Kami, there are now 2 FDA-approved products for relapsed large B-cell lymphoma, and there’s another 1 that’s going through the process, hopefully to get approved. The trials are different, in regard to how patients went on them, but there are some very real differences in the constructs of these therapies. Do you think they’re different? Do you use different therapies for different patients? Will you use one CAR T-cell therapy for 1 patient vs another? Can you discuss some of the differences and similarities among these?

Yes. The general structure is similar. They differ in their combinations of the transmembrane and costimulatory domain. All 3 are a bit different in that regard. When you look at the trial populations, they all included relapsed/refractory diffuse large B-cell transformed lymphoma, high-grade lymphoma. Axi-cel [axicabtagene ciloleucel] also included primary mediastinal patients, as I believe Amit Mehta mentioned. Liso-cel [lisocabtagene maraleucel] included primary mediastinal patients and grade 3B follicular lymphoma patients.

The axi-cel trial did not allow bridging therapy, whereas the tisa-cel [tisagenlecleucel] and liso-cel [lisocabtagene maraleucel] trials did allow bridging therapy. So there’s a little bit of a difference there.

Of the 2 approved products, axi-cel [axicabtagene ciloleucel] is typically given as an inpatient therapy, whereas tisa-cel [tisagenlecleucel] can be given as an outpatient therapy.

In regard to the liso-cel [lisocabtagene maraleucel] product, when you look at the general patient population they didn’t seem to treat as robust of a patient population. Almost 40% or a little higher of the population was over age 65, whereas with the other 2, about a quarter of patients were over age 65. So it’s an older population. The cutoffs for both, as Loretta mentioned, from renal function and cardiac function were lower than in the other trials. There were differences in the patient populations, as you mentioned.

Only axi-cel [axicabtagene ciloleucel] and tisa-cel [tisagenlecleucel] are approved. At our institution, it seems that we tend to use it in the older population.

Are you standardly using just 1, or do you use both?

OK. We’re going to get Loretta’s take on the real-world data in a second, but do you think the CD28 construct has a different adverse-event profile compared with a 4-1BB product, or are those just the differences we’re seeing in the trial—different time, different patient population—and maybe that explains it? What is your experience treating people with a commercial product off-trial?

It varies. Based on the patient population and the patient you’re treating, there’s probably a difference. There’s some difference in the product but also the patient’s disease status and underlying comorbidities, at least from what we’ve seen.

The major question that comes up a lot, at least in the marketing wars between trying to differentiate 1 from another: Does persistence matter? What’s your take on this? Some of them have a different area under the curve, for lack of a better term. Do you think that is a difference, or are the results the results, and it doesn’t really matter how you got them?

I think there is some benefit to the persistence.

Videos

CAR-T Treatment Options for R/R DLBCL

We should probably spend a couple of seconds talking about treating people in the second-line setting. We have these criteria, Loretta, for frontline therapy: big, bulky lymph nodes; organ compromise; cytopenias; things like that. Do these same criteria vie in the second line? Do you wait that long? Are you treating people earlier? What are your thoughts?

I tend to agree with you. There’s a more systematic approach to patients who are untreated. Most clinicians follow the GELF [Groupe d’Etude des Lymphomes Folliculaires] criteria for tumor burden when deciding when to subject someone to chemoimmunotherapy. In the relapsed setting, it’s much more heterogeneous. That makes it incredibly challenging when we start looking at the outcomes across studies, because there are not consistent criteria applied despite who is in need of therapy. Oftentimes, you’re restricted by the eligibility criteria of a lymph node of 2 cm or larger. In my general practice, I do tend to follow the GELF criteria when deciding who should be exposed to potential toxicity with treatment and who is in need of therapy. But I don’t think that is consistently followed.

 Yeah, there is a lot of heterogeneity. There is even inconsistency within institutions. Maybe I’m inconsistent in my own practice.

Krish, there are a number of things that are important to think about when choosing therapy for patients in the relapsed setting: Rate of progression, whether the patient has transformed, young, old, fit, unfit. Can you walk us through some of that? What are some of your thoughts? We may get some other people to weigh in here as well.

Sure. As you all pointed out, there are a number of factors that help inform our choice of second-line therapy. In particular, if we think about the length of time somebody has had a remission after frontline therapy, as Caron pointed out, we’re expecting most patients to have very long remissions. Those who have much shorter remissions—recurrence within 24 months of initial chemoimmunotherapy—have particularly poor outcomes. Those are patients who we may want to adapt our therapies to and are often the types of patients we think about clinical trials for. We really don’t have a consensus on what is the best approach for those patients.

