Dr. Laurie Sehn:
Welcome everybody to The ASCO Post Roundtable Series on Evolving Treatment Landscapes of Indolent Lymphoma. I'm Dr. Laurie Sehn, from BC Cancer in Vancouver, Canada. And I'm joined here today with two of my esteemed colleagues, and I'll invite them to introduce themselves. Dr. Salles?
Dr. Gilles Salles:
Yes. Hello, my name is Gilles Salles, from Memorial Sloan Kettering in New York. Happy to be there.
Dr. Laurie Sehn:
And Dr. Smith?
Dr. Sonali Smith:
Hi, I am Soni Smith. I'm from the University of Chicago. Very happy to be here.
Dr. Laurie Sehn:
Great. Well, today we're going to be discussing the treatment and management of indolent lymphoma. And we'll be reviewing three patient case studies. So our first installment will focus on the management of early relapsing follicular lymphoma in the second-line setting.
So, this is a patient that I saw in my own clinic. The patient is a 41-year-old gentleman and really had no comorbidities. In 2023 he noticed an enlarged cervical node that then progressed on both sides of his neck, in the context of fatigue. He underwent staging investigations that included a PET/CT scan that showed lymphadenopathy above and below the diaphragm. He had quite a large mass in his abdomen measuring up to 12 cm, but the SUVmax of all sites was 8, and his LDH was normal. He underwent an excisional biopsy from an inguinal lymph gland, and this revealed grade 1 to 2 follicular lymphoma.
So he clearly had clinical indications for treatment with his symptomatic bulky disease, and he went on to receive what was our standard first-line at the time, and actually continues to be my first-line treatment for most patients. And that was bendamustine and rituximab for six cycles, and he had a good response to that achieving a complete response on PET/CT scan. He then started on maintenance rituximab, but unfortunately after four cycles of maintenance he started to develop symptoms that included shortness of breath on exertion, as well as night sweats.
So we repeated imaging, and at that point his PET/CT scan actually confirmed that he had recurrence of lymphadenopathy, both above and below the diaphragm. But also this time he had a quite notable new finding of a pleural-based mass, as well as a pleural effusion, and also peritoneal deposits. And the SUVmax was 16 at the site of that pleural-based mass, but his LDH was still normal. So maybe I'll throw it out to you Gilles, to start? What are you thinking about in this patient, and what workup would you recommend at this point?
Dr. Gilles Salles:
Yes. This is a case we see rarely, hopefully. But this is a patient who had the progression of disease shortly after having completed his first-line treatment, and basically within 24 months after having initiated immunochemotherapy. So this group of patients that was defined as POD24 experience progression of disease. So I think the first question we should ask for this patient, is whether he has a possibility of having a transformed disease?
He was in CR at the end of the induction, but we do know that there are emerging clones or re-emerging clones that may occur. So I think the most important point at this time is really to obtain a biopsy, ideally in the site where the disease shows the highest SUV on PET. This is not always perfect, and not always feasible, but that will be my recommendation, before to make any decision regarding the management of this case.
Dr. Laurie Sehn:
Yeah. So you're raising an important point, and that we now recognize that not all follicular lymphoma patients have the same disease behavior. And one of the clinical parameters that we now pay attention to in understanding risk, is the timing of relapse. And he would qualify for that group of patients that we refer to as POD24, or progression of disease within 24 months. And that's a group of patients that we recognize. Also is, at a higher likelihood to potentially harbor transformation at the time of relapse. So there are different studies out there with a range of risk, but certainly most studies have reported at least 25% to 50% chance of harboring transformation at the time of relapse for these early progressors. So certainly I was worried about that in his case, not only because he is POD24, but also because some of the unusual behavior findings for follicular lymphoma, namely the progression at these extranodal sites.
So we decided to pursue a CT-guided core biopsy of that site of highest SUV, and I think it's worth pointing out that we often do use the PET scan as a tool to help guide where the most fruitful biopsy might come from. And in his case, the highest SUV was in that pleural-based mass. So we approached that with a CT-guided core biopsy, and it showed follicular lymphoma, grade 3A. We sampled his pleural fluid and that cytology was actually negative for any evidence of lymphoma. So Soni, I'll throw this question out to you. Does he have transformed disease?
