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Dr. Jeremy Abramson:
Welcome to The ASCO Post Roundtable Series on Clinical Advances in Diffuse Large B-Cell Lymphoma. I'm Jeremy Abramson from the Mass General Cancer Center in Boston and Harvard Medical School. And joining me today are two of my wonderful friends and colleagues, Drs. Laurie Sehn and Kieron Dunleavy.
Dr. Laurie Sehn:
Hi, I'm Laurie Sehn. I'm from BC Cancer and the University of British Columbia here in Vancouver, Canada.
Dr. Kieron Dunleavy:
I'm Kieron Dunleavy. I'm at MedStar Georgetown University Hospital and Georgetown University in Washington, DC.
Welcome to you both. And today we'll be discussing recent updates in the treatment of diffuse large B-cell lymphoma and integrating new developments into different patient scenarios. Our second installment will now focus on second-line treatment for relapse/refractory DLBCL. So we're going to come back to the case of LE.
LE has diffuse large B-cell lymphoma non–germinal center subtype, who was initially treated with polatuzumab-R-CHP. Unfortunately, she relapses 11 months after achieving initial remission and now has biopsy-proven relapse involving nodes above and below the diaphragm, as well as multifocal bone involvement. She's now 73 years old and has an ECOG Performance Status of 1. Organ and bone marrow function are normal. So I may go to Dr. Sehn and say, Laurie, you've got this patient, unfortunately relapsing less than a year after pola-R-CHP. She's 73 years old. How would you approach her second-line therapy?
So this is an area where we're seeing a huge amount of change and really practice change in terms of the recent guidelines. Historically, the only real treatment we had to cure patients was really to take them to an autologous stem cell transplant with high-dose chemotherapy. And that was often the first question we would ask at the time of initial relapse. Is this patient a transplant candidate or not a transplant candidate? I'd have to say at 73 years of age, unless she was super, super fit by age alone, that often, in our center, pushes people out of the transplant range, but we'd have to consider whether or not she truly would be a transplant candidate. But the game is different now. So we've got data from three trials that has looked at this group of patients, so those who are either primary or refractory to upfront chemotherapy or relapse within 12 months, pitting CAR T-cell therapy against autologous stem cell transplant or I should say our usual approach of salvage therapy and stem cell transplant.
And what we've learned is that from two of those trials, there was a strong benefit for proceeding onto CAR T-cell therapy in the second-line setting rather than salvage and transplant with strong progression-free or event-free survival advantage. And most recently, from the ZUMA-7 trial, we saw an overall survival advantage. So I would argue that the data from those CAR T-cell therapy trials are highly applicable to this patient, who's now relapsed within 11 months. And if we did consider her a transplant candidate, for example, we would say that CAR T-cell therapy would be far preferable based on that recent data.
Yeah, I agree. And it's really striking that these randomized trials, both the ZUMA-7 and the TRANSFORM trial, found a 60% reduction in the risk of progression or death favoring CAR T-cells over high-dose chemotherapy, autotransplant, platinum-based chemotherapy. I think it really is one of these really dramatic practice-changing events in our field. And I agree that this patient would certainly be a candidate for CAR T-cells. Not everyone might consider her a candidate for high-dose chemotherapy, although the randomized trials would've included her, but the key is that even the third-line and later trials included patients well into their 80s with CAR T-cell therapy. And so I don't per se consider age a limit to CAR T-cell therapy, where, historically, I did for autologous transplant.
Kieron, we've got two different FDA-approved CAR T-cells in the second-line setting. Do you have a way that you would think about picking among these products or selecting a particular product for a given patient?
I mean, we have typically used axi-cel for most of our patients because it was the first CAR T-cell that was approved. But there are differences in toxicities. There are some groups that prefer one over the other in older patients. So we have typically been using axi-cel, but we have two other FDA-approved anti-CD19 CAR T-cells. So I think only with time we will get a better understanding and sense of which subsets of patients clinically and maybe biologically benefit from one CAR T-cell over the other. Yeah.
Yeah, I agree. I think one thing that we know from the data is that both CAR T-cells that are approved in the second-line setting can work in younger and older patients alike. There is a clear difference in the toxicity profile and so axi-cel does have a higher rate of cytokine release syndrome and neurologic toxicities, as well as high rates of severe cytokine release syndromes and neurologic toxicities. But these are highly manageable and almost always reversible in patients. It's just important when using these products to counsel patients accordingly. And if a patient is sort of frail or borderline or maybe unable to tolerate the toxicity at hand to think about maybe the lower-risk product. But I do agree the most important thing is having one of these available for patients in the second-line setting.
The other thing, as well, I guess, which we have seen recently, is these three randomized studies in the second-line setting have all been constructed quite differently with, I mean, the ZUMA-7 study not allowing any bridging therapy. And when you see these patients, I mean, some of them will need bridging therapy, and we're still, I guess, trying to figure out exactly what the impact of bridging therapy is on the final outcome because the ZUMA-7, TRANSFORM, BELINDA study, all do things a bit differently. So I think that that's important to point out and discuss, as well, as many patients will need bridging therapy before access to CAR T-cells based on logistical challenges, et cetera.
