Dr. Laurie Sehn:
Welcome to The ASCO Post Roundtable Series on Evolving Treatment Landscape of Indolent Lymphoma. I'm Dr. Laurie Sehn from BC Cancer in Vancouver, Canada, and I'm joined here today with some of my esteemed colleagues and I'll ask them to introduce themselves. Dr. Salles?
Dr. Gilles Salles:
Yes. My name is Gilles Salles from Memorial Sloan Kettering in New York.
Dr. Laurie Sehn:
And Dr. Smith?
Dr. Sonali Smith:
Hi, I am Soni Smith from the University of Chicago.
Dr. Laurie Sehn:
Great. Well, today we'll be discussing the treatment and management of indolent lymphoma with three patient case studies. And our second installment we'll focus on the treatment of relapsed refractory follicular lymphoma in the third line setting.
So this again is a patient case that I saw in my own clinic and this was a 74-year-old female who had some comorbidities with type 2 diabetes as well as osteoarthritis. She presented way back in 2014 with asymptomatic low bulk stage IVA follicular lymphoma. At that time she had small lymph glands above and below the diaphragm as well as bone marrow involvement. But she was asymptomatic and essentially went on at that time to receive just rituximab monotherapy for four doses for low burden asymptomatic disease.
That actually kept things in check for about 5 years until 2019 when she did develop symptomatic progression. At that time, she had multiple enlarged nodes above and below the diaphragm more than 7 cm, and she went on to receive front-line therapy with bendamustine and rituximab for six cycles and achieved a complete response. Although it's typically my practice to offer patients maintenance, this was in the height of COVID pandemic and we elected not to move on to any maintenance. So similarly, she actually had good control of her disease for an additional 5 years, but in December of 2024, came back with fatigue, progressive lymphadenopathy, fairly enlarged nodes up to 7 cm, but she had no B symptoms, her LDH remained normal and the PET scan demonstrated an SUVmax of 10. So maybe I'll start by asking you, Soni, should this patient have a biopsy to plan out the best care?
Dr. Sonali Smith:
I think it's really important at each relapse to at least make an attempt to ensure that there is not transformation. I mean I think the likelihood is relatively low given the SUV, but there is a relatively high tumor burden and I would try to get a biopsy of at least one of the sites if it's at all possible. Sometimes it's not possible and something's not accessible and in those cases we go by the clinical judgment and then I would likely treat for a follicular lymphoma.
Dr. Laurie Sehn:
Okay, I would agree. So what we're always concerned about is are we dealing with the same disease, and particularly for these patients that have long remission durations, although we are always worried about transformation and getting biopsies in the setting of suspected transformation, I think it is important to biopsy them regardless. Because I'm always surprised sometimes, sometimes you turn up an occult transformation, but otherwise you do want to get some hints hopefully from their biopsy, whether or not you are in fact dealing with the same disease.
So Gilles, maybe I'll ask you, so she needs to go on to a next-line therapy. Thus far she's had just rituximab monotherapy, which was given at a time where she was asymptomatic, and sometimes I actually discount that and don't even think about it as a line of therapy. And then she went on to BR after that. Now she needs treatment again. Is this somebody who's considered a third-line follicular lymphoma patients because it does, I guess open up some doors sometimes in terms of what can be easily accessed?
Dr. Gilles Salles:
Well, I think that patients that had received two lines of systemic therapy, even if one is abbreviated and may not be as standard with long-term response, I will believe this patient is in third line. I will say the question will have been slightly different if this patient has had localized disease and has been receiving radiation, eventually I might have considered this is only one line of systemic therapy, but usually I count any systemic therapies that has proven effect. And she had 5 years of remission even with the low tumor burden, so it's even beyond that expectation. We know that for infusion of rituximab, the median time to progression is between 2 to 3 years. So she got 5 years. It was efficient. I think to me it's a third-line treatment. And again, we have so many options that are available that we can sequence them adequately. So for me, third line. I should say regarding the biopsy, among the possible surprise sometimes are also the plasticity of B-cell and discovering Hodgkin-like features or something like that. So yes, always repeat the biopsy.