For some of those patients, other factors like age and fitness become important. For example, is this a patient who could tolerate an intensive approach, including an autologous stem cell transplant? Has this patient previously had an anthracycline-based therapy, appreciating that some of our early progressors may harbor occult transformed disease, especially if they weren’t staged by PET [positron emission tomography] scans? It is really important to get in the weeds, if you will, about the details of this patient’s follicular lymphoma. How did they respond to therapy? What kinds of therapy did they have? We have a number of different pathways that we might follow.

Factors that hematologist-oncologists need to consider when selecting second-line therapy for relapsed follicular lymphoma.

R/R Follicular Lymphoma: Second-line Treatment Selection

® titled “Clinical Updates on Relapsed/Refractory Follicular Lymphoma: Where We Are Now and What Is Coming Next.”

I am Dr Ian Flinn, from the Sarah Cannon research institute in Nashville, Tennessee. Joining me today in this discussion are my colleagues Dr Caron Jacobson, from the Dana-Farber Cancer Institute in Boston, Massachusetts; Dr Andrew Evens, from the Rutgers Cancer Institute of New Jersey; Dr Loretta Nastoupil, from the University of Texas MD Anderson Cancer Center in Houston; and Dr Krish Patel, from the Swedish Cancer Institute in Seattle, Washington.

Today we are going to highlight a number of topics pertaining to systemic treatment for relapsed and refractory follicular lymphoma. We will consider the impact of recent clinical trial data on clinical decision-making, including from the 2020 ASH [American Society of Hematology] Annual Meeting. Let’s get started with our first topic.

Caron, let’s start with a general discussion on prognosis for patients with follicular lymphoma in general. Maybe you can indicate the prognosis for patients who relapse after frontline therapy and highlight the time course to relapse for patients.

Thanks, Ian. This is obviously a really important question when we’re thinking about the treatment landscape for follicular lymphoma. It’s important to remember that most patients with follicular lymphoma have an excellent prognosis. About 75% to 80% of newly diagnosed patients with follicular lymphoma will do great with initial observation, or frontline chemoimmunotherapy, or more recently, a CD20 blockade with lenalidomide therapy. Many patients have very long natural histories—on average, 20 to 30 years at a time.

We do expect that given enough time, patients with follicular lymphoma will relapse. But depending on age at diagnosis and when treatment is needed, that may or may not happen over the course of the history with this illness, and you may or may not need second-line therapy.

We do know that about a quarter of patients with follicular lymphoma—about 20% to 25% of patients by a number of prognostic indices, or markers, or factors—do less well and have a more aggressive course. A lot of what we’re going to talk about today has really important implications for those patients, because they’re not the ones who have these 20- to 30-year natural histories.

Andy, Caron was pointing out the natural of this disease. There are some people who do less well compared with others. Many, fortunately, do very well with this disease. But we do know that with each subsequent therapy, the prognosis may change. How do you look at that? Also, does that affect subsequent therapies and what you use to treat patients?

Ian, thank you. Those are 2 very important questions. I’ll take the first 1, in terms of prognosis changing over time with subsequent relapses. The quick answer is, yes, there are historical data saying that the first remission is usually the longest. With each subsequent treatment, those remissions are shorter and shorter.

There are some recent data to help guide us. Memorial Sloan Kettering Cancer Center published on this a few months ago. This was a data set of about 1000 patients. It was from 1998 to 2009, so it doesn’t include the contemporary era with some of the new therapies. What they showed was that the first remission was more than 8 years. But at that second remission, the median PFS [progression-free survival] was only a little over a year, or a year and a half. Then the third was a year, and the fourth was a little less. So it definitely decreases with time.

The hope is that we can change or improve that with the new and novel therapies that we’ll talk about later. In terms of the sequencing aspect, does it affect that trajectory? I’m not sure it does. Or at least there are not great data to support it. An exception to that may be for the patient who we think about a stem cell transplant for, whether autologous or allogeneic.

Insight regarding the prognosis for patients with follicular lymphoma who relapse and impact of treatment sequencing on this trajectory.

R/R Follicular Lymphoma: Patient Prognosis

Amit, I want to get back to you. Let’s switch gears and focus on CAR [chimeric antigen receptor] T cells. In which patients are you using CAR T cells on a routine basis?

That’s a great question. Both of the products that are approved and the 1 that is going to be approved soon are approved in second-line and beyond settings. Patients have to have failed 2 lines of treatment to be considered for CAR T. As we were discussing about frontline treatment of large B-cell lymphoma, those who are at high risk, high IPI [International Prognostic Index] patients, or double hit, double expressors are the patients who tend to relapse early. If I start a treatment in a patient with double-hit lymphoma, they are on my radar to consider for CAR T down the line. But currently, the FDA indication is a failure of 2 lines of treatment.

