Cancer Topics - New Therapies for Lymphoma (Part 2)

In the second part of this ASCO Education Podcast episode, Dr. Sonali Smith (University of Chicago Medicine) and Dr. Paolo Strati (MD Anderson Cancer Center) discuss the application of new therapies for mantle cell lymphoma and follicular lymphoma through examination of challenging patient cases.

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Air Date: 11/15/21

 

TRANSCRIPT

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SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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SONALI SMITH: Hello, and welcome to part 2 of ASCO Education Podcast on New Therapies for Lymphoma. My name is Dr. Sonali Smith, and I'm a hematologist and medical oncologist specializing in lymphoma and clinical trials for lymphoma. I am also the Elwood V. Jensen professor and chief of the Hematology and Oncology section at the University of Chicago.

PAOLO STRATI: Hello to everybody. I'm Dr. Paolo Strati. I'm a hematologist, and medical oncologist, and assistant professor in the Department of Lymphoma and Myeloma and in the Department of Translational and Molecular Pathology at the University of Texas MD Anderson Cancer Center in Houston, Texas. In part one of this podcast episode, we discuss recently approved therapies for diffuse large B-cell lymphoma. And today, we will be exploring instead new therapies for follicular lymphoma and new therapies for mantle cell lymphoma.

SONALI SMITH: Wonderful. So we are going to start off today with a discussion about a patient case. The individual is a 55-year-old woman with previously untreated follicular lymphoma, low-grade advanced stage, and low tumor burden, and low FLIPI. She was diagnosed three years ago and had observation but more recently developed a 7-centimeter retroperitoneal mass with impending ureteral compression and no PET/C concern for transformation, specifically with an SUVmax of 5.3.

Despite this radiological finding, the patient had a performance status of 0, no symptoms, no significant comorbid health conditions, and was given R-CHOP time six cycles, followed by achievement of a CR. She was then observed, but, unfortunately, 18 months later, the PET/C showed diffuse low FDG-uptake adenopathy, and a lymph-node biopsy was repeated. This showed a follicular-lymphoma relapse.

So Dr. Strati, tell us a little bit about your approach to follicular lymphoma in the initial setting. Do you consider GELF criteria? And how do you select second-line therapy in this patient? Does the early progression of disease within 18 months-- she falls into the category of POD24, or the Progression Of Disease 24 months-- how does this affect your treatment choice going forward?

PAOLO STRATI: Thank you, Dr. Smith. Those are all very good questions. So going to your first question-- we typically use GELF criteria, as you know, developed in France now many years ago, most of the time of initial diagnosis. And that's to determine whether a follicular-lymphoma patient does, indeed, have an indication for treatment.

And this criteria, as you know, are based on lymph node size and number, oragnomegaly, cytopenia. However, it's still debated whether this should also be applied at time of relapse. And in this particular case, the patient, as you said, had what we call a POD24, or progression of disease within 24 months from initiation of chemoimmunotherapy.

Given the suboptimal outcome of these patients, I think that it will not be unreasonable to treat these patients even if they don't formally meet GELF criteria-- so even if they don't have formal indication for treatment at time of relapse. Once the decision is made, standard second-line options for patients with follicular lymphoma currently include chemoimmunotherapy

So if the patient received R-CHOP in frontline, it would be BR. But if they receive BR in frontline, of course, R-CHOP, but also, immunotherapy with R-squared-- so Rituximab, Revlimid-- or lenalidomide, a single-agent anti-CD20 monoclonal antibody, obinutuzumab, which is specifically approved by the FDA in the United States for rituximab-refractory follicular-lymphoma patients, and in very selected cases-- and this is still open for debate-- a high-dose chemo with a platinum-based agent followed by autologous stem-cell transplant.

We don't know at this time what's the ideal second-line strategy for patients like the one that you described in your case-- so a follicular-lymphoma patient with POD24. And to this regard, all are very eagerly awaiting the results of an ongoing SWOG trial, 1608, which is a randomized phase II study comparing in second-line chemoimmunotherapy, immunotherapy, and also, [INAUDIBLE] kinase inhibitor for this patient with POD24.

Finally, one thing which I think is important to consider is that even if R-squared is not currently approved by the FDA in the frontline setting in the United States and, actually, is not approved at all in Canada, in Europe as a frontline treatment, in the United States, it's possible to use it in frontline thanks to existing guidelines. And over the last few years, its frontline use in our country has actually meaningfully increased.

This is creating a new clinical scenario that we never met before. And there are no standard second-line options currently established for these patients, patients who receive frontline R-squared, emphasizing the need of translational research to understand more of the biology of patients who relapse after frontline R-squared but also, emphasizing the need to mostly look into clinical trials when these patients, unfortunately, experience a relapse.

SONALI SMITH: Yes, thank you, Dr. Strati. I agree. I think that it is the way that frontline follicular lymphoma and in the relapsed setting exists is that we have a toolbox and no real clear data on how to personalize the therapy. So your comment about needing some better translational work to fine-tune the clinical trials is really important.

So for this patient, though, she did receive R-squared for 12 cycles and achieved a complete remission after six cycles. 12 months later, a PET/CT showed diffuse, low-level adenopathy, "low level" meaning low uptake on a PET scan. And she had another lymph-node biopsy. This showed persistent follicular lymphoma. So now how do you select your third-line option knowing that we have biologic therapy, as well as cellular therapy, available to this patient?

