Dr. Andrew Evens:
Welcome to The ASCO Post Roundtable Series on Treatment Options for Relapsed/Refractory Follicular Lymphoma. I'm Dr. Andy Evens, Deputy Director at the Rutgers Cancer Institute of New Jersey and Medical Director of the RWJBarnabas Health Oncology Service Line. Joining me today are two of my fantastic colleagues and lymphoma experts.
Dr. Carla Casulo:
Hello, I'm Carla Casulo. I'm an Associate Professor of Medicine at the Wilmot Cancer Institute at the University of Rochester, and thank you for the invitation.
Dr. Elizabeth Budde:
Hello, I'm Dr. Elizabeth Budde, Associate Professor in the Department of Hematology at City of Hope National Medical Center. Thank you for having me.
Dr. Evens:
Great. Today we'll be discussing the treatment and management of follicular lymphoma with three patient case studies. Our final installment will focus on third-line treatment of follicular lymphoma with high-risk features.
This patient is a 65-year-old African American man who presented with relapsed/refractory follicular lymphoma after receiving two prior therapies. His initial diagnosis was about 10 years ago in 2014 when he was treated with R-CHOP at the time at an outside center, followed by 2 years of rituximab maintenance. He did well overall for about 6 years, although had progression of disease, clinically speaking, in 2020 and had a biopsy of a peripheral lymph node at that time that did show grade 3a follicular lymphoma with a slightly elevated Ki-67 up to 30%.
At that time, he was treated with bendamustine/obinutuzumab reinduction therapy, he re-entered a complete remission, and this was followed by 2 years of obinutuzumab maintenance treatment that he completed in April of 2022, and he did well during this treatment without any significant or serious complications. Unfortunately, the following year in early of February 2023, he presented with increasing abdominal pressure, fatigue, and bonafide drenching night sweats, meaning change-your-bedsheets-several-times-a-night night sweats.
One question I have, Dr. Budde, in terms of routine imaging after surveillance, whether for initial treatment or secondary, do you follow patients with CT scans or PET scans or does it depend on the case?
Dr. Budde:
It's probably depends on the case. Routinely, I do not use the imaging study in a patient who just for a standard routine follow-up. Only if there's any clinical suspicion or there's new symptoms that doesn't really get better, then I will do a targeted imaging in those cases because I think that multiple studies have shown that the surveillance PET/CT scans is really not cost-effective, for the majority of patients, 95% of the time, the recurrence is really determined by other measures.
Dr. Evens:
Dr. Casulo, let's break that up a little bit. So a patient who finishes treatment and is asymptomatic, what do you do for imaging, number one? Number two, what about a case where they have definite symptoms and you're worried clinically about a relapse? How do you approach those?
Dr. Casulo:
I agree with Dr. Budde on the imaging on a case-by-case basis. Some patients really welcome the imaging, it gives a sense of security, but at the same time, we have to balance that against the risk of radiation exposure over time and the fact that even if we find some small increase or decrease in lymphadenopathy, it may not be actionable. So it's not as clinically relevant. However, in someone that's developing symptoms, I would perform a CT scan, and if there's something palpable and I know that this is likely something that represents progression, then I may go straight to a PET scan. That helps to target the biopsy of the most metabolically active spot, so that's helpful in that regard.
Dr. Evens:
And that's exactly what was done in this case. I should have mentioned, also, he had an LDH that was three times normal and with the drenching sweats, I think there was a clinical concern early on of a possible transformation. So he did have a PET/CT scan, as you can see here, and on that he not only had progression, he had a pretty bulky mass, in particular, as you can see in this coronal image on the left lower quadrant near the lumbar spine that involved the psoas muscle and an aggregate was 10.8 by 8.4 cm, with an SUVmax ranging up to 17.
He did have a biopsy. We've talked about the importance of that on the other two cases, and I think that would continue through to this case. And it was interesting, it was a needle biopsy of that large retroperitoneal mass, and they just called it grade 3 because they didn't have great architecture on it. There's a lot of necrosis. There were patches of large cells. They couldn't quite call it sheets of large cells. But nonetheless, it was CD20/CD10-positive, BCL2, BCL6 with a pretty elevated Ki-67 proliferative index of 60% to 70%. He had molecular studies done that showed translocations of MYC, BCL2, and increased copies of MYC. Also, at this outside center, they had sent for next-generation sequencing and listed here are some of the additional mutations that were identified on that sequencing.
So when we circle back and think about this patient, what are your initial thoughts, Dr. Budde, on his progression now he's had two prior therapies, he has this high Ki-67, big mass, and this type of pathology and molecular findings? What are your initial thoughts?
Dr. Budde:
I think I'm very worried about this case being a transformation. Given the pathology findings and these proliferative mutations and translocations and these high SUVs on the PET scan, I think my strategy will be manage this one as an aggressive lymphoma.
Dr. Evens:
Dr. Casulo, are your thoughts is part of that, it's maybe just transforming now or maybe you just missed the spot and he's likely transforming in another area?
