Roundtable Discussion: Burke Leads Review of Later-Line Therapies in DLBCL

John M. Burke, MD

Hematologic Oncologist

Rocky Mountain Cancer Centers

Aurora, CO

SOO: I would [say] performance status.

BURKE: How is that going to help you pick, and what are you going to pick for third line?

SOO: If [the patient has a] good performance status, I will pick chimeric antigen receptor [CAR] T-cell therapy first. You anticipate the cytokine storms. Our group is experienced with high-dose IL-2 [in the context of] renal cell carcinoma, so we feel pretty comfortable with managing the immunotherapy-related cytokine storm. If you look at the [renal cell] populations, all very young and healthy, they have excellent performance status.

So if you have a long remission to relapse, between the second and the third line, and the patient still has a good performance status, that tells me that most likely they’re going to be able to tolerate the immunotherapy cytokine storms and their bone marrow is likely to be in reasonably good shape. Because if you think about CAR T-cell therapy, theoretically [it depends on intact T cells], and I think that if you beat up the patients too much with cytotoxic agents, they may not have much T-cell [activity] left, and maybe CAR T-cell therapy would not be as effective.

Let’s say you have a patient with a very short remission and relapse is very fast, especially if the [patient has received] carboplatin. Those [patients] don’t do well. In that case, most likely I [would] pick an antibody conjugate therapy.

BURKE: Well said. To summarize, with good performance status, long duration of remission, you’re going [with] CAR T-cell therapy; with less favorable performance status, shorter duration of remission, [you would consider] some of the newer therapies, maybe the antibody-type therapies.

CHALLAGALLA: I would not differ but [would offer an] alternative point of view, because patients who are not transplant candidates can still get CAR T-cell therapy. That’s what I understand as a community oncologist. If [a patient has a] great performance status, and they’re a transplant candidate, I would go for transplant. And if they’re not a transplant candidate for whatever reason, they still have an option for CAR T-cell therapy.

[In the context of] salvage, post transplant, or even if they are not a transplant candidate, CAR T-cell therapy is still a viable option. That’s what I understand today. If the [patient is] not a candidate for transplant or CAR T-cell therapy, we always have antibody-drug conjugates and other options.

SOLANKI: I would agree with Dr Challagalla. Experts like yourself say, “Consult your CAR T-cell transplant team.” Just because your patient is not transplant eligible doesn’t automatically mean they’re ineligible for CAR T-cell therapy. As a community physician, you may not assess the situation as accurately as one probably should, and it is encouraged that this patient be seen by [the CAR T-cell transplant team].

The patient may be transplant ineligible, but they may be fairly suitable for CAR T-cell therapy, so I agree with that part. That’s why early consultation with the CAR T-cell therapy provider and the transplant team is encouraged when we are looking for the best option for the patient.

BURKE: I think that’s excellent advice. I just did it myself the other day. I had a patient with relapsed disease, who was pretty sick, in the hospital, and I called my CAR T-cell providers and I ran the case by them. I think you’re right.

STONE: I can start by saying that, fortunately, we’re close to our partners who have access to CAR T-cell therapy. I usually get our transplanters involved at first relapse to start making plans in case the patient doesn’t tolerate second-line therapy and to help make decisions about possible transplant or CAR T-cell therapy. So we’re fortunate to get them involved very early [in the process].

BURKE: What do you see as challenges for you [and others] in community practice?

STONE: Again, we’re fortunate to be pretty close to a center, so distance isn’t a big challenge. When patients are…candidates for CAR T-cell therapy or for a transplant, typically [the treatment is] approved by insurance, at least from what I’ve observed. Fortunately, at least where we are, the challenges aren’t very significant. If the transplanters feel that the patient needs either of those therapies, it usually can be done.

NGUYEN: [I am located in] Las Vegas, Nevada. We’ve had a difficult time. Our closest centers would be in Los Angeles or Southern California. The last 2 patients I sent to the University of California, Los Angeles [UCLA], did quite well. I think they were put on a protocol. At UCLA, they were doing an autologous stem cell vs CAR T-cell therapy protocol. One patient was young, the other one was a geriatric patient.

Both of them had the financial means [to access the therapy]. We have a lot of patients for whom travel is not [financially feasible], but I always tell them to call their insurance, and they usually have a stipend for travel. I think that trial at UCLA covered a little bit of the hotel cost. These are real-life things that patients have to deal with.

In general, we don’t have a large population of patients with huge financial means, so it’s a big deal. Fortunately, the last 2 patients I’ve seen didn’t have a lot of trouble getting in. But we are far from a CAR T-cell transplant center, so it’s quite challenging.

SOLANKI: This is one of several situations we are seeing in oncology, where some specialized monitoring or treatment is necessary. You will hear 2 different opinions: from those who are close to a center or who have patients who are willing to travel and have all kinds of support, and then from practices where distance is an issue—for example, in a small-town community practice where long distances are involved.

