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 fantastic colleagues and lymphoma experts.
Dr. Carla Casulo:
Hi. I'm Carla Casulo. I'm an Associate Professor at the University of Rochester, the Wilmot Cancer Institute, and thank you so much for the invitation.
Dr. Elizabeth Budde:
Hi, I'm Dr. Elizabeth Budde, I'm a hematologist focused on hematology and transplant from City of Hope Medical Center. Very glad to be here today.
Dr. Evens:
Great. Today we will be discussing the treatment and management of follicular lymphoma with three patient case studies. Our second installment will focus on relapsed follicular lymphoma with POD-24.
Mr. JH is a 71-year-old fit, White man who presented initially with increasing generalized fatigue and was found to have diffuse lymphadenopathy. Initially an FNA was done, which showed a monomorphic population consisting of a CD10/CD20-positive B-cell lymphoma. He ended up having an excisional lymph node biopsy and a hernia repair during that. That showed follicular lymphoma grade 1/2 out of 3. A staging PET scan at that time showed multifocal hypermetabolic lesions with pretty extensive foci throughout the neck, carotid, submandibular glands, mediastinum, pleural-based, as well as abdominal pelvic disease with the largest up to 6.1 cm, and SUV maxes ranging from 6.0 to 8.7.
He initially received bendamustine and rituximab induction therapy for six cycles, with full dose and supportive care measures, which he tolerated well, and entered a metabolic complete remission at end of therapy PET imaging. It was decided not to give rituximab maintenance. Despite that excellent response, only eight months later or 16 months after his initial diagnosis, he presented with swelling of his right eyelid that was fairly rapid in onset.
As you can see on the right, on the coronal MRI of the orbit, he had an ovoid mass involving the right inferior orbital preseptal soft tissue of the right lower eyelid measuring up to 2.3 cm. On imaging PET scan and on physical exam, he had multiple soft tissue lesions, some of which were painful, some were painless. But as you can see on the sagittal PET scan on the lower right, they were hypermetabolic throughout the soft tissue. This one in particular showing in his upper back as well as other areas that are listed here with an SUV max of 7.7.
So if we step back for a minute and think about the title of this, Dr. Casulo, can you tell us first about the meaning and implication of the term POD-24?
Dr. Casulo:
Sure. So POD-24 stands for progression of disease within 24 months. And it's really a classification to signify someone who relapses what we call “early”. And that was based on work we did several years ago now looking at patients who, really the idea was, looking at patients who relapsed earlier than the average. And on average, if you look at most patients with follicular lymphoma after first-line treatment, the average remission is around 3 to 5 years. So there were many studies that were consistently demonstrating that a subset of patients, and consistently around 20%, had a recurrence that happened earlier than that. So that's where the designation of progression of disease within 24 months came about.
And within a research study that we led looking at the survival implications of that early recurrence, we discovered that patients that have that early recurrence have a poor survival compared to those who did not relapse within the 24 months. So we found that survival was 50% at 5 years if someone relapsed within 24 months compared to 90% if they didn't. So that observation has been repeated in multiple other studies and in pooled clinical trials, with some variability but the general gist of it is that we can conclude that those patients do poorly.
And so what we've come to think about is that is this really kind of a surrogate for biology that there's something about this biologically that makes people relapse early. So that's really what we mean when we say POD-24 and what the prognostic implications of it are.
Dr. Evens:
Dr. Casulo, yes you and your group have done a fantastic job at not only the initial observation and publication, but as you alluded to, those follow-up confirmatory analyses that have shown that. Can you also talk about the risk of within that, those 15% to 20% of cases of possible transformation to an aggressive lymphoma?
Dr. Casulo:
Right. So it is possible that some of the drivers of this early recurrence is transformation to diffuse large B-cell lymphoma, which is why it's really important to get a biopsy. Depending on the literature, it could be as low as 30% to 50% of patients may have transformation. So it's really important to assess that with a biopsy. There's some literature that suggests it's higher, but it's unclear whether that's the case. Whether or not someone though has early transformation or early relapse of follicular lymphoma, their outcomes are still equally poor.
So I think it's still a high-risk population of patients. But because we would treat someone differently if they were transformed, I think it's really important to have a biopsy to know exactly what we're dealing with and perhaps put them on a clinical trial if there's one available.
Dr. Evens:
And Dr. Budde, I'm sure you agree and this is something you look out for, because we don't know really who are those patients with POD-24? Obviously there's some really good science ongoing to see, can we understand that earlier? Is that something you're looking out for to make sure you catch and understand that?
Dr. Budde:
Definitely. I think POD-24, as we discussed, definitely carries much higher risks of transformation and this patient has a poor prognosis. So I would always in this particular patient we let the PET scan show the highest SUV, maximum was around 7.7. So that's a little bit reassuring, but PET scan does not equal to a biopsy.
Dr. Evens:
So just as you guys are indicating, yes a biopsy was done in this case. And he obviously had that superficial, so to speak, soft tissue disease. And that happened to be the highest SUV. And it did interestingly still show follicular lymphoma. And the Ki-67 was interestingly still relatively low and the phenotype is what we would expect. And the final diagnosis on the repeat biopsy did show follicular lymphoma grade 3a as we would fit into that definition of POD-24.
