Dr. Nastoupil:
Welcome to Relapsed/Refractory Follicular Lymphoma: Choosing the Right Regimen for the Right Patient, an ASCO Post Roundtable. I'm Dr. Loretta Nastoupil, a community oncologist from Southwest Oncology in Durango, Colorado. Joining me today are two of my colleagues. Dr. Casulo.
Dr. Casulo:
Hi. I'm Carla Casulo from the University of Rochester. Thank you for having me.
Dr. Nastoupil:
And Dr. Maddocks.
Kami Maddocks:
Hi. I'm Kami Maddocks from the Ohio State University. It's great to be with both of you.
Dr. Nastoupil:
In our third and final case, we'll discuss the treatment of relapsed refractory high risk folic lymphoma in the third line and beyond. We're actually going to revisit case number one. If you recall, he's a 62-year-old fit male. He presented with peripheral adenopathy, had front-line bendamustine/rituximab, followed by about a year of maintenance rituximab. At his first relapse, which was within 24 months, he actually goes on to receive second-line R-CHOP. Though he initially responds based off of an interim PET, he still has persistent disease at the end of treatment. The formal response assessment by the radiologist is that this is a Deauville 5.
He's had more than 50% reduction in the disease burden, but based off of PET, there's still a number of sites with active disease including adenopathy in the pelvis, the inguinal region. Though he had lung nodules that were more prominent at the beginning, we still see some uptake in the lung. How about you approach a young, fit patient who was characterized as a POD24 following front-line bendamustine/rituximab, technically has a partial response to second-line R-CHOP. Just to influence your discussion, there were a number of considerations we talked about.
Would you extend out maintenance rituximab maybe to deepen the response? Would you pursue a biopsy just to ensure we know what's still persisting at the end of our CHOP? We had a biopsy prior to proceeding with second line. Would you just observe this patient since he's feeling better? We essentially reduced the amount of disease burden he had. I'm curious how you might approach this patient at the end of his second line with a PET that shows still persisting disease. Kami, what are your thoughts about this case?
Dr. Maddocks:
This is a tough case. I think probably I'm going to biopsy to just see what I'm dealing with, rule out transformation, or just make sure that we have active disease. Then I'm probably going to have a long discussion, and say that with a PR to this treatment and his response to the first line treatment that I expect that this PR is not likely going to last long. If we're not going to transition to a new therapy now, we probably need to watch you pretty closely because I expect that you might have a little bit of time here, but we're likely going to see progression pretty quickly.
I think probably what I would do is either transition, or recommend close follow-up and then transition to a new treatment. I'd talk about rituximab maintenance, but I'd probably be less likely to recommend it given that he had rituximab-based therapy now with rituximab maintenance pretty quick relapse after that, and now is getting rituximab with his therapy and hasn't had a CR to therapy. There is data in the front-line setting using rituximab maintenance after chemoimmunotherapy can help convert a good PR to a CR. But I think in the relapsed/refractory setting in this patient, I probably would find less benefit and would just think that that would lead to more potential for infectious complications. But this one's tough.
Dr. Nastoupil:
Carla, what are your thoughts?
Dr. Casulo:
I agree, this is a very tough case, and I don't know that there's only one right answer here. I probably would want to be more conservative in assessing what is that remaining FDG uptake. There could be occult transformation there. I mean, he's had R-CHOP and there's still some positive uptake and that would worry me for something that's biologically more aggressive. My temptation would be to probably pivot to another form of treatment, if that's something that he would be open to. I know he's worried about side effects. He had pneumonia with bendamustine and with the maintenance before, so he may not be open to that. But at minimum, I would recommend a biopsy followed by another treatment. But if he's not open to that, then I would probably pursue very close surveillance with the expectation that we're probably going to need to pivot to something very quickly.
Dr. Nastoupil:
As follow on, I shared all of those thoughts with this patient, including a consideration for referral to a tertiary center because he is young, he's fit. This disease is not behaving like a less aggressive or more indolent follicular lymphoma. There are a number of trial options out there. His initial pushback though, as many of you have seen with anthracycline-based chemoimmunotherapy, they're beat up at the end of treatment. He's nearing the age of retirement. He's really hoping to return back to work to try and regain some of that time loss, but also potential revenue loss and wants to feel better before we start down the path of another line of therapy.
He does agree at least to undergo a biopsy just to ensure that waiting is appropriate. Unfortunately, he still has persistent follicular lymphoma. After a period of observation, he's actually now progressing. He's recovered, so he's feeling better. About three months out, he's now open to the idea of considering another line of therapy. Again, this is a young patient. He's fit. He's had two lines of chemoimmunotherapy. Had a partial response now progressing within three months of the end of his last treatment. He's open to discussing third line options. What are those options? Again, maybe Kami will start with you. What would you consider next?
Dr. Maddocks:
Yes, this gentleman does have a lot of different options. Third line here, he has option to think about bispecific antibodies. We have two different bispecific antibodies. The mosunetuzumab or epcoritamab can be used as single agent. He would be able to get epcoritamab with R2 as we've talked about in any line of therapy, and he would be able to get tafasitamab in combination with R2. He would also be able to get CAR-T-cell therapy, so he has three different products that he could get for that.
I probably would talk to him about bispecific antibody therapy. It's not clear to me looking at differences between bispecific antibody vs bispecific antibody plus the R2 really in this setting if there's any benefit to adding R2 to the bispecific antibody or not. I think I would probably also have the conversation about CAR with this patient, but typically in follicular lymphoma, at least I tend to think about bispecific antibody before CAR-T.