Yeah, no question about it. ZUMA-7, only steroids were allowed as a sort of bridging therapy between apheresis and CAR T-cell infusion. In TRANSFORM, they could receive a cycle of platinum-based chemotherapy, one of the same chemotherapy regimens administered on the standard of care arm, just a single cycle. And the majority of patients, about 60%, did get that at the discretion of their treating investigator. So these are aggressive lymphomas. They often need some degree of disease control during this period of manufacturing.
But Laurie, there's this other period that has emerged in the kind of real-world management of these patients, which Kieron is alluding to, which is you're referred a patient from outside of Vancouver, who is now progressing their primary refractory DLBCL. And they're referred to you because hey, there's this new data saying they should get a CAR T-cell. But, of course, they wait to get an appointment, which I'm sure is very quickly, but then they have to meet you, you have to talk to them about the process, you have to get an apheresis date set up. And there are patients who potentially need some treatment even before they get apheresed because they, at the first place, need to be referred in for consideration of this therapy. And that's a real-world consideration that wasn't part of the ZUMA-7 and TRANSFORM trials and probably needs a word other than bridging, maybe pre-bridging or pre-apheresis. But do you have any pearls in how you approach these patients who you're meeting, you're setting up, you've got an apheresis date in 2 weeks or 3 weeks, but something needs to control their disease before then?
Yeah. So we don't have any randomized data to tell us how to bring people best into CAR T-cell therapy, but I think the reality is that many of these patients have biologically very active disease, particularly this group of patients we're talking about, the primary refractory patients or the early-relapsing patients. Their disease is often on the move. And one of the challenges of getting people to successful CAR T-cell therapy is I think that you often do need to have their disease under control to be able to get them there, but also to have probably the better outcome. So many patients do require, as you said, initial bridge to be able to buy them time to successfully go through the treatment. I think it's important because these patients are now managed in a multi-center environment sometimes. So the doctor administering the CAR T-cell is not necessarily the doctor who's giving them the bridging therapy.
So I think communication is really important so everybody feels comfortable with the plan and so that things are timed appropriately. My goal is usually not to close any doors or to minimize the benefit from anything I might have to offer. So I think pola-BR is a regimen that is now approved for relapsed/refractory DLBCL. And using that data as a backbone, many people are using pola as a bridge to CAR T. So it's important to understand that bendamustine, prior to leukapheresis, is a bad idea because we know that it's highly lymphodepleting and we may not acquire the T cells appropriately. But there's also data that suggests that, even if you can get the T cells, bendamustine, in the 6 to 9 months preceding CAR T, may actually decrease the benefit from the CAR T. So I try to avoid bendamustine prior to CAR T-cell therapy, but I do find that polatuzumab together with rituximab can be very effective to accomplishing that bridge to CAR T.
Yeah, I agree. Pola-R has been my sort of preferred bridging approach. I guess we'll have to see, as polatuzumab gets adopted in the upfront management, if it becomes a less appealing bridging option. And I suppose it wouldn't be an appealing bridging option if the patient was primary refractory to pola-R-CHP, but still might be reasonable for this patient who's relapsing 11 months later.
Kieron, any other thoughts on how you would think about bridging therapy at a personalized basis for your patients?
Yeah, I mean, I would agree with what you have said. I mean, I've typically been using polatuzumab, polatuzumab-BR with significant reductions of the bendamustine part. But I think as you said, as we head into a new era, where a lot of these patients will have had pola-R-CHP as frontline treatment, then is pola going to be as effective in the second line as a bridge to CAR T-cell. So we are probably going to have to think about replacing that, I think, in people who have early refractory disease following pola-R-CHP.
Yeah. My personal favorite bridging, if it's possible, is radiation therapy. Other patients have a single dominant symptomatic bulky site of disease. Some radiation therapy can avoid systemic therapy, provide nice cytoreduction and symptom palliation. A very short course of corticosteroids can bridge patients. In the non-GCB patients, lenalidomide or ibrutinib can be considered, although won't work in all patients, but may be an option to consider. And then sometimes you go back to good old-fashioned R-GemOx for a relatively well-tolerated, low-intensity chemotherapy approach based on prior treatment. So I think it really does have to be personalized to the patient because the ultimate goal is we need to make sure we get them to the CAR T-cell treatment. And we know that if their disease is really exploding and very bulky at the time of CAR T-cell treatment, their outcomes are inferior compared to patients with some degree of disease control going in.
I wonder, Kieron, if I sort of change up the case a little bit and say what if this patient were relapsing 24 months instead of 11 months after pola-R-CHP, what would you do then?