The only difference between the tisa-cel [tisagenlecleucel] and axi-cel [axicabtagene ciloleucel] is that axi-cel [axicabtagene ciloleucel] allows for primary mediastinal B-cell lymphoma because those patients were part of the study. That’s the only difference in the label. A high-risk patient that I’m starting treatment on is on my radar for the CAR T treatment down the line. 

Also, it is important to know how they are relapsing. We cannot put every lymphoma case in the same bucket. Some patients have a low burden of disease, some have a high burden of disease, some also have CNS [central nervous system] involvement, for some their LDH [lactate dehydrogenase] is high and the velocity of their progression is high. This is important because CAR T is a process, right? You have a collection, and then you have, depending on the product, 2 to 3 weeks before that product will be ready. We have to see, in that perspective, whether the patient can be held, so to speak, during that time. If they explode between the collection and the infusion, they cannot successfully get the CAR T. All those factors are important.

Also, like transplant, it is important that they have social support. For 8 weeks, maybe they cannot drive. All those are factored in when we consider using CAR T-cell therapy. It also depends on the patient’s insurance status, whether they have good social support, and how their financial systems are. Those all factor into decisions regarding use of CAR T.

 Loretta, Amit just nicely outlined a few of the issues, but there are some real issues in regard to delivering CAR T cells to patients, from financial barriers to logistical issues. You hear some people say, “If he couldn’t get a transplant, there’s no way he’s going to get CAR T cells.” Do you find that to be true? What are your thoughts on that?

It’s grossly underutilized because the logistics are challenging. It requires referral, and it requires commitment from the patient and family members. That being said, when you have a patient who you know would be dead and now they’re cured with this treatment—this is a onetime treatment, though I recognize it includes 6 weeks weeks leading up to it and another several months post infusion where you’re monitoring and adjusting things—it is really rewarding when we see it work.

Where I struggle is, can you actually optimize patients who you’re concerned about? I see the discussion often happening in referrals to me when hospice is offered vs CAR T. I don’t think it should be utilized in that setting where it’s a last-ditch effort. The logistics are so challenging, just as Amit mentioned, so you need a patient who has disease stability while you’re undergoing manufacturing, at least for these auto products. But I still think it should be considered, at least at some point in the disease course for any patient with relapsed/refractory large B-cell lymphoma. You cannot utilize the same criteria we apply to identify transplant candidates.

 So you don’t have a litmus test. You’re not requiring every patient to have an echocardiogram and have an EF [ejection fraction] of 50%, or pulmonary function tests, or something like that, is that correct?

You have to use your physician eyeball test that you already have heard about. You have to be able to predict that they’re going to tolerate the therapy if they have severe CRS [cytokine release syndrome] or severe neurotoxicity. You have to predict that they’re going to have the pulmonary, cardiac, renal, and hepatic reserve to get through that. But it’s not the same stringent criteria we utilize to identify who’s going to tolerate high-dose chemotherapy. You don’t have the whole notion of, “They have to have chemotherapy-sensitive disease—step 1. Step 2, make sure they don’t have comorbidities that would predict for bad outcomes.” That part is still very fuzzy to me because we looked at ejection fractions of less than 50%, and we looked at renal insufficiency and liver insufficiency. So far none of those has held up as being a really strong factor associated with either safety or efficacy.

CAR T-Cell Therapy for R/R DLBCL

 John, I want to go back to you and talk about some of the other therapies that have recently been approved for relapsed large B-cell lymphoma. First, let’s talk about polatuzumab. Polatuzumab was approved in combination with bendamustine-rituximab. What has your experience been here, and how are your using this regimen?

Just to summarize, polatuzumab is an anti-CD79b antibody-drug conjugate linked to MMAE [monomethyl auristatin E], the same drug that’s in brentuximab vedotin. Data supporting its use comes from a randomized phase 2 trial, a relatively small trial of 80 patients, where the addition of polatuzumab to bendamustine and rituximab improved many efficacy outcomes, including complete response rates, progression-free survival, and overall survival. To my knowledge, this is still, since the PARMA study decades ago, the only randomized trial in relapsed large B-cell lymphoma that demonstrates a survival advantage with 1 regimen over another. This was a pretty significant leap forward.

Even bendamustine-rituximab can lead to considerable toxicities in these patients. The polatuzumab–BR [bendamustine-rituximab] combination can cause neutropenia, and polatuzumab is also associated with peripheral neuropathy. 

I have found this to be a useful regimen for a similar patient population relapsing after an autotransplant. I even used it before CAR [chimeric antigen receptor] T-cell therapy was around. And I’ve used it as a second-line therapy in patients not eligible. 