And so transitioning to thinking about treatment options, and he is now about 73, still very fit, maybe performance status 1 due to some of the symptoms associated with the lesion under his eye and the cutaneous disease. What are, Dr. Casulo, some things of initial options for such a case you would think about?
Dr. Casulo:
So this is an area of ongoing investigation right now, there's no established treatment options for someone with the designation of early recurrence. But there's a lot of clinical trials seeking to explore what treatments may be best for those patients. So there's one national comprehensive cancer center trial from the SWOG Institute which is looking at a randomization between obinutuzumab and chemotherapy or lenalidomide for those patients. So that's an option potentially, if that's available. However, there are other options that he may qualify for.
But outside of a clinical trial, I think that really similar options that we've discussed earlier could be considered. Lenalidomide with rituximab could be considered. Other things could be, for example, if he had another line of therapy, then we could have considered bispecific antibody or a CD19 CAR T-cell therapy. But technically, with only one prior line of therapy, outside of a clinical trial I don't think that he would be approved for that, because that's not the FDA label currently.
But I think honestly what we know is that any treatment is possible because we don't have a standard right now. So that's sort of where the field is right now, but again I think the clinical trials are the way to go.
Dr. Evens:
Dr. Budde, let me get your thoughts and just I'll couch it with, knowing that City of Hope is a big transplant center, so I'm sure that won't influence your thoughts here, but he is 73, so does that enter the calculus at all in terms of I know with new targeted therapies we've really started to elucidate here, is that still an option, a possible autologous stem cell transplant?
Dr. Budde:
Yeah, so a really good question. Autologous stem cell transplant I think has been probably the best way to get this kind of patient into a prolonged progression-free survival. But there's really no overall survival benefit. So traditionally what we do in such a patient would be giving them another salvage treatment and patient gets into remission and go to autologous stem cell transplant. So his age, 73-year-old, that's really not a major determinant that he's not a transplant candidate.
But we know that there are CAR-Ts and bispecific antibodies already approved in the third-line setting. So in this particular patient, a patient like him with POD-24, for third-line above option, we have very good regimens. So my practice these days is really I'm doing much less transplant. In this patient I would consider a second-line treatment, nontransplant based treatment probably as a bridge to the next one, which is a more definitive treatment.
Dr. Evens:
Yeah, that's right. And he is in that kind of donut whole you could say where he's second line and officially bispecific antibodies and CAR-T by the letter of the law are not FDA approved. And Dr. Casulo, like you highlighted, such an unmet need. Clinical trials should really be the top of the list. Could you just give your thoughts and stance? I know there was a publication that albeit in a retrospective manner, it looked like autologous stem cell transplant may have a role for the right patient with POD-24. What are your thoughts?
Dr. Casulo:
Right. So this was something that we looked at through the CIBMTR and had the control comparator be the National LymphoCare Study. So about 500 or so patients, again as you said retrospective. And it showed that there was a progression-free survival benefit, and if done early an overall survival benefit in patients who had early recurrence. Some other studies have observed similar findings. But I think that as Dr. Budde alluded, in the setting of bispecifics and CAR-T, I'm not seeing as many patients referred for autologous transplant as much anymore because we have novel therapies that are supplementing it.
So perhaps it will be falling out of style as a modality. But not something that you could eliminate altogether because there are many studies showing that long-term follow-up you may even cure a subset of patients if they never relapse after 10 or 15 years, theoretically that could be something that's desirable and appealing.
Dr. Evens:
And Dr. Budde, just to finalize here, so he's right on the border of being rituximab-refractory. It was 8 months officially afterwards. But if you were going to choose lenalidomide, I'm curious have you ever mix-matched antibodies and used obinutuzumab with lenalidomide or you would just go back to R-squared, so to speak?
Dr. Budde:
My practice no, I usually would just go back to R-squared. But I have... It require a good conversation with the patient. So sometimes I do offer obinutuzumab in addition to lenalidomide.
Dr. Evens:
Dr. Casulo, what are your thoughts?
Dr. Casulo:
Yes, definitely I do as well. I think with the rituximab refractory, I probably would be more likely to offer the obinutuzumab. It is a little bit more toxic, there's more infusion reactions I find and more thrombocytopenia. So I think that that's something to look out for. But in general I do and because we have this clinical trial that's looking at that combination, that tends to be the direction that we are leaning towards. But rituximab is certainly reasonable as well.
Dr. Evens:
Great discussion. So in terms of key clinical takeaways, early follicular lymphoma relapse, defined as progression within 24 months of frontline therapy, aka POD-24, has been known in multiple studies to occur in approximately 20% of patients. Within that subset, 20% to 40% of these patients with POD-24 may have transformed disease, especially due to diffuse large B-cell lymphoma. Yes, PET scans in particular, high SUVs can be indicative of that, but of course a biopsy is diagnostic to rule that out and indicated in most cases. And we know unfortunately the 5-year overall survivor rates are markedly inferior for patients with POD-24, upwards of 40%, 50% percentage points worse at the 5-year mark.
And this is a critical unmet need. Optimum therapy for POD-24 is not known, thankfully there are some clinical trials and we have novel targeted agents that should be thought of. And of course, more biologic and therapeutic studies are critically needed in POD-24.
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.
