Dr. Laurie Sehn:
Welcome, everybody, to The ASCO Post Roundtable Series on the Evolving Treatment Landscape of Indolent Lymphoma. I'm Dr. Laurie Sehn from BC Cancer in Vancouver, Canada, and I'm here today with two of my esteemed colleagues, and I'll ask them to introduce themselves. Dr. Salles?
Dr. Gilles Salles:
Hello, I'm Dr. Gilles Salles from Memorial Sloan Kettering in New York. Excited to be here with my colleagues.
Dr. Laurie Sehn:
And, Dr. Smith?
Dr. Sonali Smith:
Hi, I'm Soni Smith from the University of Chicago. Really looking forward to the discussion.
Dr. Laurie Sehn:
Great. So today, we're going to be discussing the treatment and management of indolent lymphoma with three patient case studies, and our final installment will focus on the treatment of relapsed/refractory nodal marginal zone lymphoma.
I'm going to present a case that I saw in my own clinic. This is a 68-year-old gentleman who has some comorbidities with hypertension and hypercholesterolemia, but he's generally quite well. In 2019, he presented with abdominal pain and bloating, and a PET/CT scan demonstrated that he had a very large pelvic mass up to 9 cm, it's actually involving the bladder and causing left-sided hydronephrosis, with an SUVmax of 7 and a normal LDH. So he underwent a biopsy that confirmed marginal zone lymphoma, and he went on to receive front-line therapy with bendamustine and rituximab for six cycles and achieved a very good complete response on PET scanning.
About 4 years later, though, he did have documented recurrence on a surveillance CT scan. So he was completely well, but, lo and behold, his CT demonstrated that that pelvic mass had regrown now up to 8 cm. He also had several mesenteric lymph nodes up to 3 cm. Aside from that, there was no additional disease and SUVmax remained 6.
So my question is, what do you do now for this patient? He has fairly localized disease. Is radiation therapy on the list of options for somebody like this? Soni, what do you do now?
Dr. Sonali Smith:
Yeah, so marginal zone lymphoma isn't as common, but certainly we see quite a bit of it. It's often extranodal, and I'm not surprised that, in this case, there might've been some bladder involvement or perhaps it arose from the bladder at the time of initial diagnosis. His very good outcome and the fact that he is asymptomatic right now I think are important features to keep in mind. And in terms of next steps, I do believe he needs treatment, partly because of the size. That's 7 cm. This could easily grow and cause hydronephrosis, and so there is some treatment that's needed.
When it comes to treatment options, I have favored systemic therapy over localized radiation in the recurrent setting, partly because I think that these cells are already out of the bag, if you will. And the other piece is the location, and I think radiation to the abdomen can sometimes have some other side effects. So not that it's wrong to do radiation, but it wouldn't be my preference. And then the other smaller lymph nodes that are there are also suggesting that there's more than just what meets the eye in terms of one mass.
Dr. Laurie Sehn:
I agree, and I think that that kind of swayed me. I do remember presenting this gentleman in our interdisciplinary conference, and our radiation colleagues brought up the fact that they felt they could radiate the bladder mass without much in the way of comorbidity and they can protect the kidney, but I was, I guess, swayed by the fact that we now had evolving lymphadenopathy, including these mesenteric nodes, that it probably was just going to be kind of a stopgap; and ultimately, proceeding on to systemic therapy seemed preferable. So he did go on to receive lenalidomide and rituximab for 12 cycles, and actually did quite well with that and achieved a PET CR.
So, Gilles, I might ask you, would you have selected lenalidomide and rituximab as a second-line therapy? What do we know about its use for marginal zone lymphoma? Is it as effective as it is for follicular lymphoma?
Dr. Gilles Salles:
Yeah, so the data regarding lenalidomide and rituximab derived from, I think, the AUGMENT study, which was a study comparing rituximab single agent vs rituximab-lenalidomide, which was overall very positive favoring the combination. I think there are probably data from the observational study MAXIMA or something like that confirming these results.
After that, we have to dive into subgroups. And when we look at the patients with marginal zone lymphoma, it's a little bit unclear if they have achieved exactly the same benefit as the ones that the patient with follicular lymphoma achieved. So I'm not really a fan of this combination personally in patient with marginal zone lymphoma, but I think it's an acceptable option, and the proof is that your patient actually achieve a PET CR. Whether we will have achieved a PET CR with rituximab alone, I don't know, and it's possible.