Just to elaborate on that, the FDA approval for this combination is for treatment in the third-line setting or beyond. But the study included second-line patients. In fact, those patients, in a subset analysis, had better outcomes. I’ve used it as either second- or third-line therapy. I have not had any trouble getting it covered by insurance, even in the second-line setting. That’s where I’ve used it.

 Thanks. You talked about using this prior to the introduction of CAR T cells. It’s attractive as a bridging therapy for patients who require it, that were acquired CAR T cells. But I certainly worry about a T-cell–depleting agent like that and giving it prior to acquiring the leukapheresis product. It’s an important new therapy for patients. I’ve been very impressed with its efficacy.

Kami, what about the selinexor? This is an oral agent, and it’s attractive because of that. How are you using that in your practice?

I’ll be honest, I have not used this in my practice. Where I see a role for this is based on it being an oral therapy. In regard to toxicities, we see cytopenia, some GI [gastrointestinal] toxicity, fatigue. It does require some work, as far as the premedications you use. However, it seems tolerable with those premedications. To me this is something that if you have a patient who relapses after CAR T-cell therapy, isn’t eligible for a trial, wants to try something, or maybe if you have an older patient who is not eligible for transplant, is not eligible for CAR T, and wants to try something, it’s an oral therapy. As I said, it has toxicity, but that can be managed. That’s really where I see it being used. I have not personally used it.

 You’re not using it in the second-line setting mostly because the results weren’t as impressive as the results with BR [bendamustine-rituximab]–polatuzumab or other agents, I assume. Is that right?

Yeah. I would say that in the second-line setting, for somebody who’s not going to be eligible for a curative therapy, I’m using tafasitamab-lenalidomide; or prior to that, if I could get access to it, as John said, BR [bendamustine-rituximab]–polatuzumab.

I was just going to add 1 thing, Ian. The trial with selinexor required at least 2 prior lines of therapy. It hasn’t been well studied as a second-line therapy. As was pointed out, the responses are probably less impressive than what we’ve seen with some of the other drugs that we’re mentioning that have become available in the last couple of years for relapsed disease. Moving forward, selinexor may potentially be combinable with chemotherapy or other drugs. That may really be the future of this drug—to combine it with some of the other therapies that are out there to see if they can improve efficacy. There is personal hope for this drug, in regard to having more utility.

One more thing on that. There were a few case reports of CNS [central nervous system] penetration with selinexor. I’ve seen responses in CNS involvement. There are also studies ongoing. So that’s an extra niche for this drug.

 Great, we’ll look forward to the results of that trial that you mentioned.

Novel Therapies for R/R DLBCL

Amit, have you started using this regimen, tafasitamab, lenalidomide, in your practice? Maybe I’ll get a few opinions on this, actually. What patient population are you using the regimen in? What are your thoughts?

This is a very effective regimen, especially for those patients who are not eligible for transplant, as approved based on the L-MIND study. As I was mentioning, in the frontline setting for frail, older patients who are not candidates for aggressive therapy, and similarly in the relapsed setting, those patients are perfect for this combination.

And as Dr Kami Maddocks mentioned, the key with this combination is management of lenalidomide adverse effects. If you manage those, you will be able to successfully implement and get a successful outcome in your patients who are frail. I’ve been using this regimen. As I mentioned, the dose and management of lenalidomide’s adverse effects is key in these patients.

 John, I want to get your opinion on this. I’ve also heard Loretta speak eloquently on this in the past. In regard to sequencing, should we just be using this regimen in older and infirm patients? Some people worry about using a CD19 antibody in patients for whom you’re considering trying to get them to CAR [chimeric antigen receptor] T cells. There are a lot of theoretical reasons, probably less data. Maybe you could walk us through how you’re using this regimen in your practice. Is it similar to Amit, or are you doing things differently?

I’ve used it only once in an older patient who was frail. Her prior therapies included R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], or mini-CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], and then POLA-BR [polatuzumab vedotin, bendamustine, rituximab]. She had been through both of those regimens and then had another relapse. It came down to, “Well, she’s not an autologous transplant candidate.” We also decided she was probably not a CAR T candidate for various reasons. So we had excluded using curative therapies, as Loretta had alluded to before. You know, “Is this someone we’re going to really try to cure?” We felt she was too frail because of her comorbidities.

That’s an example of where I’ve used it. In this particular case, it didn’t go well. She was probably even too frail for tafasitamab and lenalidomide. She got pretty weak and was tired after just a couple of weeks, and wound up having various unrelated medical complications. But that’s an example of how I would attempt to use it. It’s approved for second-line therapy, but it’s not something you want to use in someone who’s going to go through an autotransplant. 

