But before we do that, David, I want to ask you your take on this PR after second-line therapy patient who is lined up, intended to get a transplant. You have a young patient who progresses after R-CHOP [rituximab (Rituxan), cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone]. You are planning a transplant. They get a couple cycles of your second-line chemo of choice, and they get a decent PR. Do you take that person auto transplant? Do you give them more chemo? Do you try to get CAR T if you can get it? Do you do something else? Give us a feel for it. I realize at least on our team it’s like it’s a PR but it’s a good PR. Not so good PR, we’re a little more worried. A little less worried. It’s hard if it’s an elderly patient I find because then you’re less excited about pushing for the transplant if you’re less excited that they’re chemo sensitive. For a younger patient, how do you think about it?

David Rizzieri, MD: I appreciate that. I appreciate Loretta’s point before about who is determining whether they’re transplant eligible or ineligible. It always surprises me at any of these relapse/refractory studies that are leading to these new agents being studied. There are only about 20% of the patients with relapsed DLBCL [diffuse large B-cell lymphoma] that get a transplant before they go on these studies. Somebody is deciding they are not eligible. It’s not often the transplanter. For a lot of these patients, it is several factors that we as transplanters would not consider hard stops. But they don’t get in for consults. It continues to be perplexing to us. To your point specifically about this PR. When all you have is a hammer, all the world’s a nail. When we did our studies, when you and I were younger 25 years ago, we had transplant and that was it in a relapse setting. We took everybody who had a modicum of response. Fifty percent shrinkage. We’re good to go. We’re not in that same ballpark anymore. For that reason, we really want to see if there is a good chemo-sensitive response in remission. If they are not in remission I am not enthusiastic at all about offering auto transplant to that patient because we have so many effective options. As you pointed out, that’s the type of patient that if induction fails them to get a remission that’s the second regimen. They would be unable for a CAR T. What a great option. Or if I have to use a third or fourth regimen to get a young healthy person to remission, I’m going to strongly consider an allo [allogeneic] transplant with some post-transplant immunotherapy. That’s the way I have come to look at it now that we have more options as was pointed out.

John Leonard, MD: Cyrus, any other takes on that? Our data and others, I don’t think third-line chemo in this setting does anything. I think if you’re going to try to do something, do something different than third-line chemo it seems to me. Or solely third-line chemo let’s say.

Cyrus Khan, MD: I agree. I mean even my take has evolved over time. Naturally, when CAR T wasn’t available it was taking some of these patients that I wasn’t too sure were going to do well with auto but that’s the only approach left to us. Now I really look for reasons not to take the patient to auto, and instead focus on other therapies, such as CAR T or transplant.

TRANSCRIPT EDITED FOR CLARITY