Dr. Casulo:
Right, I think that both of those are equally possible. There's a lot of things here that worry me too. Some of the features of his biopsy with the translocations are seen in cases that may be headed towards transformation. So it's either bad follicular lymphoma or it's becoming a large-cell lymphoma. And in either case, I think that has to play into the decision-making capabilities. Fortunately, though, a lot of the treatments that we would offer someone in the third-line setting for follicular lymphoma have efficacy for large-cell lymphoma too, so sort of a benefit for him, hopefully.
Dr. Evens:
That's right. I'm just curious, Dr. Budde, I think we all have our own institutional studies and protocols, I'm curious for whether a case like this or other follicular lymphoma cases, are you guys doing anything beyond the basic FISH molecular studies such as whether an internal or a send-out next-generation sequencing?
Dr. Budde:
Yeah, we do have an internal clear validated testing called HopeSeq. So basically we're looking at more than a hundred different genes looking at if there are any mutations or duplications, which will help us to decide what be the best treatment for patients.
Dr. Evens:
Dr. Casulo, what about you guys? Because my question always is when we do these, whether internal or send-out, is, are they actionable, of course?
Dr. Casulo:
I think it's really fascinating to see the spectrum of things that you discover on some of these panels, and we certainly have the capability of doing them here too. But as you said, not everything is actionable and it may be something worth keeping for a future therapy should it become available or for a clinical trial, but at this moment we don't have anything that we can do with the information, unfortunately.
Dr. Evens:
Great. Let's move on. We have the biopsy and he’s now 65. He was pretty young when he was initially diagnosed at age 55, and he's a very fit gentleman with really minimal comorbidities with this high-risk disease as we've talked about. I'm curious, let's go down to treatment options. And so, Dr. Casulo, you had mentioned about there are similar therapies, almost two for one, whether it's follicular lymphoma or diffuse large B-cell lymphoma. Could you tell us more what you're thinking?
Dr. Casulo:
Sure. For someone who is getting third-line therapy, we have several things that can be offered. We talked about some of them already. Lenalidomide could be an option for someone, another chemotherapy could be an option. But the two that I would probably go for would be either bispecific antibody therapy targeting CD20/CD3 or anti-CD19 CAR T-cell therapy. Both of those classes have been approved for patients in the third-line setting, both of them have very high response rates, very high complete response rates, and if you kind of pool all the studies together, the median progression-free survival is around 18 months or so. I think that that would be a very appealing option. The choice between bispecifics and CAR T-cell therapy is highly dependent on the person and highly dependent on what types of therapies they're eligible for given some of the unique toxicities of each of these drugs. So those are important considerations.
Dr. Evens:
Dr. Budde, I know you've really been a leader in the field of bispecific antibodies, and so let's drill into that a little bit more. In general, choosing, if we're at such a decision point, between, in follicular lymphoma, bispecific antibodies and CAR-T therapy, how do you choose?
Dr. Budde:
Well, I think for this case it's a little bit different. But for most cases, if a third-line follicular lymphoma patients, I probably would go with mosunetuzumab, which is the only approved bispecific antibody in this setting, although two other CD20/CD3s are also coming. The main reason I choose bispecific before CAR-T is it's immediately available and it's outpatient use, and also, more importantly, the cytopenia you seen associated with bispecific antibody usually is transient and that can be usually reversible. But for CAR-T, sometimes you will see some patients have very prolonged cytopenia, then it's very difficult to go to the next line of therapy.
But it's also a personal choice. So I would do a discussion with patients. Some patients they definitely will prefer going to CAR-T because it's one-time treatment and this doesn't interrupt their life that much. For other patients, they would rather go with something that’s gentle, but they're able to come in to get multiple cycles of treatment. So it's not really one is definitely better than the other. It's more balancing the toxicities at the time and caregiver commitment.
Dr. Evens:
Yeah. Dr. Casulo, this is obviously a unique case because we're thinking it's not a bona fide transformation, whereas it's more of a high risk. But is that influencing you vs just a typical, nothing's typical, every case is different, generic follicular lymphoma in the third-line setting? Does that steer you one way more vs another?
Dr. Casulo:
I think it really does depend on the person. Yes, I think it would steer me a little bit. But as I said, both of these classes of drugs have efficacy in large-cell lymphoma. Fortunately, you have the ability to sequence them. So if someone is to have disease recurrence after a bispecific antibody and if they're fit enough to go on to CAR T-cell therapy, that would be an option. But as Dr. Budde alluded to, you need caregiver support to be able to qualify for CAR-T. Some of our patients come from rural areas, so they need drivers, they can't drive, they have to be within an hour of the cancer center, et cetera, so there's a lot of considerations that go into the decision for CAR-T vs bispecifics. But I think for him, it makes sense to go in that direction.