Dr. Nastoupil:
Carla, your thoughts?
Dr. Casulo:
Yeah. I agree. I think it depends to some extent on his tolerance for long treatment. It sounds like this is someone who wants to rapidly pivot back to his normal state. The advantage of CAR-T-cell therapy for follicular lymphoma is that this is the population in whom we think earlier use of CAR-T might be better. A younger patient, high-risk disease, someone who has a likelihood of having a very long duration of disease control, that could be appealing to him if he wanted to have a therapy that's a solitary therapy without any maintenance component. I don't typically view CAR-T-cell therapy as one and done because there's so many multiple steps required before and after, but at least it's a time limited approach and it's a single therapeutic approach. He would have to tolerate the toxicity and the hypogammaglobulinemia and cytopenias after that.
The other aspect, which he may be open to would be zanubrutinib and obinutuzumab, which was tested against obinutuzumab monotherapy in the Rosewood trial. Again, we don't have this cross-trial comparison, but if he's seeking something that's relatively well-tolerated oral treatment, he can start with that, and then always have the bispecific antibody and CAR-T-cell therapy available to him later. That's another consideration. But I fully agree with Kami that these two, the bispecific antibody vs CAR-T option would probably be what I would offer him first. Recognizing that we have a plethora of things at our disposal, which is a good thing for follicular lymphoma.
Dr. Nastoupil:
Maybe asking you to speculate a little bit, there's a lot of discussion about sequencing of bispecific and CAR mostly in the myeloma world where the target's the same, essentially targeting BCMA. You both highlighted on this, but in follicular lymphoma where it's an indolent disease and we've mostly been targeting CD20s with the bispecific antibody and you have a CD19 targeted CAR. How much do we know about sequencing, and are there considerations that you need to think about if you're both acknowledging that you could do a bispecific alone, or a combination or you could do CAR-T and does the sequence matter? Kami?
Dr. Maddocks:
I'm not necessarily aware of any data, particularly in follicular lymphoma that the sequence matters. I think if we're talking about large cell lymphoma, then that's a different conversation. But I think to a point that Dr. Casulo mentioned in an earlier case, if somebody's watched all the cases, is that it is important these patients have been treated with a lot of CD20 therapy and we know that patients who are CD20-negative do not have good responses to the CD20-based bispecific. I do think that biopsy and looking for that is an important consideration in this kind of patient who's been heavily pretreated with rituximab therapy in the front-line maintenance and second-line setting.
Dr. Nastoupil:
Then Carla, what are your thoughts about infection mitigation? We talked quite a bit about CRS and maybe ICANS to an extent if you're considering CAR-T. Though my assessment of that is we've gotten much better at identifying and managing it, but now the focus is shifting a little bit towards infection risk, and I think you've even alluded to that. Obviously, this is someone who's had a bad pneumonia before. We're getting past that, but that's clearly going to be one of the questions he's going to pose is, what is the downside to some of these novel therapies, and what strategies are available to mitigate that risk?
Dr. Casulo:
With bispecific antibody, you do have to prophylaxis against pneumocystis and viral infections. Post CAR T-cell therapy, we also use pneumocystis and antiviral prophylaxis. I think that it's, I would say, likely that an infection will occur or at least he's at high risk of that because of the prolonged B-cell depletion and then likely then now T-cell depletion. I think that that's something we have to prepare for.
Mitigation strategies outside of the prophylaxis would include measuring IgG levels and administering IVIG. We've had luck in sometimes measuring IgG subsets if there's an insurance barrier to getting IVIG approved, but those are the primary sources at our disposal. Sometimes post CAR-T patients will have prolonged cytopenias, and will require intermittent GCSF. That's another consideration for this patient if he really wants to minimize the risk of infection moving forward.
Dr. Nastoupil:
Well, perfect. Well, again, just to summarize this case, we have a young fit male who's progressed quickly following front-line chemoimmunotherapy and essentially, refractory to CD20 and alkylator in second line. I will highlight that both of you, when we talked about how you might've approached this patient at first relapse with the novel treatments available, both suggested maybe we should move away from chemotherapy because you anticipated a short response. Again, highlighting that these novel therapies available to us we hope may overcome some of these chemo resistance disease characteristics. Recognizing what that prior treatment was when that relapse happened, may inform how we approach them in later lines.
In third line or later follicular lymphoma, we have a number of options. You both highlighted you could still circle back to those lenalidomide rituximab combinations with either epcoritamab or tafasitamab, you now have CAR-T-cell therapy available and then the single agent bispecific antibodies. Again, trying to navigate those patient specific characteristics with the disease we're trying to control, and then managing what those toxicities of each individual regimen might look like are important considerations.
I'll also suggest that we still need to continue to support clinical trials. We're getting more and more effective standard of care options, which I think is really important for patients, but there are still questions that need to be answered and the fact we have so many options available and don't really have clear risk stratification of biomarkers, maybe we need to do a better job of harnessing these rare patients, so that we can continue to address the unmet needs in the field.
Then we're always going to be balancing patient specific goals with our desired therapeutic outcomes as we continue to navigate this rapidly evolving landscape. Again, I really appreciate you both, Kami and Carla, for allowing me to pick your brain about some challenging cases, but illustrate how there are new options available for patients that we hope are going to be so much better than what we've done for these patients to date. Thank you so much.
Dr. Casulo:
Thanks so much for the invitation.
Dr. Maddocks:
Thank you so much.
