Roundtable Discussion: Wagner-Johnson Highlights New and Emerging Approaches for DLBCL

WAGNER-JOHNSON: I would be interested to hear what is driving your decisions [in a patient case like this]. Other than the general gestalt of the patient, are there certain things that push you one way or another?

PROOTHI: Well, the eligibility for allogenic transplant is one [factor]; eligibility for CAR [chimeric antigen receptor] T-cell therapy is another. Then [I consider] the safety and tolerability of the regimen, comorbidities, patient preference, logistics—I think every item matters.

WAGNER-JOHNSON: Yes, it is sort of a combination of things. If you have a patient for whom you would consider CAR T-cell therapy, what things do you try to avoid as your second-line regimen?

EFIOM-EKAHA: One of the things [to consider] in terms of second-line therapy is the timing of the relapse, right? I think in [cases of] relapse within 12 months, the outcomes are better with CAR T-cell therapy, and maybe allogeneic transplant would be reasonable for someone who has relapse 5 years out from the initial therapy.

As far as the salvage therapy, if I am thinking about doing CAR T-cell therapy, I want to avoid therapies that [cause] lymphodepletion, as things like bendamustine [Bendeka] probably would not be part of that salvage regimen.

WAGNER-JOHNSON: Do others try to avoid bendamustine in the second-line setting for this reason?

NATHAN: Yes, I would avoid bendamustine for this reason.

EFIOM-EKAHA: Another thought would be [to consider, for example, that] you just, logistically, could not get a patient to CAR T-cell therapy early, [even though] that [might have been] your intention.

Should I also avoid CD19-directed therapies in that setting? Though I know for a fact that CAR T-cell therapy would still work [in the future] if I used loncastuximab [Zynlonta] or tafasitamab [Monjuvi] and [the patient] had a nice response. I do not know the answer to that.

WAGNER-JOHNSON: [The answer to that question] may reflect [whether the respondent is] from an academic center where they are going to keep [rather than refer] their patients, [and it may also reflect] patient preference and [the overall] patient population. I have heard from people in the community that some of their patients do not have any desire to come and see us [if they are referred here].

FAROUN: This patient had disease that was refractory to rituximab, and he relapsed 5 months after secondline therapy with rituximab-based therapy. In my opinion, [rituximab]-based therapy is not an option here. That leaves us with [loncastuximab], or [tafasitamab plus lenalidomide]. I think, because this patient has germinal cell subtype, lenalidomide probably is active in this setting, so I would choose tafasitamab plus lenalidomide, with dose adjustment.

WAGNER-JOHNSON: Some of you definitely have some experience with these regimens. [There is not as much experience with] loncastuximab, if I remember correctly; that was the newer one to be approved.^1-3

RIZVI: Polatuzumab, in my experience, has been very well tolerated. Generally, for people who are not eligible for transplant or [for] any other treatment option, I have found polatuzumab to be pretty effective and pretty well tolerated.

WAGNER-JOHNSON: When you are giving it, do you typically give it with the BR [bendamustine/rituximab] or without?

RIZVI: These are patients who are very frail, so I end up giving [polatuzumab] by itself.

WAGNER-JOHNSON: Got it—I have not given [polatuzumab] singly yet. I often have given it as a bridge for my patients [when they] have had their CAR T cells collected and we are waiting for manufacturing, and I will frequently give, at that point, bendamustine.

At that point, the patients have already had their cells collected, so I am not as concerned, and [these patients] are typically more fit because they are heading to CAR T-cell therapy, and if I need to give bridging, they have [aggressive] disease. But I have not given [polatuzumab] singly yet.

I am pretty sure Dr Gladstone has some experience in that regard. Do you frequently give it [as part of a combination] or not? What is your experience?

GLADSTONE: I always [anguish] about it. Also, when I do use it, [my choice] depends on the disease burden. [That is, it depends on whether] I think I am going to get the patient to collection easily, or [I think] it is going to be very hard because [their disease is] so bulky. I know that does not answer the question, but that [is what] goes into my thinking, even though it is a non sequitur.

WAGNER-JOHNSON: [I see.] Dr Rizvi, you have had good experience [with polatuzumab] as a single agent, per the National Comprehensive Care Network [NCCN] guidelines, [which] clearly indicate [that option].⁴ Who else has had some experience with this regimen and wants to give their thoughts on choosing to give [polatuzumab] with or without the BR?

PROOTHI: I have used it with the rituximab [only], without the bendamustine. Obviously, if [the patient] had a neurotoxicity a year before, then I would not pick the polatuzumab. If [the patient] has a high-risk [status after] transplant, I would rather go with the loncastuximab; otherwise, I would not have any preference.

