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:
Hi, I am Carla Casulo. I'm an Associate Professor at the University of Rochester at the Wilmot Cancer Institute, and thank you for having me.
Dr. Elizabeth Budde:
Hi, my name is Elizabeth Budde. I'm a hematologist from City of Hope National Medical Center. Thank you for having me today.
Dr. Evens:
Great. Today we will be discussing the treatment and management of follicular lymphoma with three patient case studies. Our first installment will focus on follicular lymphoma in the second-line setting in a patient with multiple comorbidities.
Mr. HS is a 69-year-old Asian man who noticed initially increasing growth of lymphadenopathy in his left groin over several months that was causing some pressure. He initially sought care by his primary care physician and was referred for imaging. As you can see on the left, he had left inguinal confluent nodal adenopathy measuring up to 7.5 by 5.5 cm with also other multifocal abdominal pelvic lymphadenopathy.
The patient had an excisional lymph node biopsy showing follicular lymphoma, grade 1/2 out of 3 with a follicular pattern and a relatively low Ki-67 proliferation rate of 5% to 10%. At this time, his ECOG performance status was 1 and he had multiple, mostly stable, comorbidities including dilated cardiomyopathy with an ejection fraction of 40 to 45%, history of cardiac arrhythmia, diabetes, hypertension, and a history of pulmonary embolism. Adding up his comorbidity score using the CIRS-G scale equaled 12. His laboratory data besides elevated random glucose, was fairly normal, including LDH and beta-2 microglobulin. At that time, at an outside center he received single-agent rituximab therapy and achieved a metabolic complete remission. He was then given 2 years of maintenance rituximab, one dose every 2 months, and did well during this time.
Overall, from initial treatment, his remission was maintained for 4 years. However, about a year and a half after his last rituximab, there was notation of new symptoms. He presented with really, over about a 2-month period, right leg swelling. A Doppler ultrasound was done, which was negative for deep vein thrombosis. This was followed up by imaging, which you can see in a coronal PET/CT scan, showed a new large right peritoneal mass. It looked to be abutting his right psoas, and likely causing compressive physiology encasing his iliac vessels and ureter.
So at this point, I'd like to open it up to my colleagues of the importance and timing, obviously individualized, of biopsy and tissue in follicular lymphoma. Dr. Casulo, any thoughts?
Dr. Casulo:
Yes. Interesting case and definitely something that we come across frequently. So some of the favorable things for him are that he's had a long remission duration, which I think many have shown that is a favorable finding if patients have late recurrence, and he's really only been treated with rituximab, so that's another favorable feature.
He does have these comorbidities, but I think that, that shouldn't preclude us from pursuing a biopsy. I think a biopsy is really important because we have to ascertain whether there's been any transformation, even though, clinically, it seems unlikely. And if we do find that, it would drastically change our management so I think that that's an important consideration.
Dr. Evens:
Dr. Budde, thoughts? Is this something you would also consider, in terms of biopsy?
Dr. Budde:
Absolutely. I think getting a biopsy is extremely important in addition to the reasoning was just mentioned. I think nowadays we are learning so much about lymphoma behavior and there's so many novel treatments, clinical trials, so knowing what the lymphoma is at the relapse stage will help us to better design the next line of treatment.
Dr. Evens:
Yeah, I agree and it's always tricky. Sometimes we'll look at SUV max, but obviously the higher that is, there is an increasing positive predictive value for a transformation, but it's not diagnostic, and as we always say, tissue is the issue, and that is true for follicular lymphoma to be sure.
So he did have a repeat biopsy and consistent, I think, with his clinical history, although reassuring it showed essentially the same follicular lymphoma grade 1/2, although there was a diffuse pattern now, and a little higher Ki-67 up to 20%, and EZH2 mutation testing was done and he did have an EZH2 mutation that may inform treatment options as we move on.
So now he is a 74-year-old man, to recap. No new comorbidities. His creatinine is a little increased, now, up to 1.9. He is on a couple new cardiac medications, although that wasn't for deterioration, he's now on an ARB inhibitor, as you can see, an aldosterone antagonist and other stable medications.
So if we look at this patient, he was only treated with single-agent rituximab. Yes, he has comorbidities and he has a need for treatment, I think we would say, given the swelling, et cetera. What, Dr. Budde, are your initial thoughts on treatment for such a patient, options?
Dr. Budde:
Yeah, I think that this is actually, I think quite those common daily patients we see in the clinic. The elderly patient with some comorbidity, but still reasonably enough to have a treatment that, hopefully, will put him back in remission. And for these patients, the NCCN recommendation is now always try to screen the patient for clinical trials. And so outside of clinical trials, note the patient, this is a second-line use for a biopsy proven follicular lymphoma. Ki-67 is around 20%.
So my first choice in this case will be a nonchemo-based, that will be lenalidomide/rituximab–based regimen.
Dr. Evens:
Yeah, absolutely. And I'm curious, Dr. Casulo, are you just generally thinking about a nonchemotherapy approach or this particular patient, given the comorbidities and his age, are you more hesitant with a bendamustine-based regimen?
