Roundtable Discussion: Hill Discusses Systemic Therapy for Relapsed/Refractory DLBCL

Brian T. Hill, MD, PhD

During a Targeted Oncology Case-Based Roundtable event, Brian T. Hill, MD, PhD, director, Lymphoid Malignancies Program, staff physician, Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, and associate professor, Cleveland Clinic Lerner College of Medicine, discussed the case of a 43-year-old woman with diffuse large B-cell lymphoma.

ISLAS-OHLMAYER: Considering [that the patient’s disease] has not responded to 2 lines of therapy, I think we would move on to chimeric antigen receptor [CAR] T-cell therapy.

HILL: You’d just go ahead and get insurance approval and get lined up for cell collection and so forth?

ISLAS-OHLMAYER: Correct. And if we did need bridging therapy, a gemcitabine–based regimen has been our go-to regimen.

MAHAJAN: We have a couple of antibody-drug conjugates, and we have other treatment options if this patient…[does not want] to go for CAR T-cell therapy.

HILL: Just so we’re all on the same page, what is the goal of treatment here? Do you think we can cure this patient?

CHOWDHARY: …With CAR T-cell therapy, there’s still a very good likelihood of a long disease-free survival. I’m not sure with this kind of aggressive disease what the cure rates are going to be; I think…modest at best.…[The goal would be] as long a disease-free survival as we can achieve.

NEMUNAITIS: If they go on to get CAR T-cell therapy in this situation, they’re no longer a transplant candidate, I assume?

HILL: For patients with large B-cell lymphoma that’s refractory to second-line treatment, we would say that they’re not a transplant candidate, but they are a CAR T-cell therapy candidate. CAR T-cell therapy will work even in chemotherapy-refractory cases, whereas autologous stem cell transplant really doesn’t carry the day if their disease is not chemotherapy sensitive. So after CAR T-cell therapy, if they get a complete remission, we’re done, and we don’t do an autologous transplant after that.

The problem with the NCCN [National Comprehensive Cancer Network] guidelines is that they say you can do a lot of different things, and they don’t really tell you what to do. In a nontransplant candidate, which we’re calling this patient because her disease is refractory to chemotherapy, according to NCCN guidelines the preferred regimens would be gemcitabine-oxaliplatin—so that would be like a third-line regimen, and there are data showing some activity—or polatuzumab vedotin [Polivy] with bendamustine and rituximab.¹

Other recommended regimens [include] cyclophosphamide, etoposide, vincristine [Oncovin], and prednisone; etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin; gemcitabine, dexamethasone, and carboplatin; gemcitabine; and rituximab—standard third-line chemotherapy regimens. And you do have another targeted agent, tafasitamab [Monjuvi], which is FDA approved in combination with lenalidomide [Revlimid] to treat adults with relapsed/refractory DLBCL who are not eligible for autologous stem cell transplant.1

In patients intended to receive CAR T-cell therapy, bendamustine should be used with caution, unless after leukapheresis prior to CAR T-cell therapy, because it could impact the success of the patient’s T-cell collection. Another thing to keep in mind is that in the case of tafasitamab or the newly approved loncastuximab [tesirine; Zynlonta], which target CD19, it is unclear if [bendamustine] would impact subsequent CAR T-cell therapy, which also targets CD19. Just to remind everyone, polatuzumab targets CD79B, whereas tafasitamab and loncastuximab both target CD19.

HILL: Can you can share with us what your other option would be?

NEMUNAITIS: My office is only 15 to 20 minutes from our tertiary care center, so I would talk her out of it and say she’s got to do CAR T-cell therapy.

BOND: I provide CAR T-cell therapy care. There are a lot of barriers, and travel is one that we hear a lot. I would question what the discussion was before starting R-ICE in the first place, because the thought is with starting that, you’re looking at doing autotransplant, and CAR T-cell therapy would involve a lot of similar challenges to autotransplant. There are probably more resources for patients for CAR T-cell therapy through some of the manufacturers that could help with the financial aspects of it. I would really try to explore what the barriers were, because a lot of times what we’ve found—at least with patients who’ve made it to our center—is that we can address a lot of those specific barriers, particularly in a patient this young.

