Dr Elizabeth Brem Discusses the Evolving Landscape of DLBCL Treatments

Treatments for patients with diffuse large B-cell lymphoma (DLBCL) are evolving with novel therapies moving into earlier lines of treatment, said Elizabeth Brem, MD, associate clinical professor, School of Medicine, University of California, Irvine.

Already, chimeric antigen receptor (CAR) T-cell therapies are moving into second-line treatment, and now people are looking at where and when bispecific antibodies can be used, she explained.

In an interview with The American Journal of Managed Care^® (AJMC^®), Brem discussed the current treatment landscape of DLBCL, determining patient eligibility for treatments, managing the disease in geriatric patients, and more.

AJMC: What is the role of CAR T-cell in the current treatment landscape of diffuse large B-cell lymphoma? What is the potential role of bispecific therapy in this space?

Brem: CAR T-cell therapies are, as many people are aware, finding their role in earlier lines of treatment of diffuse large B-cell lymphoma. The earlier studies examining CAR T-cell therapies kind of looked in the third line and beyond setting, but thanks to a couple of studies presented at ASH 2021, many patients are receiving CAR T cells in the second line. There were 3 studies presented that year looking at CAR T-cell therapy versus standard of care—in that case, it was a salvage chemotherapy and autologous transplant—for patients who relapse within 12 months of their original R-CHOP or similar chemoimmunotherapy. All 3 studies were slightly different in terms of eligibility criteria, whether or not bridging could be allowed and such, but 2 of those 3 did show a benefit to using the CAR T-cell therapy in second line. The third that did not show a benefit was called BELINDA. There are probably several reasons why that study did not show a benefit. I personally think a large amount of it is that the time from collection to reinfusion of the T cells in that particular study was over 50 days compared with 21 to 28 days for the other 2 studies that did show a CAR T cell benefit.

Now, 2 of the CAR T-cell therapies are FDA approved in second line—lisocabtagene maraleucel (liso-cel) and axicabtagene ciloleucel (axi-cel)—and I do believe that most of us are using them for eligible patients who relapse within 1 year of their initial therapy. For patients who relapse several years later, I think there's still a role for salvage chemotherapy and autologous transplant. What we really don't know is for those who relapse 1 to 2 years, for example, after their original R-CHOP chemoimmunotherapy, should those patients be getting CAR T-cell therapy in the second line? I think you can make an argument for it, and I think you can make an argument against it. The reality is, we just don't have data, and it's ultimately up to the individual provider and their patient to decide what to do.

There are currently studies of CAR T-cell therapies in the frontline. So, whether or not, ultimately, that is what we will be doing from the get-go, I do not know. I can come up with a lot of reasons why it could be complicated to give CAR T-cell therapy in the frontline—in particular for patients who need treatment as soon as possible—but in the next couple of years, we'll get some readout of those studies about whether or not it actually makes sense to reach for the CAR T cells in the frontline. But for now, for the majority of patients it is at the second line and beyond.

Where bispecific antibodies will fit in is a debate we're having not only in diffuse large B-cell lymphoma but also multiple myeloma. They are approved third line and beyond. However, now that they're out there and commercially available, people are kind of going to do what they're going to do. There is not data like there is for CAR T-cell therapies, for example, to give in the first relapse and the upside to using the bispecific antibodies is you don't have to go make a product, they're what's called “off the shelf.” One of them is approved with a limited duration therapy. One of them is approved as indefinite therapy, I suspect we're going to be just generally moving towards time limited therapy. They are an excellent option for someone who, for example, can't go to a CAR T-cell therapy for one reason or another—sometimes that's patients, sometimes that's logistics. They are potentially an excellent option after CAR T-cell therapy. There are unfortunately patients who relapse after CAR T-cell therapy. But I think now that we have them commercially available, we’re going to be figuring out the appropriate place for bispecific antibodies.

AJMC: What are the potential benefits and drawbacks of these therapies compared with conventional chemotherapy and immunotherapy?

Brem: We have learned that for certain patients—and I think studies like ZUMA-7 looking at CAR T-cell therapy early on, supported this theory—there are certain times or certain patients where it doesn't matter if you switch chemotherapy to a salvage regimen or change the intensity, but chemotherapy kind of just isn't going to work. There are these primary refractory patients who relapse relatively soon after their R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone], and we all know—and there is some historical data from things like SCHOLAR and the CORAL study—that those patients just don't do well no matter what you do. You can give them salvage therapy, but they're unlikely to respond and very few of them actually get to the autologous transplant—it's something on the order of about 20%. We've always known we needed something else for those patients, and that's why there was so much excitement, I think, for utilizing CAR T cells in this sort of situation.

We all have those patients where we just kept giving therapy after therapy after therapy and they just don't seem to be chemosensitive no matter what the regimen is. These newer therapies—CAR T-cell therapies, bispecific antibodies, and even some of the other things that have been approved in the last couple of years like tafasitamab, lenalidomide, and loncastuximab tesirine—are just completely different mechanisms of action. Whether it's training the immune system against the malignancy or targeted delivering of the therapy or what have you, it's been pretty clear that we needed things like this for a long time.