Dr. Sonali Smith:
Yeah. I think this is a really important question and certainly he started out with very high-risk features, including somewhat bulky and very extensive disease. And then the early relapse, as has already been pointed out, already puts this person at a higher risk for occult transformation. Making a diagnosis of transformation typically requires a biopsy. It would be really helpful to have histology proving that there's transformation. But often we are left with trying to make a clinical decision, because there's always the possibility of a sampling error. That the place that the biopsy was done does not reflect the disease that is elsewhere in the body. And certainly with the extranodal involvement, the pleural effusion, and the early relapse, it's somewhere high up. On the other hand the LDH is stable, and we typically do see that the LDH is elevated if there's a transformation. So this is a really tricky, tricky case.
In my mind the biopsy is helpful, it's always required in my mind, to try to make a diagnosis. The grade 3A, just to take a step back, since grade is something that has been confusing for some people in the past. There are three grades... grade 1, 2, have been collapsed into one group and then grade 3A and 3B. And typically grade 3B is the same as diffuse large B-cell lymphoma, whereas grade 3A, typically follows the pattern of grade 1 to 2. So by the biopsy he does not have transformation. But as we said, there's so many other pieces here, I would consider the possibility that there's occult transformation, and I personally would include that in my decision making.
Dr. Laurie Sehn:
Gilles, what do you think?
Dr. Gilles Salles:
Well, I'm aligned with Dr. Smith for sure. I think the features of these patients are not very reassuring. I mean he relapsed with quite significant amount of disease, the fact that he has pleural effusion. After that, we have to adapt sometimes our treatment and we can follow a path and adapt the path. I don't think it will be a mistake to treat him as follicular lymphoma at this time. But clearly very carefully monitoring the response to whatever line of therapy we choose, in order to evaluate that if he's behaving and responding like a classical follicular lymphoma; while if he's not responding well to whatever option we choose, we can pivot and choose something that will be encompassing the risk of histologic transformation.
So as Dr. Smith said, it's very tricky case, and we can debate this case in tumor boards. The sampling error can always occur. And I will say what we are probably missing here nowadays, is probably new tools such as, for instance, circulating tumor DNA. Which eventually in the future may enable us to identify some possible pattern of mutations, that are associated with transformation. But these tools are not ready for prime time, and are just very investigational here. So I will say I will try to discuss with the patient also the goals, and/or hesitation, and try to make a shared decision regarding his management.
Dr. Laurie Sehn:
Though I completely agree with you, this is the kind of case I generally bring to our tumor board, and we kind of thrash it out, and I'm pretty sure that I did present him in our tumor board. We do the best that we can to try and establish true transformation vs not, with a biopsy. But as you mentioned there's sampling error, and in the end you land up sort of putting all the clinical constellation of factors together, and making a clinical judgment call. So I was particularly concerned about transformation. But having said that, in the process of organizing these biopsies, we had some time that went forward, and in the context of his pleural tap, they removed quite a bit of the fluid around his lung. And he symptomatically was much improved, and he actually was fairly asymptomatic sitting in my clinic with a normal LDH, and biopsies telling me that all I could find was follicular lymphoma.
So after having a discussion with him about the possibility of missing transformation, and what might be best to treat him with. He elected to kind of not go the R-CHOP route, because he was a little bit concerned about exposing himself to multi-agent chemotherapy that involved an anthracycline, without absolute certainty. And we agreed to go forward and treat him as though this was early relapsing follicular lymphoma, knowing that we'd have to shift gears if there was any concern that, that was not the right path along the way.
So we decided to move forward with treatment as though he were having unfortunately, progression of disease relatively early. So I throw out that question... We now have somebody that we're going to move down a path of treating them with second-line treatment for follicular lymphoma, that's already proven fairly resistant to our first-line approach of BR, followed by rituximab maintenance. Does this timing matter if we're going to call him follicular lymphoma? And what are you thinking in terms of treatment options, Soni?
Dr. Sonali Smith:
Yeah. So first of all, I think the resolution of his symptoms is really important, because that with the normal LDH really does tip you more into the category of, "You have what you have, and that's follicular lymphoma on the biopsy." So I agree with that completely. I think the early relapse, you know, we've talked about the POD24... The problem is, although we know it's an adverse prognostic sign with inferior survival, we don't know what to do about that, necessarily? There isn't a specific treatment.
