David Rizzieri, MD

This content originally appeared on our sister site,

Videos

The professor of medicine from Duke University School of Medicine discussed treatment approaches for after relapse on CAR T cell therapy or for patients who are ineligible for CAR T therapy.

Treatment Options After CAR T Therapy for Large B-Cell Lymphoma

This content originally appeared on our sister site, 

 I now want to move to CAR [chimeric antigen receptor] T-cell therapy, and that certainly has been the big development over the last several years, and I think we would all agree, has changed outcomes and rescued some patients who had few other options. The modality doesn’t work for everyone, clearly, but enough people that it has made an impact. I want to ask Greg first, and then David, your take on who you recommend for CAR T. I want to ask Greg more from the perspective of what clinical scenario versus the others, and then David, your take with regard to risk for toxicity, and who you might exclude or be more or less hesitant to consider. Greg, why don’t you start, and then we’ll go to David?

 One patient category that clearly would be candidates for CAR T-cell therapy, and I do those referrals quite often, are patients failing salvage chemotherapy prior to transplant. This is a group we alluded to, very difficult to salvage with subsequent lines of chemotherapy, and get them to transplant. And even if we do, the benefit of the transplant in this setting is questionable because they were already chemotherapy refractory. Those patients usually have good performance status and good organ function because they were candidates for transplant. That’s a big category. Obviously, folks who relapse unfortunately after transplant are also candidates for CAR T-cell therapy, and I do refer those quite often. There is this expanding group of patients who are not initially considered for transplant due to age, performance status, or organ function limitations who are now potentially candidates for CAR T-cell therapy as well. It’s a little bit of a moving target, it depends on the approach of the center, and sometimes if it’s on the protocol inclusion criteria, but I’ve been able to get CAR T-cell therapy for patients older than we typically would consider for the transplant.

 David, your take on this, and who are the patients you think are eligible, or perhaps less? One of the questions that comes up, do you debulk patients? Do you try to give them some chemotherapy first, beyond the bridging treatment? Are there people who are at greater risk for toxicity, where you’re more concerned from that angle? How do you approach it, as far as a candidate? And then, in a minute, we’ll get into the individual constructs.

 Sure. I think this is an evolving area of our understanding. We were so worried early on about killing off these living, dividing, proliferating cells, and not intervening early to manage adverse effects such as CRS [cytokine release syndrome] or neurotoxicity with steroids and whatnot. We now know that we can safely do that, and we’ve minimized toxicities much more so than our first studies, and we haven’t compromised efficacy, at least from our current data. And so, while we’re concerned about patients being more infirm, and if they get CRS or neurotoxicity, being able to have that reserve to recover them, by being more aggressive and more proactive at heading off these adverse effects at earlier grades, I think we’ve made a big impact on tolerance and the ability to offer this therapy. In terms of who I consider, it’s much as Greg and others have mentioned, in my practice, it would be the reinduction therapy failing the patient. Then I think they’re an excellent candidate. And age-wise, this is a stumbling block. Age is not by itself a reason not to transplant a patient today. Based on comorbidities, etc, we regularly and routinely are performing autologous transplant in patients well into their 70s, and that’s the same type of patient we’d be thinking about for CAR T. Not to be ageist, but how old is too old to have a durable benefit, either from auto transplant or CAR T? Is it 79, is it 81? I don’t know the answer to that, but it’s something we have to come to terms with, I think, as a community as well.

 David, let me ask you this as a follow-up, the other question that comes up, before we get into the constructs. These are CD19-directed therapies, tafasitamab, loncastuximab are CD19-directed. Is your general advice to people that if you’re planning on referring a patient to CAR T to avoid those drugs? Do you think it’s fine? I know there are data suggesting that people can respond even having a different CD19-directed therapy. Clearly, this is under study, and it’s not absolutely contraindicated, but what guidance do you give people who might be thinking about sending patients for CAR T but need something first?

 I’ll clearly show my bias, because I have no data, so I’ll put it out there for others to blow back at me, but as you mentioned, there are conflicting data out there. In the ALL [acute lymphoblastic leukemia] setting, we’re concerned about prior CD19-directed therapy before CAR T, but even there, some of the data are conflicted, and we have even less guidance in the lymphoma setting. My own practice pattern is I would like at least one chemoimmunotherapy regimen to fail a patient before I go to the newer, targeted therapies, given we don’t quite yet know that we’re going to have the same robust response with overlapping CD19-directed therapies. But after that, given as you, and Loretta, and others have mentioned, with the principle of diminishing returns with further chemoimmunotherapy, I’m not going to keep using that, and I would go to a CD19-directed therapy potentially before even, as a bridge to CAR T.

Experts discuss the use and selection of CAR T therapies in relapsed/refractory diffuse large B-cell lymphoma.

Selecting CAR T-Cell Therapies for R/R DLBCL

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?

 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?

 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?

 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.

 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.

 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.

Experts discussed their recommendations for second-line treatment options for patients with DLBCL.

David Rizzieri, MD

Articles

Treatment Options After CAR T Therapy for Large B-Cell Lymphoma

Selecting CAR T-Cell Therapies for R/R DLBCL

DLBCL Second-Line Therapy Recommendations