The other thing is, obviously, the toxicity profiles of these things are very different. Most people tolerate the R-CHOP or the pola-R-CHP [polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisolone] or whatever it is you give them frontline relatively well. But once we get into the salvage regimens like R-ICE [rituximab, ifosfamide, carboplatin, and etoposide], R-DHAP [rituximab, dexamethasone, cytarabine, and cisplatin], even GemOx, those people have more neutropenia, they have more neuropathy, many of them have to go in the hospital. They are difficult regimens to give.

While nothing is perfect, in my limited experience, so far these kind of alternative therapies do have a risk of cytokine release syndrome with bispecifics and CAR T-cell therapies, but it's limited duration and it's very manageable. Not only does it provide us with a brand-new, unique mechanism of action, but it also presents us with a different and typically relatively manageable toxicity profile. All of these things differ greatly in their dosing schedules and routes of administration. So obviously, on a patient level, that’s something that goes into the decision of what to do next.

AJMC: What type of patients are these treatments targeting? What is the screening process to determine which patients are eligible for these treatments?

Brem: This is also an evolving field. When you looked at studies like ZUMA-7, one of these studies that looked at CAR T-cell therapies versus salvage therapy and anticipated autologous transplant, the patients who enrolled in these studies had to be patients who seemed to be traditionally eligible for transplant. Typically, that will mean a specific organ function, performance status, ejection fraction, limited comorbidities, these sorts of things. These patients who are going into the studies were traditionally transplant eligible. But what we're sort of discussing and learning as a field, is CAR T-cell eligibility the same as transplant eligibility? And the answer is probably no. Probably we can take people with slightly more comorbidities to CAR T-cell therapy than we've traditionally taken to transplant. Some of that it does rely on the individual CAR T-cell construct. We kind of lump these into a category: axi-cel, liso-cel, tisagenlecleucel (tisa-cel), they all target CD19, but they all differ in terms of what their rates of cytokine release syndrome are and also in terms of how much data there is surrounding about things like outpatient administration and giving them to older patients.

Liso-cel and tisa-cell have some data about outpatient administration, safely giving them to some older patients, and those sorts of things. Probably, CAR T-cell therapy eligibility is not exactly the same as transplant eligibility as long as you're being thoughtful about how and which CAR T-cell construct you're giving. I do think there are a couple of patients who I have who are older, who have a couple of comorbidities, but they're generally well functional, who people maybe would not have traditionally thought of them as transplant candidates, but I do think that they are CAR T-cell therapy candidates. There's not strict criteria. Every center kind of has their own way they do it, but I do think there's a difference between the 2.

Then you add in, for example, the bispecific antibodies, and that's probably an even wider eligibility. Yes, there's a risk of cytokine release syndrome, but it is lower typically than with CAR T-cell therapies. Different products are being approved with different kinds of suggestions in terms of admissions for monitoring, but they're short—maybe it's 1 or 2 days depending on which bispecific antibody you're looking at versus CAR T-cell therapies, where people are being admitted typically for a week or even autologous transplant when it's more like 3 to 4 weeks.

I do find for some patients, the idea of any hospitalization is a bit of a barrier. I don't know if we'll always be hospitalizing people. I think we will be for manufacturer guidelines, at least in the beginning, as we get used to these things. Though, it may be that when those need for admissions eventually fade away that more patients will be eligible. But there are still going to be patients with severe renal impairment or difficulty caring for themselves or memory impairment, or a number of other things where you may even feel like bispecific antibodies are kind of off the table. Luckily we live in an era where we still have other therapies available for those patients where this is where I may think about things like tafasitamab and lenalidomide or loncastuximab if the patients haven't had them before, and it seems appropriate otherwise.

AJMC: Many patients diagnosed with B-cell lymphoma are of geriatric age. How does this affect management of their disease as opposed to diagnosis in younger patients?

Brem: This is another evolving field. I think that my answer today and my answer in 3 to 4 years might be different. I think we're learning that age is only one of the factors that goes into this, and a lot more of it has to do with the comorbidities and the functional status of the patient. This isn't necessarily specific to diffuse large B-cell lymphoma, but it's an important conversation in diffuse large B-cell lymphoma, because we're talking about a disease that if you give a younger patient R-CHOP, there's a 60% to 70% chance you cure them. There's a lot of wonderful work with geriatric assessments and other solid tumors, but sometimes in those situations, you're not necessarily looking at a curative intent of therapy. When you decide not to give an older patient with diffuse large B-cell lymphoma some variation of R-CHOP, for example, you're essentially choosing not to give them curative therapy, and I think that's why it's more complicated in this disease and perhaps in other tumors.