Yeah, so I think that we have all this data from people who relapsed within the first year or are primary refractory, but if you look at outcomes with auto, they're better or they have been better historically in DLBCL in patients who have a very long remission after initial relapse. So for me, within 2 years, that's still a pretty short time. And the fact that she's had a superior treatment to R-CHOP, I think probably does not bode well for her with auto in addition to everything else. So I would be less inclined to do auto. So I would favor CAR T-cells, but, of course, they're not approved if the relapse happens beyond 12 months. So what we often do is we start with another treatment that is approved and re-image the patient and then can use CAR T-cells as a third-line treatment. But I think in this patient, if she relapsed within 2 years, I would favor CAR T-cells based on the data we have, but understanding that we haven't done a study outside of a year in her case, so it wouldn't really apply to her, the studies that we have discussed. Yeah.
Yeah, there is a caveat in the US but not in Canada, which surrounds transplant eligibility. And so for the late relapsers, the more than a year, those are the patients I still say, are they transplant-eligible or not? Because the transplant-eligible patients are still candidates for platinum-based chemotherapy and high-dose chemotherapy for chemosensitive disease. But if patients are not transplant candidates, they weren't included in the ZUMA-7 and TRANSFORM trials. But there was a separate trial called the PILOT trial, which was a phase II trial, specifically in non–transplant eligible, second-line patients, which actually did show that liso-cel, as a second-line treatment, induced a complete response in more than half of patients, about 40% of patients remaining progression-free with a plateau on the curve at a year and a half. And so when the FDA granted the second-line label for liso-cel, they included the PILOT population.
And so if you were to consider this patient non–transplant eligible, which, as Laurie pointed out earlier, is often in the eye of the beholder, and I think at 73, it'd be quite reasonable to say she's probably not a great transplant candidate, then liso-cel in the US would be an approved and available regimen. Because I agree with you, Kieron, my preference would be to give this patient a CAR T-cell. If she was 40 and relapsing 4 years later, I'd be very comfortable with platinum-based chemotherapy and transplant. But there's a lot of gray zone, I think, around these patients. So I think, how can I get them to a CAR T-cell potentially to maximize the likelihood of cure?
And Laurie, let me ask you. You don't have CAR T-cells available in second line, and most of the world doesn't, so Canada is not an exception to that, it's the norm. So how would you approach second-line, non–transplant eligible patients without a CAR T-cell option?
Yeah, I think that, right now, because we don't have access to CAR T, as you say, in the second-line setting for that type of patient, it becomes a bit of an artificial endeavor. So that's a patient that we do know from the third line beyond CAR T-cell therapy data that it does offer curative potential. So the goal is really to ask yourself the question, is there anything I still have left in my toolbox that's going to cure the patient, and CAR T-cell therapy can be curative for that patient, but has been relegated due to access issues in some environments like Canada and probably most of the world right now into the third-line setting. So my goal is still to get the patient to CAR T, but I'm usually required to do something first. So I think about what can I give this patient that is going to maybe control the disease temporarily with the ultimate goal of getting to CAR T.
So in this type of patient, I have to say I've actually resorted to pola-R and again continued to avoid the bendamustine because I intend to take them onto CAR T as a next step. The question becomes kind of at what point do they go to CAR T? They don't have a full CR to pola-R. Can I kind of then squeak them to CAR T? Do I have to wait for them to progress? It really becomes kind of a bit of a balance in timing. But ultimately, I try to give them something to see if I can get some disease control, hold their disease under control with the intent of coming in with CAR T in the third-line setting at the right and optimal timing.
Right. And Kieron, if you had a patient in second line, they weren't a transplant or a CAR T-cell candidate, is there a preferred approach that you have for that type of patient?
I think that based on all of the data targeting CD19, I mean, there are other ways that CD19 can be targeted using for example, loncastuximab or tafasitamab and lenalidomide. So I would probably favor an anti-CD19 approach, but there are, of course, other options as well. And in this case, you may want to take her cell of origin into account as well. But that's probably how I would be thinking about approaching her if we couldn't do CAR T-cells or autotransplant.
Yeah, I agree. I think if I have a patient who's not a transplant or a CAR T-cell candidate, which isn't a large population, but it exists, that's sort of where I think about the tafasitamab-lenalidomide combination targeting CD19 with a synergy, potentially, of the lenalidomide. And obviously, in a non-GCB patient, there's potentially added rationale there.
So let's go through some key clinical takeaways for the second module. On second-line management of diffuse large B-cell lymphoma, anti-CD19 CAR T-cell therapy with either axi-cel or liso-cel should now be considered preferred second-line treatment for DLBCL that is primary refractory or progressing within 1 year of initial treatment. And that's based on the ZUMA-7 and TRANSFORM randomized trials showing superiority over the prior standard of care of platinum-based chemotherapy and autotransplant. An autotransplant approach should still be considered as second-line treatment for transplant-eligible patients with a late relapse of DLBCL, although since most patients relapse early, that's a small population in the modern era. Non–transplant eligible patients also may receive liso-cel as a second-line therapy regardless of their duration of initial remission based on the PILOT trial, which garnered FDA approval in the United States. Whereas non-CAR options in the second-line setting or patients who are not candidates for CAR T-cells might include tafasitamab and lenalidomide or polatuzumab-based treatment.
So that brings us to the end of this case. Please see the other segments for further discussion about the latest data in diffuse large B-cell lymphoma or visit ascopost.com.