Dr. Laurie Sehn:
So we did go ahead and actually got a CT-guided core biopsy of her abdominal mass and it did confirm that she still had follicular lymphoma and was deemed grade 1 to 2. Gilles, are there relevant biomarkers for follicular lymphoma that we would be looking for in that biopsy to help guide management at this point?
Dr. Gilles Salles:
Yes, this is an important question and unfortunately as the answer very simply is no. I think we have learned so much by the work of many groups, including new groups in Vancouver regarding the biology of follicular lymphoma, the landscape of mutation, the role of immune cell in the environment, T-cell, microphages and things like that. But none of this marker has been really guiding therapy at this time. And I think these are either academic studies or investigational studies and I don't think it will guide therapy.
The only exception possibly is the presence of EZH2 mutation. We do know that one drug, tazemetostat, which is an EZH2 inhibitor, has been approved for patients in the third line who carry this mutation. However, I think that at this time as a single agent in this setting, we have better options to propose to this patient, even with some comorbidities. And remember she had diabetes and maybe something else. But I will say we have agents that have a higher chance to bring her into another complete remission, which hopefully will have a similar duration of a couple of years while the progression-free survival after tazemetostat single agent is in the range of 12 to 14 months.
Dr. Laurie Sehn:
Soni, do you test for EZH2 mutations in your patients with relapsed/refractory disease?
Dr. Sonali Smith:
We often do NGS on our biopsies and EZH2 is part of our panel. But similar to Gilles, we don't specifically test for it. And I think one of the encouraging outcomes from the tazemetostat monotherapy studies, even if that's not what we choose right now, shows that there is activity independent of EZH2 mutation status. And so I don't specifically test for it. This patient actually with a late relapse, whether you call it second line or third- ine, there's a tremendous number of really great options for her. Whether we go back to talking about R-squared (R2), know one of the bispecific agents, a clinical trial is always a really good option. I think she has a good prognosis here.
Dr. Laurie Sehn:
Okay. Well, with that framework, that was my next question for you. And that was not only what her treatment options are, but what factors are you considering when we think about an individualized approach in this patient to help guide your choice on the next treatment option?
Dr. Sonali Smith:
So I think for her, the age, the comorbidity, this is always shared decision-making with the patient because we don't know necessarily what's the best treatment. We don't have that kind of head-to-head comparison. What we know is that there are several good options and so we talk about the schedule, the potential adverse effects as well as the efficacy. And luckily in this particular situation, I think the efficacy would be predicted to be quite high no matter which way you go. The nice thing about R2 is that, but it is more intense. And there are cytopenias and an increased risk of infection. The bispecific agents which are available, and there's mosunetuzumab and epcoritamab that are both approved for follicular lymphoma, mosunetuzumab is time-limited, especially if there is a good response after eight cycles, I'm sorry, and that may be an option for her as well. And really talking about the ability to come to clinic to receive a bispecific agent enters the conversation.
Dr. Gilles Salles:
I think I will add to that. While we had favored and try to opt for oral therapies, I think except tazemetostat, there is no available options anymore in the US for these patients. So as you said, R2 or R2 plus any agent in the clinical trial is an option. We should mention the approval of the combination of a BTK inhibitor in the case of zanubrutinib plus obinutuzumab based on a randomized study showing that this was better than obinutuzumab single agent, with moderate toxicity, I will say. So whether we use R2, which will require at least administration of rituximab bispecific, this treatment, I think this will be the options I will consider.
If the patient was probably without comorbidities or younger, I might eventually discuss with her CAR T-cell therapies. Those are approved in this setting. I rarely recommend them for patient. I think there are side effects and you can always think about using them later in the course of the disease if needed. But it's also an available option. So to me it comes to R2, mosunetuzumab or epcoritamab, the combination of zanu-obin. And I will say in case I will likely recommend mosunetuzumab given that it's rather practical and after having spent the first months with some side effect and some close monitoring, I will say that after that it's pretty straightforward.