HILL: So your point is that from the beginning—as soon as her disease relapsed—she really should have been destined for an autotransplant or CAR T-cell therapy, which are basically done at the same types of centers. Maybe the patient didn’t fully understand that, or the R-ICE was started with the assumption that she would do it. At any rate, she’s now not responding to R-ICE.

MAHAJAN: We have a lot of options; we are in a phase where we have more drugs than we have patients. We have 3 new options: polatuzumab vedotin, tafasitamab, and then there’s loncastuximab. There are pluses and minuses with all 3. Loncastuximab has the advantage that it is a single agent, so you don’t have to [combine it] with anything else. So, tolerability becomes a factor. Polatuzumab vedotin, you’re going to have to combine with bendamustine, which is a little difficult.

Now, tafasitamab has the best data. These are cross-trial comparisons, but in that L-MIND study [NCT02399085], 40% of patients had a complete response and I think progression-free survival was touching 20-plus months.² So I picked tafasitamab based on those data, but the problem is lenalidomide. I generally start with the lowest possible dose of lenalidomide and I think you have to consider the data and all the other factors, too.

HILL: With tafasitamab and lenalidomide, are you encouraged by the response rate and durability?

MAHAJAN: Durability, yes.

ISLAS-OHLMAYER: Well, I’d stick with my gemcitabine-based regimen and hope that she would change her mind soon.

SRIKANTIAH-SAHA: I’m not at a large center but more of a community center. A lot of patients say, “Currently, I’m not interested in going to a larger center.” But sometimes, seeing how well…they respond [or don’t respond] to treatment that we can do locally, such as the gemcitabine-oxaliplatin-rituximab, …I think with her being young [that] maybe she’s not interested now, but that could certainly change. We’re keeping that option open vs going with the polatuzumab vedotin–bendamustine option.

BOND: I think our use of polatuzumab has probably gone down somewhat, just with tafasitamab-lenalidomide taking a similar space. But we had a patient who was not able to receive CAR T-cell therapy because they were incarcerated, so I used polatuzumab vedotin–bendamustine-rituximab third line…and [they have] done well with it.

I have used polatuzumab at least in 1 patient after collection, to bridge to CAR T-cell therapy, and for that patient we were able to achieve disease control before they received CAR T-cell therapy.

ISLAS-OHLMAYER: Was that polatuzumab alone, or with bendamustine and rituximab?

BOND: In that case, it was polatuzumab alone. The patient’s disease had been refractory to chemotherapy and they had had a gemcitabine-based regimen third line while waiting for CAR T-cell therapy authorization, so I didn’t think the bendamustine was going to add much.

KARAMLOU: How necessary is the bendamustine and rituximab in the combination?

HILL: It doesn’t [appear as though] the bendamustine is doing that much on its own. There were some prior studies of polatuzumab as a single agent, which showed [an approximately] 30% to 40% overall response rate.3 In my experience, we used it as a single agent, often right before leukapheresis, because we didn’t want the bendamustine. We’ve certainly seen responses. There are some real-world data out there from multi-institution series—not clinical trial patients, but real-world series that have been reported—[and] a lot of the patients aren’t getting the bendamustine; they’re just getting the polatuzumab.

BILBEISI: Even though I have never used polatuzumab before, I think the data are pretty good. I do question the need for bendamustine in this situation, but I probably would do the regimen as is, just to make sure that I had the full response.

MAHAJAN: I have used it 2 times, but I think it’s not the efficacy, it’s the tolerability, that is a concern. The peripheral neuropathy and myelosuppression, those were high and were very challenging for this pretreated patient population. One of our patients had myelosuppression and 1 had a serious infusion reaction.