And in my practice, my most common second-line regimen, whether it's early progression or not, would be lenalidomide and rituximab, for this patient. And so R-squared (R2), there's certainly permutations of it, and it's become I think a really good backbone for other agents to be added on. But that's what I would go to, as my next line.
Dr. Gilles Salles:
I think I agree with you. I will, obviously given the characteristic, try to find any treatment options in clinical trial, that will eventually offer him a different path. Including any combination with R2, and as you mentioned, this is a very well-established backbone. I think there are about 9 trials or 10 trials that are comparing R2 vs R2 plus, something else, or vs something else? So adding another agent to R2 will be one of my favorite option, within a clinical trial, because no one is approved at this time.
We have seen the EZH2 inhibitor tazemetostat in clinical trial. We have seen the bispecific antibodies in some clinical trials with R2. We have seen phase II data actually regarding one of these antibodies plus R2. And recently Dr. Sehn at the ASH meeting presented also data with the anti-C19 antibody, tafasitamab in combination with R2. So this will be good option for this patient. Should also mention that there are trials that assess the role of cellular therapy, CAR T-cell, in this patient with similar features and given his young age and discussing the risk/benefit of CAR-T, including the long-term possible toxicity. This is something I will eventually discuss and bring on the table for this patient.
So I think we have a couple of options, and I will say for this patient. Yes, standard of care is adequate and R2 will be also my favorite choice. But I will really push to try to offer him the opportunity even in a randomized trial, to benefit from a combination of R2 plus, one of these new agent, which most of them are relatively safe in this setting. And likely offer a higher, at least, complete response rate, and possibly duration of response.
Dr. Sonali Smith:
I was going to mention CAR-T as well, and I'm so glad you brought that up. Because we typically think about CAR-T as being something for third-line and beyond, and currently that's really where it stands. But, if we still have that concern for transformation with early progression, CAR-T is something that would treat both the aggressive as well as the indolent element.
All of that being said, I think second-line for somebody who had chemosensitive disease to begin with, and then had a relapse, as opposed to primary refractory? CAR-T is there, but I might push it later, and I agree that a trial with R2 plus, whatever, would be appropriate.
Dr. Laurie Sehn:
Mm-hmm. Can I just ask you a question in that regard? So in my own center I'm not able to access second-line CAR-T yet for follicular lymphoma. Is that something that you can access, or is it a patient-by-patient basis?
Dr. Sonali Smith:
Not generally, but we have been able to negotiate for it, with some people.
Dr. Gilles Salles:
There are at least one, if not two trials, that are addressing this question of a... second-line therapy, and there is always a discussion, what's the appropriate second-line therapy, is it R-CHOP, BR, R2 or something else, vs CAR-T? So I think, I can't remember the number or the name of these trials, but I know they're running. They are not open in our center, which tells you. There will be eventually an investigation of CAR-T that might be open for this patient, and I will discuss that. But you can also choose, and we have managed a few patients like that. And I have been also given second opinion about this patient, is initiating a treatment with standard of care, and if we agree that R2 is the appropriate one.
And I agree with that, as Soni Smith mentioned, eventually obinutuzumab then could be an option, not necessarily better, but at least you switch the antibody. He relapsed during rituximab maintenance. But starting that and monitoring closely as I said with the PET/CT in 2 or 3 months to make sure he achieved a rapid response, and if not, then eventually document biopsy and discuss CAR-T, which will be now approved in the third line.
Dr. Laurie Sehn:
So I think your point about a clinical trial opportunity is extremely important. Because we're going to be talking in other segments about the options that are available now in third-line and beyond follicular lymphoma. And those are moving forward in clinical trials, and not necessarily accessible, or not necessarily with full data yet available, in the second-line setting. So in the context of clinical care for this patient, I was left with the options I have on the table to treat him with. We did not at that point have a clinical trial available for him. Because he does fall into that category of POD24, one of the things we've thought about... I guess, it's most attractive not to come back with the same kind of treatment.