Dr. Laurie Sehn:
I think this conversation really highlights the multitude of options that are now available. So I know it's a bit semantics, but I would consider her to be a third-line patient, which helps open up the door, at least for me, to access some extra treatments. But certain a patient like her would've been eligible for most of the third-line trials that have been performed because a round of rituximab monotherapy was often considered as a line of systemic therapy. So I think the information that we have from those trials certainly applies to her.
I would fully agree, I think in a patient like this, it comes down to a bit of a wealth of riches. Having had delayed relapses and good behaving disease, I think that her outcome is likely to be good no matter what you choose. And in a patient with numerous comorbidities, we're certainly more concerned about the toxicities of the treatments than we use, than perhaps trying to give her the most intensive therapy to get the longest remission.
I agree, this is not a scenario where I would be considering CAR T-cell therapy next, although we know it is a very highly effective treatment for follicular lymphoma that can offer some patients rather durable responses. But keeping her comorbidities and age in mind, I think either a bispecific antibody lenalidomide-rituximab right now, or even as you mentioned, zanubrutinib as well as obinutuzumab, are all very attractive options. So I at this point would sit down with my patient and describe these options and see which one if she has preference for, because some of it comes down to lifestyle and the effort that it would take patients to be treated with. Having said that, after having a discussion with her, she did opt to go on lenalidomide and rituximab, which she thought was maybe the easiest path forward, and she's currently receiving that and actually doing very well.
Dr. Sonali Smith:
One thing, if I could just add, Laurie, before we go forward, is that people do get concerned about giving bispecific agents. And as Gilles said, the first month is the more intensive part and we do have to look for cytokine release syndrome as well as, even though neurotoxicity has not been described at a high level in the trials, I will say in my personal experience of using mosunetuzumab in the community, I do see this from time to time. So it's helpful to partner with an academic institution or a place that has some experience.
Dr. Laurie Sehn:
Yeah, I think that's really important and we know that bispecifics are rolling out in many scenarios for lymphoma patients. So they are becoming treatments that I think are rolling out into the community and will continue to be delivered more broadly in the community. But it is sometimes a challenge for an individual doctor to get that up and running. So onboarding at a central site and then continuing the treatment really is something that works very well and sometimes is necessary.
Dr. Gilles Salles:
I think in this shared decision process regarding the constraints of the different treatment, how many times the patient comes to the hospital to receive which treatment, monitoring these blood counts and things like that, I will also take into consideration the support. As just as Dr. Smith said, if you have to administer bispecific, you need to be able to have the patient coming back to the hospital the day after the injection. So having a support system, caregivers that can help during this process is very important as opposed to what you have with the other agents. So again, the understanding of the goal, the understanding on the constraint, the support system, the possible pattern of side effect is important.
Dr. Laurie Sehn:
Excellent. Well, with that, a few key clinical takeaways. So we know that patients with late relapsing follicular lymphoma generally have a good prognosis with an overall survival that is often considered to be similar to an age match population. So there are an increasing number of treatment options and certainly there's a lot of thought going into optimal sequencing, but essentially I think trying to individualize the treatment to the patient right now is most appropriate. Many of these treatment options that we have available now down the road in the third line setting, really rely on mechanisms that are not chemotherapy-based. And of course that is good both for efficacy and tolerability for many of these treatments.
Aside from EZH2 mutations, which might make the EZH2 inhibitor tazemetostat more attractive. There are no real validated biomarkers for clinical care, although we certainly know that that's an active area of research and look forward to having more guidance in the future. But right now I'd say treatment selection should consider a number of factors and that includes what the patient's prior treatment history is and how long they benefited from that treatment, how they tolerated that treatment, what the patient's comorbidities are, what our available options are, and what we know about the efficacy and toxicity balance between those available options. And then ultimately, patient preferences because many of these treatments get given on different types of treatment schedule, might require different effort on the patient's part to come into the clinic more regularly or less regularly, and patients certainly should weigh in with their preferences on that.
So this brings us to the end of this case. I encourage you to please see other segments for further discussion about the latest research in lymphoma or to visit ascopost.com.