The other question I have is, for the tafasitamab plus lenalidomide combination, if the [lenalidomide] dose matters, at 25 mg,⁵and if [the patient] gets grade 4 neutropenia, should I use the growth factor and [maintain] the dose or should I lower the dose?

WAGNER-JOHNSON: I have given growth factors successfully and have been able to maintain [the dose]. I think it frequently happens that [the patient’s neutrophil count] is so, so low that you must [stop treatment] for a bit or lower [the dose]. I usually do not have the luxury of catching [the neutropenia] early, [such that] I can give the growth factor and avoid problems. Often, I do both simultaneously, [and when] I give the growth factor, the counts recover, and then I consider escalating.

I think part of the problem is the logistics of [finding the appropriate] dose for the patient because [every adjustment] requires a new prescription. But I do often try to push [the dose] back up. I have not had as much luck when giving that with just rituximab, and I need to gain some more experience with [tafasitamab].

FAROUN: I am hopeful that, soon, polatuzumab is going to move to frontline therapy for [patients with] DLBCL. I think it is not going to be used in the second line or beyond. So we [will be] left with 2 regimens: loncastuximab [and the combination of] tafasitamab and lenalidomide.

I think if the patient is refractory to rituximab or has germinal centers, we will use tafasitamab plus lenalidomide. I do not have any experience with loncastuximab yet but [I am hopeful that] we can use it in the future, but again, if polatuzumab is moving up [to the first line], I think that will leave us with 2 options only.

WAGNER-JOHNSON: That is a good point. Could we hear from a few more people about their thoughts in terms of which [option] seems the most appealing, or [in terms of] the perfect fit for a particular drug?

PROOTHI: [Regarding] polatuzumab, some centers are taking vincristine out of R-CHOP [and replacing it with] polatuzumab instead.⁶

EFIOM-EKAHA: My concern is that in the community, a lot of times, we want to salvage these patients with CAR T-cell therapy, but logistically, sometimes [it is] a little tricky to get them to CAR T-cell therapy, and so we have inertia. We say that we do not want to use a CD19-targeted drug [because] we do not want to burn the bridge, but while you are trying all kinds of bridging therapies, the disease could be progressing. I [think that] tafasitamab plus lenalidomide, with a 40% complete response [CR] rate and almost a 60% overall response rate,⁷ is a great regimen [From the Data7].

So I say to myself, why don’t I just use my most active therapy and worry about the logistics of CAR T-cell therapy later rather than be afraid of using a CD19-targeted therapy [just] because I think [the patient] may get to CAR T-cell therapy [eventually]?

GLADSTONE: I believe it is a true statement that the tafasitamab molecule binds to a different section of CD19. But the concern that tafasitamab is going to outcompete [rituximab is] probably not going to be borne out in the future.

WAGNER-JOHNSON: Yes, and we [have not talked] about bispecific T-cell engager [BiTE] therapies; none of those are currently approved but they look incredibly promising.

It is going to be interesting to see [how things develop with respect to] naked antibodies, antibody-drug conjugates [ADCs], BiTEs, and CAR T-cell therapies. There is going to be a breadth of available treatments.

And from a practical standpoint, if our ADCs compare relatively well with a BiTE, my guess is that most in the community will be more comfortable choosing the ADC. Similarly, [we will see] whether the BiTEs, especially in combination with other agents, hold up in competition with CAR T-cell therapies. Of course, we do not have mature data to make these statements, but I think it is interesting to look at [the] CR rates [because] they are impressive. I think a lot is going to be learned about these novel agents, and where they fit in, with further follow-up in the next few years.

GLADSTONE: The thing that is impressive, I think, is that tafasitamab by itself does not get a [grade of] A-plus. Tafasitamab plus lenalidomide is much better than tafasitamab alone, and for patients who are chemotherapy resistant, [it is important to note that] bendamustine is chemotherapy, and loncastuximab is [not]. What is nice about the combination of tafasitamab and lenalidomide [is that] it is purely immunologic. So if you think a patient’s cancer cells do not have the ability to respond to a chemotherapy signal, tafasitamab plus lenalidomide does not use chemotherapy.

WAGNER-JOHNSON: True.

GAFFAR: I did use loncastuximab recently for a patient with horrible renal sufficiency and relapsed DLBCL. I did use tafasitamab plus lenalidomide, and then recently I put him on loncastuximab, and he has had a good response so far. As an aside, he did have a repeat biopsy; he has gingival involvement, so they [easily biopsied] it and found that it was still CD19 positive.

WAGNER-JOHNSON: Good. [Were there] any problems with the unique toxicities that we are seeing, edema or elevation of liver enzymes?

GAFFAR: Not really. Maybe a little bit of edema but nothing else.