Dr. Evens:
Well, to that point about being rural in the community, et cetera, let's maybe drill down a little bit on CD3/CD20 bispecific antibody therapy, and Dr. Budde, as you said, only one is approved now, although likely we'll have more on the market to choose between. But what are your thoughts of patients in the community setting? Is this bispecific therapy in particular, CAR-T probably is a separate discussion, is this a treatment agent, whether for follicular lymphoma or maybe even diffuse large B-cell, can it be safely given in the community? And if so, what are your thoughts on how you help coordinate that?
Dr. Budde:
Yeah, I think this one definitely has a great potential to be used in a community setting. Mosunetuzumab, in the pivotal trials, the response rate, it's 80%, where 60% of patients can get into a complete remission. And many patients that were treated on the pivotal trial continued to stay in remission. So the duration of response is very long. And looking at the side effect profile, the main worry is cytokine-release syndrome, neurologic toxicities.
But for bispecific antibodies compared to similar side effects we're seeing with CAR-T, though bispecific treatment actually gives you a much less incidence of severity of cytokine-release syndrome or neurotoxicity. Neurotoxicity or ICANS is very minimal in this patient who is receiving bispecific. Cytokine-release syndrome is also quite different, although we're using the same definition, but it's quite different for CRS you're seeing with a bispecific vs a CAR-T. So we know bispecific, especially the intravenous, some of the cytokine release syndrome could be due to an infusional reaction, and those can be easily managed in the outpatient setting in the case of mosunetuzumab for follicular lymphoma. I think it takes some education and experience to really learn about how these molecules can do to patients for the community oncology to be more comfortable. But it is giving the outpatient setting no less requirements off the shelf, so I think there's a great potential to really to make it available in the community.
Dr. Evens:
Yeah, I agree. We've been maybe a little conservative here in New Jersey. I mentioned our service line, we're throughout the state of New Jersey, 15 hospitals, and some of them are smaller hospitals with a hem/onc practice of one or two docs. And I think part of it, to your point, is not even following the protocol and knowing about the medications, but it's how do you educate the emergency room, the inpatient staff? In terms of, even though it's less common than CAR-T, but certainly that CRS, and I know when we were starting to approach, Dr. Casulo, some of our colleagues, they didn't have tocilizumab in their pharmacy, and so we had to make sure to go through some of this training and I know the companies provide that as well. How have you guys managed this in New York?
Dr. Casulo:
We have developed a standard operating procedure for all bispecifics, and it's communicated to our inpatient staff, the intensive care unit, it's on our SharePoint, so it's accessible to anyone that is caring for a patient. It definitely requires reiterating and a lot of education and in-service, but we have developed the system where the patient receives SOP, we have it, it's a smart phrase in our notes, so whoever reads the note can access it and know what to do in what setting and when to use steroids and when to call, when to use acetaminophen. So it's become a much more standard practice and patients are able to remain ambulatory instead of going to the hospital, which has been a game changer.
Dr. Evens:
Some of your community practices, are they tip of the spear starting it or only you transfer out to a community oncologist after they've started?
Dr. Casulo:
I have not seen the uptick in utilization yet, but I do believe that it's coming based on how frequently these drugs are being used now.
Dr. Evens:
Great. To wrap us up in this case, Dr. Budde, let's think beyond, even though as active as they are in terms of CAR-T and bispecific, are there other new agents you're excited about in the field of follicular lymphoma?
Dr. Budde:
Well, I think that one of them in particular is the one that was recently approved based on the ROSEWOOD study, the combinations of zanubrutinib together with obinutuzumab. I think that's another great option, though, for these patient who has multiple lines of treatment but not in remission. So that's something you could do. You could sequence, you can give it before or after a bispecific or CAR-Ts. So many more options. And we know there are many more clinical trials also in clinical development combining bispecific with lenalidomide or polatuzumab. Those are, based on the preliminary data, we are seeing much higher remission, and the duration response is also pretty good. Bispecific and CAR-T are moving in the earlier line. So I think that, as we say, the future is bright, though, we're going to see a very different outcome for patient nowadays diagnosed with follicular lymphoma.
Dr. Evens:
Well, there's no way to end it beyond that. Great summary. So in terms of key clinical takeaways, as we've mentioned as a fairly common theme throughout the cases, repeat biopsy should be considered in follicular lymphoma to identify transformation to a more aggressive lymphoma and also possibly to look at molecular perturbations as well. There are several nonchemotherapy therapeutic options available for relapsed/refractory follicular lymphoma in the third-line setting and beyond, which include lenalidomide-based, tazemetostat, zanubrutinib/obinutuzumab, as was just mentioned, and especially with very high activity, CD19 CAR T-cell therapy and CD3/CD20 bispecific therapy. Both very active, but of course, needs to be proactive management in terms of following for possible cytokine release syndrome or neurologic events related to this. Collaboration, as always, between the academic and community colleagues is vitally important.
This brings us to the end of this case. Please see the other segments for further discussion about the latest research in follicular lymphoma or visit ascopost.com.