[For example, when] belantamab mafodotin-blmf [Blenrep] is used for myeloma, ophthalmologic evaluation is recommended every month.¹ Well, for a big center, it’s easy. It is not that easy in clinical practice….If you’re in a metropolitan city where there are a couple of centers, where patients can travel quite easily, it is not a problem. There was a study published in JAMA where they outlined very clearly what the real-world issues are with CAR T-cell therapy.² It’s not so much that [patients] don’t want it, they just can’t get to it. The availability’s low, and then there are serious logistical issues for working [patients] and working families.

BURKE: Yes, absolutely true. From Las Vegas to Southern California is a long drive or even a plane flight for many [patients, and a trip involves] arranging hotel stays and moving family.

How about the question of who’s involved in the decision-making? How does it work in your practices? If you have a patient who relapses, do you start that discussion about CAR T-cell therapy vs [an alternative] approach in the third line? Do you sometimes make the decision without referring to a CAR T-cell center?

For example, I have an elderly patient, and when I told her about CAR T cells, she said, “Well, I don’t want to do that. What else have you got for me?” Then I discussed some of the novel agents. Is that how it works in your practices, or are you commonly using the transplanters and CAR T-cell team to help make that decision?

NGUYEN: It’s been a lot easier with telemedicine; we’ve been able to get consults. Again, it’s typically very challenging for our patients in Las Vegas, but they have a good rapport with our transplanters and they can do teleconference visits. But in the end, it [can] come down to a patient who says, “I’m not going to travel.”

I still like to have tertiary care center involvement just because they can make recommendations for the third line [and so on]. Because sometimes I don’t know what to use; I’m guessing. I don’t have a ton of experience choosing a third-line therapy for these patients, so it’s nice to have the second opinion from a tertiary person. I use City of Hope and UCLA. It depends on our payers; our payers sometimes divert patients to where they want the patients to go.

But a lot of times I’ll start [the conversation] with, “Do you feel like traveling?” [If the patient] says no, that [determines] the direction we’re going toward.

BURKE: When you refer a patient for CAR T-cell therapy, does the process start with a telemedicine visit with a doctor in Southern California?

NGUYEN: I always tell the patient that they have to show some commitment. I try to encourage them to go [in person for the initial visit]. Sometimes it’s easier, especially during the COVID-19 pandemic, to use telemedicine. But in general, I try to get them to actually show up, because I think the centers commit to more [if the patient comes in person], and they sometimes want to put the patient on protocol. Some patients have [done telemedicine] just to get their feet wet and then they get the second visit in person. But a lot of the [patients] who are motivated usually drive right away or fly right away. They don’t want to mess around and do a televisit.

BURKE: Are there any cross-state barriers with telemedicine? For example, I had a patient who wanted to go to New York, but they can’t do formal consultations by telemedicine in Colorado. There are some legal [considerations]. Have you come across any of that?

NGUYEN: I’ve seen that. I’ve seen some out-of-state physicians who don’t want to follow the patient, but then I’ve seen others do it. It’s confusing. I think UCLA and University of California, Irvine, do it. I do a lot of the West Coast stuff, because we’re in Las Vegas, but I don’t know the rule on that.

BURKE: I heard New York can do telemedicine visits with some states but not others. I don’t know.

BURKE: Let’s hear the opinions of those who prefer polatuzumab vedotin-piiq [Polivy] plus bendamustine and rituximab [BR], and likewise the opinions of those who prefer tafasitamab [Monjuvi] plus lenalidomide [Revlimid].

MAZHARUDDIN: I chose polatuzumab plus BR, because I recall hearing a lot of good things about polatuzumab [regarding] tolerability and other things—good data [from the trial (NCT02257567)].³ Plus, it’s higher ranked in the National Comprehensive Care Network recommendations.⁴

WANG: I have to completely agree just based on the ranking. I have not [used] polatuzumab or tafasitamab myself. The polatuzumab plus BR would probably be my next choice.

CHAE: I picked polatuzumab as well. [I’ve had] good personal experience with it. It can be given as an outpatient [therapy], and my patient who received polatuzumab did [achieve a complete response] with it. So that’s why I picked it.

ARJUNAN: I picked tafasitamab plus lenalidomide. I like that regimen because of the [data from the] L-MIND study [NCT02399085].^5-8

I think a lot of the toxicities are mostly from the lenalidomide,⁹ so I find that easy to work with. We’re very familiar with that drug from [its use for] myeloma, so we are able to dose reduce as needed. That’s why I picked that one.

BURKE: It sounds [as though] you like the tolerability aspect of that regimen.

SOO: I also picked tafasitamab plus lenalidomide because of its tolerability, [its] toxicity profile.^5-9 There’s a lot of room for us to manage the adverse events, and it’s easy to give. I think it’s a great regimen.