Is there value in using this regimen prior to CAR T? Is there harm in using this regimen prior to CAR T? Is the anti-CD19 antibody removing CD19? Do you lose CD19 expression, thereby rendering a subsequent CAR T product less effective?

We don’t have great data on that. There are some in vitro data out of the Mayo Clinic suggesting that probably does not happen. There are also a couple of case reports of patients who have been successfully treated with 1 CD19 product followed by another. The best we can tell is it doesn’t seem to be a problem, but I’m not a CAR T-cell doctor. I actually don’t know what they think about this. I suspect they have some theoretical concerns, as you alluded to.

Obviously we have a lot of enthusiasm surrounding the potential cure with CAR T, recognizing it’s a small portion. It’s probably about 40% of patients. There is concern that if you’re introducing a CD19-directed therapy based on what we’ve observed in ALL [acute lymphoblastic leukemia], maybe you’re going to select out for CD19-negative clones.

However, that is not supported by any evidence. It’s theoretical, and we’ve looked at outcomes among patients who received CD19-directed standard-of-care CAR T. It didn’t matter what their CD19 expression level was prior to receipt of that therapy, whether it was determined by IHC [immunohistochemistry] or flow and not even known. But that was also in patients for whom the vast majority had never seen a CD19-directed therapy.

What we really need is more real-world experience, where people have seen these agents and they have been sequenced in various ways. I suspect we’ll have tafasitamab prior to CD19-directed CAR T-cell therapy, and vice versa. 

As John mentioned, in the small amount of data that currently exist, it does not appear that introducing tafasitamab prior to CD19-directed CAR T-cell therapy is going to impact that legacy.

R/R DLBCL: Treating With Tafasitamab-Lenalidomide

All the regimens we’re talking about are relatively toxic, right? Giving some R-ICE [rituximab-ifosfamide, carboplatin, etoposide] is not for everybody. That probably speaks to the need for newer therapies that are less harsh on patients and more tolerable. Loretta, do you have any thoughts on that? There are some new regimens recently approved, but in general, trying to give people a less toxic therapy with fewer adverse events would certainly be important.

I 100% agree. Even before I head down that path of choosing my salvage chemotherapy, I have to make a determination regarding whether I think I’m going to cure the patient—that’s going to entail more intensive therapy—or pursue a palliative approach because the toxicities associated with our traditional regimens have been so great. There’s probably a large number of patients who are having fewer of these intensive approaches because we make the determination they’re not going to tolerate it. There was a huge unmet need in terms of having tolerable but effective second-line strategies. What fills that space is tafasitamab and lenalidomide, because the investigators defined the folks they did not feel were suitable for an intensive approach, such as consolidation with high-dose therapy.

More study needs to be done to help us now that we have more options. We need to learn who the optimal candidates are for these less-intensive approaches. But we have treatment options that we didn’t have a year ago.

Yes, let’s dive down on that a little, Kami. Last summer there was the approval of the tafasitamab-lenalidomide regimen for patients with previously treated diffuse large B-cell lymphoma. You’ve done a lot of work with this regimen. I was wondering if you could help us understand some of the clinical results and the rationale for the trial.

Yes. Tafasitamab is a CD-19 antibody. In a phase 2 study, there were some responses with the single agent in relapsed/refractory diffuse large B-cell lymphoma. The few patients who did respond and achieve a complete response [CR] actually had a fairly long duration of response. That was the rationale for then combining it with lenalidomide.

L-MIND was a phase 2 study that treated 80 patients who, as Loretta mentioned, were considered not eligible for aggressive therapy and autologous stem cell transplant. Patients were treated for a year with combination tafasitamab and lenalidomide. The first 3 months were pretty aggressive. They were treated with weekly infusions, then they were treated bimonthly. After a year, patients were able to go on to maintenance therapy with the antibody tafasitamab alone if they were responding. Overall, the therapy was well tolerated. It’s similar to what you see with lenalidomide in terms of cytopenias, fatigue, rash.

In the phase 2 study there was a 60% overall response rate, with 40% of those patients achieving a complete remission. And in those patients who achieved a CR, the responses were pretty durable. Then in the summer, with longer-term follow-up, we saw that the median duration of response was almost 3 years, which is pretty impressive in this population of patients.

Tafasitamab Combined With Lenalidomide in R/R DLBCL

Amit, let’s turn to you. Can you walk us through the recommended treatment options for second-line therapy? Kami just talked about a trial looking at CAR [chimeric antigen receptor T-cell therapy, but we have transplant in that setting. What is your standard of care?