I should say that, in this disease, data recently in the first-line setting suggesting that it's important to achieve a CR, I will be a little bit less eager to absolutely achieve a CR with a second or third-line therapy. There is often residual disease, and it's a low IVDT for glucose and FDG glucose, so sometimes there is a gray zone in the response. So I will say containing the disease, containing the symptoms is something that is also one of the goal for the disease, obviously depending on the age and on the context of the patient. But I think you made a good choice because the patient achieved a CR. Yeah, it works. Whether it has the similar efficacy as the one we observe in follicular lymphoma, I don't think so.
Dr. Laurie Sehn:
So he did ultimately get a CR, but now my worry is, this is a gentleman who I had been sort of randomly doing a surveillance CT scan, picked up his evolving disease. And I guess the question is, Soni, how often do you perform surveillance imaging in a patient like this?
Dr. Sonali Smith:
Yeah, I think this is a really important question and one that we struggle with in clinic all the time. We know that in curative intent settings such as diffuse large B-cell lymphoma and Hodgkin's, there is really no role for routine surveillance once people have had a complete metabolic response. In the indolent lymphomas, it's not so clear-cut. And I often will do very close clinical surveillance, and if somebody looks well, feels well, has normal labs in a normal exam, I'll kind of buy more time and say, "Okay, let's see how you're doing next time."
However, in this case, I agree with you. I mean, this was an unusual initial presentation with extranodal bladder involvement and not a very easy area to examine. And so I typically do a scan maybe every few years just to have a benchmark, if you will, of where things stand. And often, even if I do see increasing adenopathy, we don't act on it. Although, in this case, given the size, I think that was the right thing to do.
Dr. Laurie Sehn:
Yeah, I agree. I struggle as well. It's that balance between trying not to overexpose patients to unnecessary radiation with the imaging tests, which are often very stressful for them to go under as well. But I think this is the one patient where I would be a little more careful, because his disease wasn't palpable and is sort of insidiously growing, but I probably would try not to repeat it more than an annual basis at most and try and stretch them out beyond that if possible.
So he did obtain a CR, but unfortunately, in January of this year, he now has evidence of progression of disease, again picked up on a surveillance CT scan. This time, he has disease above and below the diaphragm. Largest mass is in the pelvis measuring 12 cm, and SUVmax is 11. LDH is still normal. Gilles, do we have to worry about transformation in this patient? Is the rate of transformation that we always talk about, that risk in follicular lymphoma, is it the same for marginal zone lymphoma?
Dr. Gilles Salles:
Yeah, I think the data out are maybe a little bit conflicting, but I will say, yes, you have always to worry about transformation. Like in any low-grade indolent disease, transformation to a high-grade malignancy can occur. The definition of transformation, probably in some cases marginal zone is a little bit more complex with increased number of large-cell result really meeting the criteria of diffuse large B-cell. But you have always to consider that, because this will be an indication obviously to change eventually treatment. So I will always do a biopsy, which I will do at any recurrence of disease probably in any patient with indolent lymphoma or aggressive lymphoma.
Regarding the exact rate of transformation, I think we are also in a rate of 1% to 2% per year per patients. I think predictive factors were associated with the presence of two extranodal site of the disease, if I recall well, probably also shorter intervals. So I think this patient is a little bit intermediate, but I think given the size of the tumor, I will be concerned. So yes, it exists. My impression, because I probably see patient with smaller volume of disease, is that it's lower than in follicular lymphoma, but I think data are all suggesting it's quite similar rate.
Dr. Laurie Sehn:
So I was concerned, and we did go ahead and perform a core biopsy from the pelvic mass, which did confirm persistence of marginal zone lymphoma only. So moving on to his next line of therapy, I was considering my options. And certainly, he's had chemoimmunotherapy, he's had lenalidomide and rituximab, and I was thinking toward a BTK inhibitor as a possible next step. Soni, what do you think the role is for BTK inhibitors in marginal zone lymphoma?
Dr. Sonali Smith:
Yeah, so one of the challenges with marginal zone lymphoma is that it is relatively less common and has much more heterogeneity in terms of its clinical presentation and the subtypes, and that is translated to there being a real dearth of trials dedicated to marginal zone lymphoma and very few randomized trials. Often, they are just sort of a cohort, as Gilles said, of another larger study for follicular.