There are several geriatric assessment tools that are out there, I think we sometimes have a hesitation to use them because we have a hesitation to do anything that's going to make our clinic session longer. But many of them can be done in say 7 to 10 minutes, and the one that I most familiar with and have found most useful comes from the Italian Lymphoma Foundation. There's a really lovely publication, they had in Journal of Clinical Oncology,¹ about 2 years ago talking about their geriatric assessment, which looks at comorbidities index, activities of daily living or instrumental activities of daily living, and then age is actually an independent factor. You can sort patients into fit, unfit, or frail, and they're sort of continuing to refine this tool. Their retrospective data suggests that patients who score as fit or unfit, you really can go ahead with curative intense therapy, whether that's R-CHOP, [reduced dose] R-miniCHOP or some other. But that perhaps for the frail patients, we should be focusing on comfort and quality of life.

Now, this has not been validated prospectively. We're actually trying to do that right now in the setting of a study called S1918,2 which is an intergroup study of R-miniCHOP with or without oral azacitidine in patients aged 75 years and older. We are doing this assessment on everybody at study entry—the eligibility is separate from this, but we are trying to kind of validate in a larger data set, can this tool really predict who is going to benefit from something like R-miniCHOP versus who we think about more palliative approaches. I try to approach each one of my older patients independently and take into consideration how functional are they, what kind of support they have—that goes a long way.

Also, and this is one of the harder things to assess, how much of any functional impairment in front of you at this moment is due to the disease. Diffuse large B-cell lymphoma can happen relatively quickly and somebody can feel fine, and then 2 months later not be able to walk because they have some giant mass pushing on something. This is where the use of something called a prephase regimen can be helpful, which is basically to give somebody some steroids with or without vincristine and that can kind of debulk the tumor and make them feel good enough to show you that they may be a little more capable of handling more intense therapy.

We've sort of understudied this population a lot in the past. There are a handful of studies that have been done in Europe looking at patients 80 years and older, but many of them didn't incorporate these geriatric assessments to better understand the population as a whole. I think we are moving toward taking each patient and trying to figure out where they are individually and less about looking at just a number and making a decision based on just a number, such as age.

I think this is also translating to our patients getting potentially CAR T-cell therapies. There are publications on older patients getting CAR T-cell therapies and doing well. So, I don't personally see age as an absolute cut off for CAR T-cell therapy. In fact, I have a gentleman in his 80s who was recently collected because he's really otherwise in excellent shape. Many centers do have an absolute cut off for autologous transplant, which maybe is not inappropriate, but as we have more therapies available, I think we're going to learn how to use them more safely so that many of our patients—age aside—if they're in reasonable shape are going to be able to receive them.

AJMC: What are you working on in the management of B-cell lymphomas that you're excited to share?

Brem: I just alluded to one of them. I am the one of the study chairs for S1918.² One of the reasons I'm really excited about that study is it is not only asking a therapeutic question. I mentioned that it's R-miniCHOP with or without oral azacitidine. We have reason to think that azacitidine in particular or hypomethylating agents might be useful in this population. It's an oral medication that so far seems to be relatively well tolerated. So, maybe we're going to change the treatment for our patients.

Regardless of how that plays out from a therapeutic perspective, we designed the study in such a way to help us learn a lot about the management of our older patients. Everyone's going to get this geriatric assessment upfront, and we're also doing a longer geriatric assessment that came from our colleagues from the Cancer Aging and Research Group to look at functioning on multiple dimensions. Can people take care of their finances? Can they walk? Can they do day-to-day things? Get up and go test. Those sorts of things. We're looking not only at baseline, but we're also looking at several time points down the road. We're looking toward the end of therapy. How much did we beat them up with their 6 cycles of our miniCHOP?

But we're also looking several months after that, after people have recovered, because we really wanted to understand not only how are we affecting them the short term, but how are we affecting these people long term? Is there a long-term cognitive dysfunction? Is there a long-term neuropathy affecting people's functioning? Let's imagine we have a small benefit in terms of progression-free survival or something but a significant detriment to people's functioning. Now, we hope it's the other way around. We hope we're curing more people, and we're hoping that we're doing it in such a way that their functioning only improves over time, but we thought it was really important to get a good understanding of how our treatments are affecting people not only now, but 6 months from now, and 1 year from now. Because if the goal is to cure them, we don't want to cure them and leave them with side effects to the point where they're more dependent on the people around them.

References

1. Merli F, Luminari S, Tucci A, et al. Simplified geriatric assessment in older patients with diffuse large B-cell lymphoma: the prospective Elderly Project of the Fondazione Italiana Linfomi. J Clin Oncol. 2021;39(11):1214-1222. doi:10.1200/JCO.20.02465

2. Brem EA, Li H, Beaven AW, et al. SWOG 1918: A phase II/III randomized study of R-miniCHOP with or without oral azacitidine (CC-486) in participants age 75 years or older with newly diagnosed aggressive non-Hodgkin lymphomas - Aiming to improve therapy, outcomes, and validate a prospective frailty tool. J Geriatr Oncol. 2022;13(2):258-264. doi:10.1016/j.jgo.2021.10.003