I think the standard of care is still a consolidated bone marrow transplant for patients who are chemotherapy-sensitive. If you look at the recent data, even for patients who had a partial response, if you pursue the transplant, they still have a progression-free survival at 3 years of about 40%. In those patients, the first question I ask is whether they are a candidate for transplant. I always say that beauty lies in the eyes of the beholder. You cannot make a decision on your own. I always like to have a consultation with my transplant colleagues. If they don’t have any red flags that this patient is absolutely not eligible for transplant, the plan is to consider salvage chemotherapy: R-ICE [rituximab, ifosfamide, carboplatin, etoposide], R-DHAP [rituximab, dexamethasone, cytarabine, cisplatin], or gemcitabine–based treatment. None of them, except for R-ICE [rituximab, ifosfamide, carboplatin, etoposide] and R-DHAP [rituximab, dexamethasone, cytarabine, cisplatin], which were compared head-to-head, turn out to be similar in terms of response rates.

When investigators looked at the GCB [germinal center B-cell] and ABC [activated B-cell] subtype, there was a subgroup analysis where the GCB subtype had a bad response with R-DHAP [rituximab, dexamethasone, cytarabine, cisplatin]. So in some patients, if they can handle cytarabine, that is my favorite approach. Once they get salvage treatment, if they respond, if there is a response on the PET [positron emission tomography] scan, then I consider consolidated autologous stem cell transplantation.

I agree with everybody else. At the academic centers, these are the patients, especially primary-refractory patients, who are an area of need. They may qualify for multiple clinical trials. When ZUMA-7 was up and running, that was a trial for which we would consider these patients; it randomized patients between salvage transplant versus axi-cel [axicabtagene ciloleucel]. There are many others also looking at that approach. If the patient qualifies, we would probably consider enrolling him or her on the trial.

John, Amit just went through a variety of salvage regimens, but the question comes up, not infrequently: Should we be using a CD20 [antibody] at all? If we do, should we be switching to a different anti-CD20? Should we switch from rituximab to obinutuzumab? How are you approaching this? If you decided that you did want to do it, is it even feasible? Can you get that approved?

I haven’t personally made the switch to obinutuzumab or ofatumumab or anything like that. Based on the GOYA study, where obinutuzumab was not better and did add a little toxicity in the frontline setting, it’s not a strategy that I have tried. Back many years ago when I was training, the group I was with at Memorial Sloan Kettering Cancer Center looked at the value of adding rituximab to ICE [ifosfamide, carboplatin, etoposide], and it really didn’t add much benefit. But I think most people probably still do it, myself included. If I have a patient with CD20-positive large B-cell lymphoma who relapses, I’ll generally add rituximab to the salvage regimen, whether it’s ICE [ifosfamide, carboplatin, etoposide] or DHAP [dexamethasone, cytarabine, cisplatin].

That’s been my practice. I don’t know the answer to your question, Ian, about using obinutuzumab or some other anti-CD20 antibody, whether it would be authorized. I don’t know.

R/R DLBCL: Second-Line Treatment Options

Thankfully many patients don’t relapse, but there is a group of people who do. Some have some of these high prognostic risk factors, some do not. Can you talk a little about what you do after frontline therapy? How do you approach that patient?

Fortunately, a good portion of patients do very well. We’re particularly nervous about identifying those who will not do well. And so, prior to initiation of treatment, we’re always trying to risk stratify patients and see if there’s something other than CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] chemotherapy. We utilize PET [positron emission tomography] scans in the midst of therapy, with all of the caveats in terms of the positive predictive value and how important the interim PET is. But we’re always looking for any sign that a patient is going to fail.

A small portion of patients fail in the midst of CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone]-like therapy. It’s a larger portion who fail within the first 12 months of treatment. Another small percentage will have late relapses. My approach to those 3 different scenarios is different. We saw some data emerge at ASH [the American Society of Hematology 2020 annual meeting] utilizing an interim PET in these predefined high-risk patients—those who had double-hit features and high IPI [international prognostic index score] who had an interim PET after 2 cycles of CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] or CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone]-like therapy. If they failed to achieve a Deauville score of 1 to 3, they may be eligible for intervention with something like axi-cel [axicabtagene ciloleucel], or CAR [chimeric antigen receptor] T-cell therapy.

Again, there are caveats to that. These are patients who were treated at centers that had access to CAR T-cell therapy. These are patients who had a Deauville score of 4, and maybe they would have gone on to do well. Nevertheless, it identifies how we might utilize the tools at our disposal to find or identify those high-risk patients for whom we might start down a path separate from more intensification of chemotherapy. But again, I recognize that there is a portion of patients who do very well with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], and we’re stuck with surveillance imaging.