Dr. Casulo:
I think that chemotherapy sparing seems appealing because of some of the comorbidities. So we know that bendamustine in patients that are older is associated with a higher risk of T-cell depletion and infectious complications, some of which can be fatal. Granted that's in the first-line setting, but I think that you can extrapolate from that to apply it to the patient in the relapse setting. But bendamustine would be an option, although would not be my first choice. And then an anthracycline for him with his cardiac comorbidities also would be less appealing.
So I think he's someone that would've met the eligibility criteria for the AUGMENT study. He's been treated with immunotherapy and in that study, you only needed to have had one line of treatment. He's not rituximab-refractory, which gives him, again, more of a favorable profile, and you can dose-modify lenalidomide with his renal insufficiency. So I think that, that would be reasonable.
The other consideration would be tazemetostat, as we know that he has the EZH2 mutation and that's a gain-of-function mutation that's found in about 20% of patients with follicular lymphoma. So he is likely to respond to that drug based on his EZH2 mutation. So I think that, that's a well-tolerated drug. Probably the response rate is a little bit less than with lenalidomide, but I think it's still a very good consideration. What would you choose for him? I'm curious.
Dr. Evens:
We ended up choosing lenalidomide and rituximab, but we actually went through exactly the similar discussion, although I think tazometastat, at the time, was not FDA-approved, so that would've been on a clinical trial.
But I think it also brings up a point as we try to individualize therapy, as you guys have aptly done, when we, maybe at least as part of that context, think about endpoints of studies. We talk about response rate, progression-free survival, obviously a holy grail of all cancer, this lymphoma included—which has been hard over the years—is overall survival. And it's really been few and far between, in terms of medications that we've seen that. The early rituximab studies we saw that adding to newly diagnosed garnered that benefit. But would you say, is that something, given the long-term follow-up of the AUGMENT study, Dr. Budde, that you, albeit small, but seeing an overall survival advantage. I would think that's something that sticks out as important?
Dr. Budde:
Exactly. Yeah, I think the 5-year follow-up of that study really confirms the benefit of giving the R-squared, lenalidomide plus rituximab, in this patient population, and looking at the side-effect profile over a longer-term follow, it didn't really bring up more concerning side effects other than some of the little bit more, a few cases more secondary, primary malignancies, but otherwise, no other concerning longer-term side effects. So I think that data with the overall survival benefits definitely further confirms, though, the R-squared is a reasonable regimen.
Dr. Evens:
And Dr. Casulo, you also mentioned about T-cell fidelity, which is so important, especially as we think of great for that response and overall survival. But we think of sequencing and future therapies and immunotherapy may be part of that. Let's say he had received that, let's, maybe, spin it forward just for example purposes, quickly. If he had already received R-squared, would bendamustine in someone in their mid-70s, is that a nonstarter or with appropriate dose reduction supportive care in select patients, would you still consider that?
Dr. Casulo:
I think so, particularly because we know that it is effective and we do have to monitor for hypogammaglobulinemia, we'd have to monitor for infectious complications and the risk of viral infections and things like that. But no, I don't think it would be an absolute deal breaker for someone, particularly someone, as Dr. Budde said, if there is really no option for a clinical trial and they have high–tumor burden follicular lymphoma and they are in need of therapy, it's a very reasonable choice. So it wouldn't be a reason not to offer it, but I think just with caution and with some dose modification, particularly for this individual.
Dr. Evens:
And then Dr. Budde, finally, maybe to round it out on the tolerability aspect, for tazemetostat, if someone was to choose that in this scenario or a different case, what has been your impression in terms of tolerability of that agent?
Dr. Budde:
Well, it's actually pretty well tolerated. I think it has advantage being an oral medication and so it doesn't really require a lot of infusion time, it's easier. It's in patient with even ECOG 2, they can still tolerate. Of course, sometimes I will even give to patient with ECOG 3, which due to lymphoma, and we have seen patients getting this medication can get into a pretty prolonged remission state. The median progression-free survival for this particular patient with the mutation status, it is even better than those patients with wild-type status.
Dr. Evens:
Great. And very lastly in this case, Dr. Casulo, are you guys routinely testing for EZH2, whether or not it was done initially or is it one that you'll trust the initial biopsy if it was done?
Dr. Casulo:
If it wasn't done initially, we would do it at the time of disease recurrence, but I've not come across any data to suggest that there is an evolution in EZH2 status at the time of disease recurrence. So I don't know that we have a reason to suspect that, that would change, but it's an interesting question.
Dr. Evens:
Well that's great. So in terms of clinical takeaways for this case, I think you can see it is apparent that clinical pathologic evaluation is important, including consideration for molecular studies such as EZH2. Also, there are several therapies available for patients in the second line setting of relapsed/refractory follicular lymphoma, including, as was discussed, lenalidomide/rituximab, bendamustine with or without antibodies such as obinutuzumab, other chemotherapy options we didn't discuss, radiation for palliation and that has its place in certain cases. And then also, vis-a-vis the AUGMENT study, phase III placebo-controlled randomized study, there was an overall survival advantage seen in this exact setting as this case. And finally, of course, in all patients, especially older patients with comorbidities, really attention to detail, especially regarding potential toxicity, whether infectious, thrombosis should very closely be examined and managed.
So 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.