So this is a patient where we'd like to move away from chemoimmunotherapy, and move into novel therapies. And the immunotherapy lenalidomide and rituximab I have to say, would be my next choice for that patient, just because we want to bring in a different mentality. You mentioned the recent data that was presented on tafasitamab, so that was presented at ASH this year in the late-breaking session and it was a large phase III trial that compared lenalidomide-rituximab, vs the combination of tafa, len and R; and tafasitamab, of course, is an anti-CD19 monoclonal antibody.
So here we've got two monoclonal antibodies with the lenalidomide, and that trial has just been presented in abstract form, but did show a marked improvement for the addition of the tafasitamab. With not only higher response rates and higher CR rate, but its primary endpoint was improvement in progression-free survival, which was significantly longer with the addition of tafasitamab. And overall, the toxicity was very tolerable in that there was a slight increase in the risk of infection, but they were manageable. And there was no impedance of the delivery of the lenalidomide or rituximab.
So we'll see that combination will likely move forward to the FDA, and possibly become an approved therapy. But certainly it demonstrates the ability of other agents to augment, and in this case adding in an extra immunotherapy to augment the immunotherapeutic benefit of R2. And the other thing I would point out with that data, was that it was intriguing that patients with POD24 on that trial benefited equally from patients without POD24.
So again, probably at least a demonstration that if we can bring in alternative therapies, and particularly effective immunotherapies, having POD24 may not make as much of a difference as it did before, when we're relying on bringing in successive chemotherapy rounds. The one question I'll just throw out there is, some people have advocated for patients with POD24 to move on to a consolidative autologous stem cell transplant. Is that something you've done in your own practice? Maybe Gilles, I'll start with you?
Dr. Gilles Salles:
I have abandoned that years ago, when we showed that if the patient does not present with a transformed disease, there is probably not ultimate benefit in term of for overall survival. Probably a benefit in term of PFS. But I don't think I have brought a patient to autologous transplant with follicular lymphoma for probably 5 years, and even before coming to the U.S. So probably 7 or 8 years. So with a doubt about transformation, you may consider that, but I think now we have many other options. I should say also that the bispecific antibody which are available in this setting of third-lines, sometimes can be eventually shuffled in second-lines, are also exciting data regarding epcoritamab plus R2.
There is a randomized trial running, and I think we have had patients approved for bispecific even in the second-line setting by insurances. So I think it's also part of the agents which are probably changing the landscape. And again, the idea is really to tailor the treatment, like always in follicular lymphoma, tailor to what are the best available option we can have, and monitor closely the response.
Dr. Laurie Sehn:
Soni, what about you? Would you ever consider high-dose chemotherapy in a stem cell transplant?
Dr. Sonali Smith:
Yeah. Just like Gilles, I have stopped using auto-transplant for follicular lymphoma, and even for diffuse large B-cell lymphoma, with the exception of late relapse. It's really been replaced by some of the newer options that we have. And certainly for this patient, I think building on an R2 backbone makes the most sense, and I don't really see a role for auto. Even if there was transformed disease.
Dr. Laurie Sehn:
So certainly we're worried about this patient's overall prognosis, because he does fall into that category of POD24 and historically they have had a worse overall survival. Although I am certainly optimistic that some of the novel options that have come forward that really rely more on immunotherapy, will hopefully be showing us that outcomes will be improved for similar patients in the future.
So with that, a few key clinical takeaway messages, and that is that progression of disease within 24 months or POD24, for patients with follicular lymphoma, has been associated with poor overall survival. And when considering management, I think it is important to consider options that offer them novel approaches beyond immunochemotherapy. It's also important to recognize that transformation risk is particularly high in this group of patients. So as many as 25 to 50% of patients may harbor transformation.
So if relevant patients should undergo repeat biopsy, and be considered for the possibility of having transformed disease, which would take you down an alternate route of managing aggressive B-cell lymphoma. But most certainly what we're hearing today is novel therapies and perhaps immunotherapeutic approaches would be preferred for this high-risk patient, and that the value of further chemoimmunotherapy would be very limited. And certainly I think the use of high-dose chemotherapy in an autologous stem cell transplant, is now really considered outdated. Where we want to perhaps save the bone marrow reserve to make sure that all of these immunotherapies that are coming through the pipeline, will have the most effective chance of working.
So that brings us to the end of this case. I suggest that you see the other segments for future discussion about the latest research in lymphoma, or visit ascopost.com.