I think the other technology that might emerge and might be useful in this setting is cell-free DNA. This could potentially help identify patients who are going to fail outside of our traditional imaging approaches such as PET and CT scans. We saw some differentiating data at ASH 2020 with the adaptive approach not being an effective strategy, but maybe the CAPP-Seq [cancer personalized profiling by deep sequencing] cell-free DNA is a strategy that might be employed. I think it’s too soon to decide what the preferred method is, but I do think there is optimism surrounding that strategy to identify high-risk patients, maybe even before they fail on a PET scan.

I think the other thing that I don’t put as much emphasis on in the relapsed setting is cell of origin, or even double-hit cases. I have not adopted an approach for which I might approach them differently. I just know that if they fail early, they do poorly. If they fail late, they might do better.

 Kami, to follow up on what Loretta was saying, do you find that to be the same? Let’s take 2 equivalent patients, or 2 patients who relapse 9 months after completing R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone]. I think Loretta was saying it really doesn’t matter at that point whether they were a GCB [germinal center B-cell] or non-GCB patient. The approach is going to be relatively the same. Is that what you do at The Ohio State University Wexner Medical Center? What do you do for that patient?

I completely agree with that. The biggest indicator is going to be if they’re primary refractory or have an early relapse. We have been fortunate enough to currently have and had the prior trial looking at sending patients to CAR T. Patients are randomized to standard of care with salvage chemotherapy and autologous stem cell transplant versus early CAR T. I try to get patients on that study because I think this may be a population that benefits from that.

I think that is best for those patients. Outside of a study, we don’t have a different practice for our standard of care for these patients. Hopefully that will change.

DLBCL: Treating Patients Following Relapse on Frontline Therapy

One of the patient groups that I find most challenging to treat are patients who either have central nervous system [CNS] involvement at the time of diagnosis or those for whom you’re worried about it. They may have risk factors. Some people will use the CNS-IPI [central nervous system international prognostic index] to try to risk stratify patients. Can you tell us about your approach for patients who are either at high risk or already have it? Does that change how you treat patients? Is your work-up different? Perhaps walk us through some of your approaches.

At initial diagnosis to look at CNS risk, I look at double-hit status, double-expressor status, and then use the CNS-IPI, which is the IPI plus adrenal and renal. For patients who are high risk, CNS-IPI 4 to 6, and then double-hit and double expressor, I typically tend to offer CNS prophylaxis. This can be done with both intrathecal or intravenous [IV] methotrexate. If somebody is going to be able to tolerate it, my preference is to use the IV methotrexate. There’s some suggestion that that’s probably a better preventive, although we saw data at ASH [the American Society of Hematology 2020 annual meeting] that kind of questioned the benefit of all prophylaxis. But I usually will use that for 3 cycles. If somebody has CNS and systemic disease, we’ll sometimes use it with the R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone]. So, we will give it on days 1 and 2. We also sometimes will fold it in, giving it on day 15, especially if there are questions of tolerability. Or occasionally, we’ll use it at the end of treatment.

What kind of doses are you using, out of curiosity? Say you gave it on day 15, are you giving 4 g, 6 g?

Definitely a challenging patient population. Loretta, what about the double expressors? Are you doing anything different for that patient population?

I echo all of the comments that we’ve heard. One of the things that we’ve learned from some of these prospective studies that have failed miserably is if you have too many barriers to identify these poor-risk patients, it sways them toward standard of care treatments like R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone]. You don’t have the luxury of time to pursue a trial or something more novel. And so, for the double expressors we have some potential advantages, and you usually can determine that by IHC [immunohistochemistry], and you should have that information when you’re first seeing the patient.

I think we probably do a better job of enriching our prospective studies with the double expressors. As of this point, I’m still using R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] if I can’t get them on trial, and I have some disappointment or lower expectations in terms of outcomes. I have not pursued anything else. I know there are data suggesting that dose-adjusted EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab] might be beneficial. When we look at the randomized study, it’s not powered to address this particular cohort. It’s disappointing. We don’t really see a potential benefit there.

The other thing I’ll comment on is the Mayo Clinic group did define this time from diagnosis to initiation of treatment as being another prognostic factor. When we start thinking about how we might design those next iterations of studies, if we can shorten that time by either implementing tools that can identify these poor-risk patients that are more real-time and more readily available, or enroll them into more of a standard of care approach. And then at cycle 2, maybe distinguishing with our experimental intervention. I think we’re going to have to revisit how we do studies, or we’re going to continue to have these negative phase 3 trials.

DLBCL: Treatment Considerations for Challenging Populations

®, “The Evolving Treatment Landscape in Relapsed and Refractory Diffuse Large B-Cell Lymphoma.”