WANG: I have not used any of those agents, but I’d probably still consider sending my patients for CAR T-cell therapy or transplant if they relapse 1 time after treatment with gemcitabine, oxaliplatin, and rituximab [GemOx-R]. To continue our previous discussion, I have the luxury of very easy access to my transplant colleagues, so I can discuss [the situation with them] and then refer the patient for CAR T-cell therapy or stem cell transplant; whatever they think is appropriate.

But prior to CAR T-cell therapy, now we have polatuzumab with BR, or tafasitamab with lenalidomide, as the second line. I think I would consider using either of those 2 [regimens] if there are no other contraindications. I don’t know if there are any data [to support] giving those regimens prior to CAR T-cell therapy. The thing with CAR T-cell therapy is that sometimes a patient might have to wait several months to get insurance approvals and get everything arranged for the therapy. I think maybe [either of these regimens] would be a good bridging second-line therapy before the [patient] goes into either CAR T-cell therapy or stem cell [transplant]. Then loncastuximab looks [to be indicated] for third line.^10,11 We could consider [it] after the CAR T-cell therapy or before, but I don’t have any opinion on that.

BURKE: Yes, I think you’re right, and I think a lot of [clinicians] are using polatuzumab as a bridge.

There’s a little bit of concern about the effect of bendamustine on [the collection of] T cells, because bendamustine is toxic to T cells. There are data for polatuzumab plus rituximab [and for] polatuzumab plus obinutuzumab [Gazyva], [both] without bendamustine, from a trial called ROMULUS [NCT01691898].¹² The polatuzumab plus rituximab regimen is pretty effective, even without bendamustine. So it is an option [as] a bridging therapy prior to CAR T-cell therapy in this era.

I think the data on tafasitamab plus lenalidomide as a bridging therapy are less, and again there may be a little bit of theoretical concern about targeting CD19. I just talked to my transplanter about this case the other day, and he is using tafasitamab plus lenalidomide sometimes as a bridge to transplant. He didn’t have any major concerns. But I think that might be institution dependent.

SOLANKI: I like the L-MIND data. The only drawback of the study is that it had only 81 patients.^5-9

BURKE: Well, that’s true of all of these.

SOLANKI: Yes. I like the outcome. There was a [point that was made] that this study didn’t include primary refractory patients. That is because the definition changed over time.

The concern about CD19 depletion is somewhat puzzling to me, because with the duration of response and control of disease [that is achieved] with this particular regimen, I would not think of sending a patient for CAR T-cell therapy unless they’re relapsed. In which case, I would assume that the CD19 treatment may not be as relevant. I’d like to hear your opinion on that. But I just like that particular regimen.

The [regimen] that includes bendamustine is fairly toxic because of the bendamustine,¹³ and then there is the issue of neuropathy in patients who have already been exposed to vincristine.¹⁴ In the L-MIND trial, one of the pet peeves I have had is the dose of lenalidomide [25 mg daily].^5-8 That [dose] has been always used, and there is a high rate of dose reduction in most studies—not in all, but in most studies. One of the myeloma experts on the West Coast said he rarely started elderly patients on 25 mg; he usually used between 15 mg and 20 mg, and it was equally effective in his experience.

I’ve always wondered about this dose of lenalidomide. Just because it says in the book that’s what we should use,⁹ we keep on using it without ever looking and asking, “What is the delivered dose?” We did that with bortezomib [Velcade] in myeloma; we didn’t need what we were using, we [could use] half as much and give it not as frequently, in only half the time. I would like [to hear] your comment on the CD19 concern, because one would probably be thinking of CAR T-cell therapy at a time of relapse. When the [patient] is relapsed, do they not have CD19-positive status, or what’s the concern?

BURKE: We know that is a mechanism of resistance to CAR T-cell therapy. That is, sometimes when CAR T-cell therapy stops working, it’s because patients have lost CD19 on the cells. I don’t know that we [have evidence of] that as a resistance mechanism with tafasitamab plus lenalidomide, but in theory it might be one, of course.

I [do appreciate] your point that if you put patients on tafasitamab plus lenalidomide and they respond, especially with a [complete response], these patients are going for years and not having a problem. And so does it make any sense [for such patients] to go straight to CAR T-cell therapy? I think you may be right, and they may do very well without ever needing the CAR T-cell therapy.

The other comment you made was about lenalidomide dosing. The majority of patients [approximately 75%] were able to take at least 20 mg of lenalidomide.^5-8 Now some of the patients may have progressed and then come off lenalidomide. But believe it or not, it was relatively tolerable. Is that true in the real world? I don’t know. I think a lot of [clinicians] I’ve talked to might be a little nervous about starting their 80-year-old patient on 25 mg of lenalidomide for 3 weeks.

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