All of that being said, in the last several years, we've had an increasing attention paid to marginal zone lymphoma from a clinical trial perspective, and there is a very nice study looking at zanubrutinib monotherapy for patients who have marginal zone lymphoma. And zanubrutinib, as sort of a next-generation covalent BTK inhibitor, is well-tolerated. The efficacy in a very heavily pretreated relapse refractory setting is above 40%. And the CR rate is a little bit lower, but again, as Gilles said, the goal in this disease is really to sort of manage symptoms and you don't always have to keep pushing to get a CR. And certainly, for third-line management, that would be my standard go-to right now.
Dr. Laurie Sehn:
So maybe I'll ask you this, Gilles, but there's quite a bit of data on the presence of MYD88 mutations in, for example, lymphoplasmacytic lymphoma or Waldenstrom's and the correlation with response to BTK inhibitors. I've actually never seen that data when it comes to marginal zone lymphoma. Is it important to ask your pathologist to test for MYD88, and does it influence the likelihood of response to a BTK inhibitor here in marginal zone lymphoma?
Dr. Gilles Salles:
I think the frequency of MYD88 in true marginal zone lymphoma is much lower than it is in lymphoplasmacytic lymphoma, where it's the hallmark of the disease. So that case is reported probably less than 5% and I don't think it predicts the efficacy of BTK inhibitor. In a phase II study that was performed with another BTK, the first-generation ibrutinib, there is a paper published by my colleague, Dr. Noy, indicating that some of the mutations that are encountered in this disease which involves pathway of NF-KB and others might be associated with less efficacy. We don't routinely take that into consideration for treating patients because we don't have many options.
And that brings us back to, what are the options for this patient? Rituximab single agent, when the patient relapsed quite shortly after BR, is not really a fantastic option. Repeating chemotherapy or immunochemotherapy, CDP, CHOP, mini-CHOP will not be really great and not very well tolerated. So I think having these options of using BTK inhibitors is really what we look for. And it's really a question of choosing the right BTK. And I will agree with Soni, I will choose the zanubrutinib. I think it's a good efficacy-side effect ratio, and I will go for that, and patients will stay maybe a few years. Unfortunately, after that, at some point, the patient may progress and you have to think about other options, but they are narrowed.
Dr. Laurie Sehn:
Is CAR T-cell therapy an option right now?
Dr. Gilles Salles:
Yeah, at present time, axi-cel is part of the NCCN guidelines. This patient is not that young and axi-cel is not the easiest tolerated CAR T, but there are clinical trials, and eventually you can try to access for other CAR T. I don't know what's your experience, Soni, in this field?
Dr. Sonali Smith:
Yeah. No, I was going to... First of all, I misspoke about the response rate to zanubrutinib. It's closer to 70% or 80% and not 40%, so I just want to clarify that. But when it comes to CAR T, when those trials were initially presented, it looked as if there was going to be less efficacy with CAR T in marginal zone lymphoma, and I thought, okay, this may not go forward. However, with longer follow-up and with more patients, I think there's actually a very nice response rate and some durable remissions. And so, although it's not FDA-approved, we have certainly considered that for several patients and gone ahead if we've gotten insurance approval with that approach.
Dr. Laurie Sehn:
Yeah, I would agree. I mean, I think the recent 5-year data that we saw actually suggests the marginal zone lymphoma patients might actually have similar benefit from CAR T. But with that in mind right now and what we have on the table for this patient, we actually did choose to go forward with zanubrutinib, which he has just started, so I'll have to keep you posted on that, but I'm optimistic, hopefully, that he'll have good benefit. And I think at the time of his next therapy, I probably would be considering CAR T-cell therapy, and hopefully we'll have even more information on that option by the time he needs to consider his next treatment.
So with that, just a few key clinical takeaways. Nodal marginal zone lymphoma is less common, of course, than follicular lymphoma, but typically has a similar pattern of relapsing disease. Transformation to aggressive lymphoma can occur, so repeat biopsies should be considered if transformation is suspected. Due to its rarity, the optimal treatment approach is not well-defined, and so I think having clinical discussions with colleagues and presenting these patients in interdisciplinary conferences is often very helpful. We know that lenalidomide and rituximab as well as BTK inhibitors such as zanubrutinib have shown efficacy and are approved for relapsed/refractory marginal zone lymphoma. And CAR T-cell therapy has also shown efficacy, not currently FDA approved, but certainly we're also looking at alternative options for patients like this. And unfortunately, right now, we have very limited data on bispecific antibodies, but there are active clinical trials going on with numerous novel approaches, including bispecific antibodies, and a clinical trial should always be considered at the time of next treatment for patients.
So this brings us to the end of this case. Please see the other segments for further discussion about the latest research in lymphoma or visit ascopost.com.