HILL: With bendamustine-rituximab alone, not surprisingly, you see high rates of anemia, neutropenia, and thrombocytopenia, with 12% febrile neutropenia.4 Then [there are] the standard gastrointestinal toxicities, fatigue, and so forth. With the addition of polatuzumab, you see more all-grade hematologic toxicities and more of the higher-grade [hematologic toxicities] as well. [Of the patients who received polatuzumab,] 43% had peripheral neuropathy but none had grade 3 or 4.4 Peripheral neuropathy from a vedotin drug like brentuximab [Adcetris] or polatuzumab vedotin typically doesn’t happen on the first cycle but can be cumulative; so if the patient is responding and they get 4, 5, or 6 cycles, that’s where you start to see more of the paresthesia and peripheral numbness. It is rare for patients to experience a lot of pain, but if they do, then they probably need a dose reduction.

So how would you manage toxicities? If you had them come back in 3 or 4 weeks for their next cycle and they had really bottomed out their platelets, as bendamustine can do, what would you do on your next cycle?

MISBAH: I would dose-reduce, [and probably dose-reduce] the bendamustine.

HILL: What if they were having a lot of neuropathies but their counts were fine?

MISBAH: I guess then [I would reduce the polatuzumab dose]. I haven’t used [polatuzumab] personally, but I know that it is associated with more peripheral neuropathy, so if the counts were intact, then that would be the one to dose-reduce.

HILL: I tend to agree with you. If you found really low counts, I think it does speak to the point of, “Well, yes, the polatuzumab does worsen the counts.” But if you’re using it on label with a 3-drug combination, it’s probably the bendamustine that’s causing most of the problems with the cytopenia.

So I might skip a dose, or give the polatuzumab without the bendamustine, or dose-reduce the bendamustine.

KARAMLOU: It’s a challenge. Obviously, if the patient has the wherewithal to proceed with the CAR T-cell therapy, I think that’s what I, and probably most of us, would prefer, because it’s a 1-time therapy and can…result in complete remission in more than half of the patients with a prolonged response. From that standpoint, that’s what I would prefer, but obviously there are challenges to CAR T-cell therapy. You will have to have those other options open, but I would really favor CAR T-cell therapy just because of that possibility of limited therapy and potential long durability.

BILBEISI: In the general landscape, I’m more likely to use it as that third-line option after salvage chemotherapy. But I would still hold out to see if I could get the patient to CAR T-cell therapy—especially as she’s young and there’s a longer progression-free survival that we can see with CAR T-cell therapy. I think I would still want to hold this back as potentially a fourth-line therapy, as opposed to putting it up front, as that third line for somebody young who otherwise has a good performance status. But for people who aren’t considered candidates for CAR T-cell therapy or transplant, I think this is a good next step.

CHOWDHARY: What is your go-to regimen in this third- or fourth-line setting? I think the data for polatuzumab vedotin–bendamustine-rituximab are compelling, but how do you choose [between the different regimens]?

HILL: Well, polatuzumab was the first drug the FDA approved for DLBCL in 20 years, if you don’t count CAR T-cell therapy. When it first came out, I think we were using a lot of it and did see cases in which it worked well where nothing else had. You have compelling data—[they're from] a small phase 2 [trial;] it’s hard to do huge phase 3 trials in this setting—but you have a pretty compelling randomized trial that shows that [polatuzumab] adds to the overall response rate, complete response rate, and progression-free survival, and improves the overall survival of patients in the third-line setting.⁴ So I think those things in total are pretty compelling, but the story [has become] more complicated because there are some other options out there.

_REFERENCES:

_{1. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 5.2021. Accessed October 21, 2021, 2021. https://bit.ly/3geoS5N}

_{2. Duell J, Maddocks KJ, González-Barca E, et al. Long-term outcomes from the Phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Haematologica. 2021;106(9):2417-2426. doi:10.3324/haematol.2020.275958}

_{3. Harris LJ, Patel K, Martin M. Novel therapies for relapsed or refractory diffuse large B-cell lymphoma. Int J Mol Sci. 2020;21(22):8553. doi:10.3390/ijms21228553}

_{4. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2020;38(2):155-165. doi:10.1200/JCO.19.00172}