I’m Dr Ian Flinn, from the Sarah Cannon Research Institute in Nashville, Tennessee. Joining me today in this discussion are my colleagues: Dr John Burke, from the Rocky Mountain Cancer Centers in Aurora, Colorado; Dr Kami Maddocks, from The Ohio State University Wexner Medical Center in Columbus, Ohio; Dr Amitkumar Mehta, from the University of Alabama Birmingham Comprehensive Cancer Center [O’Neal Comprehensive Cancer Center at UAB]; and Dr Loretta Nastoupil, from The University of Texas MD Anderson Cancer Center in Houston, Texas.

Today we are going to discuss a number of topics pertaining to the use of novel agents in relapsed/refractory diffuse large B-cell lymphoma. We’ll discuss newly available agents, the latest research in the field, including from the ASH [American Society of Hematology] 2020 virtual meeting, and the impact of recent clinical trials on making decisions around treatment selection.

Let’s get started on our first topic. John, perhaps we’ll start with you. R-CHOP [rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone] is really the mainstay of our therapy for most patients, or for many patients with diffuse large B-cell lymphoma in the frontline setting. But under what circumstances would you use a different regimen, and why would that be?

I would say, Ian, there are probably a few circumstances I can think of when I might use regimens different from conventional R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone]. Examples would include to treat the so-called double-hit or triple-hit lymphomas. For those patients, my practice has generally been to use dose-adjusted EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin] with rituximab. Certainly, other regimens are reasonable as well in that high-risk subgroup. We know that those patients fare poorly with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone]. We do not have randomized trials demonstrating improvement in outcome with any other regimens. We have a number of retrospective studies that suggest that some of the more aggressive regimens may lead to better outcomes in those patients who don’t do well with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone]. One of those is the dose-adjusted EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin] regimen. Another is rituximab plus hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone]. The third is rituximab plus CODOX-M/ IVAC [cyclophosphamide, vincristine, doxorubicin, methotrexate/ifosfamide, etoposide, cytarabine.

I find that subgroup to be challenging to really know what to do with. In many areas in our field, we don’t accept results of retrospective analyses as being the gold standard. I don’t think there really is a gold standard. Simply because of relatively unfavorable outcomes with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] and the fact that the best we have are these retrospective data, I think one of the more aggressive regimens is reasonable to use. I tend to use dose-adjusted EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab] in my practice, which is a community practice. I can administer that treatment as an outpatient procedure without having to hospitalize patients. That’s a scenario for which I’ll use something different from R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone].

Another is in primary mediastinal large B-cell lymphoma. Most studies have suggested that while R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] is acceptable, the risk of local recurrence may be higher without radiation. Patients with primary mediastinal large B-cell lymphoma are frequently younger women. Radiation may result in some long-term toxicities, including coronary disease and higher risk of breast cancer. The dose-adjusted EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab] regimen has been shown to be a highly effective regimen without the use of radiation therapy. And again, in the nonrandomized trial very good results have been seen with that regimen. So I’ll choose the dose-adjusted EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab] regimen in that group.

HIV-associated lymphoma might be another scenario for which one may consider using dose-adjusted EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab], although R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] is still acceptable. I don’t treat a lot of HIV-associated large B-cell lymphoma—I just don’t see a lot of it—but I have used dose-adjusted EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab] in that group.

John, let me break in here and get a few other people on board here.

Amit, he mentioned several different groups. There are the double-hits, the primary mediastinals, HIV. What about other groups for you? Do you use any of the prognostic factors? We talked a little about FISH [fluorescence in situ hybridization] testing, looking at the double-hit cases, but are there other groups for which you might use something different?

All of the regimens use anthracycline, one of the important chemotherapies. There are 2 groups I can think of: One group is those patients who have a heart-related issue. For instance, if they have CHF [congestive heart failure]. In those patients, we cannot use anthracycline no matter what the risk factors are. In that case, we have to supplement anthracycline, classically we use doxorubicin, with something else.

There are many regimens that have been discussed. One of them is EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin] with a low dose of anthracycline we could use, or supplement gemcitabine in place of anthracycline. The other group that is an area of unmet need, so to speak, in my opinion, is the elderly population. These are patients who cannot handle full-dose CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] or EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin]. Consistently, if you look at the frontline study when they compared head-to-head R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] with rituximab dose-adjusted EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin], the outcomes were similar, but the toxicity was higher in the EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin] group. So if you have an elderly patient who cannot handle full-dose CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] or dose-adjusted EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin], using mini-CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] or a reduced-dose of CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] has been my practice.

Ian Flinn, MD, PhD, Sarah Cannon Research Institute

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