PAOLO STRATI: So going back to the metaphor that I used before, we have a very nice toolbox, often third-line. But also, in third-line, there's really no strong, robust translational data to drive us when it comes to treatment selection. Agents currently approved by the FDA in the United States as a third-line standard option for patients with relapsed/refractory follicular lymphoma include, as you alluded, [INAUDIBLE] kinase inhibitors, currently three-- copanlisib, duvelisib, and idelalisib, and an EZH2 inhibitor called tazemetostat.

The three [INAUDIBLE] kinase inhibitors currently approved in third line have very similar efficacy with a response rate of 50% and a median progression-free survival of about 10 months. And the selection among the three is typically based on toxicity profile, which is more on the autoimmune side for duvelisib and idelalisib and more on the metabolic side with hyperglycemia and hypertension for copanlisib.

Also, one element that, in my experience, is typically used to select one of these three is the route and the frequency of administration because we have to remember that idelalisib and duvelisib are both given orally twice a day, whereas copanlisib is given intravenously three times a month. And so, of course, different patients may have different preferences.

As a matter of fact, though, the use of [INAUDIBLE] kinase inhibitors for relapsed follicular lymphoma in the United States and I would say, also, in other countries, is quite limited, mostly due to toxicity and relatively limited efficacy. Tazemetostat, the EZH2 H2 inhibitor that I mentioned previously, has a response rate that can vary between 30% and up to 70%, significantly higher in patients who do have a documented EZH2 mutation. But the median progression-free survival is about a year, no matter whether the mutation is present-- so not that different from [INAUDIBLE] kinase inhibitors in the same setting.

Of interest, given the short duration of response, we may consider these agents as a bridging therapy for follicular-lymphoma patients. We [INAUDIBLE] proceed with CAR T-cell therapy because, as you mentioned in your question, CAR T-cell therapy, and specifically, Axi-cel, has been recently approved by the FDA as a third-line option for patients with relapsed/refractory follicular lymphoma based on results from the ZUMA-5 study.

It's important, however, to emphasize that Axi-cel has shown better efficacy and safety data in follicular-lymphoma patients as compared to large B-cell lymphoma patients than we discussed in the previous episode of this podcast. And, as such, Axi-cel may potentially represent a curative option for patients with follicular lymphoma, a condition that, historically, has been considered incurable.

Tisa-cel and other CAR T-cell products targeting CD19 currently approved by the FDA for large B-cell lymphoma but not yet for follicular lymphoma, may also be soon approved by the FDA for patients with follicular lymphoma based on the ELARA study. And we're all eagerly awaiting the results of this study and, potentially, its approval in the next few months.

SONALI SMITH: That's great to hear. And, hopefully, we will continue to have more options, including more cellular-therapy options for patients. So this particular patient proceeded with the standard of care Axi-cel. That went quite well.

There was only grade 1 cytokine release syndrome, no neurotoxicity. And the patient achieved a complete remission on both the day-30 and the day-90 PET/CT. Unfortunately, there was relapsed six months later. So what standard options are there at this time? And would you consider an allogeneic stem-cell transplant at this point?

PAOLO STRATI: So I have to say that, based on some of my data, I'm not surprised this patient did quite well in terms of safety, and I'm very sorry to hear that was one of those few patients who relapsed after an initial complete remission after Axi-cel. In fourth line, our options are a little bit more limited. The FDA has recently approved in fourth line, for patients with relapsed/refractory follicular lymphoma, a new [INAUDIBLE] kinase inhibitor called umbralisib.

[INAUDIBLE] umbralisib response rate is quite similar to other [INAUDIBLE] kinase inhibitors, about 50%. However, the median progression-free survival that, as I mentioned before, is about 10 months for the [INAUDIBLE] kinase inhibitors currently improving third line instead has not be reached yet two years for umbralisib. And also, the toxicity profile seems to be more limited, similarly to idelalisib and duvelisib, more on the autoimmune side. Therefore, definitely umbralisib would be an interesting option for the patient case that you described.

As for your second question, the possibility to use allogeneic stem-cell transplant for patients with relapsed/refractory follicular lymphoma, retrospective studies have shown the allogeneic transplant is effective in follicular-lymphoma patients, particularly those with POD24, like the patient you described in the scenario.

But the transfer-related mortality is significant and needs to be taken into consideration. But most important of all, as CAR T-cell therapy has been approved for follicular lymphoma very recently, we really have no data regarding the use of allogeneic stem-cell transplant in follicular-lymphoma patients who relapse or progress after Axi-cel and CAR T-cell therapy in general.

This last statement really applies to any approach as, again, Axi-cel has been approved for follicular lymphoma only within the last 12 months. And this, once again, emphasizes the importance of translational research and clinical trials for these patients. And as such, I think that, along with umbralisib, there is a standard option. Clinical trial's definitely the best option for patients with follicular lymphoma whose disease is either refractory or relapses after CAR T-cell therapy.

SONALI SMITH: Yes. Thank you for these insights, Dr. Strati. I agree. The post cellular therapy, or the post CAR-T space is a very challenging situation, and I appreciate your perspectives. So as an update, this patient received umbralisib for six months and had an initial response with a partial remission but eventually progressed and then proceeded to a clinical trial, now on a novel oral-immunomodulatory agent and has been in a complete remission for four months.

PAOLO STRATI: That's great to hear. And I hope that this remission will be durable, emphasizing, again, the importance of clinical trials for patients with lymphoma in general, and particularly, those who relapse or are refractory to standard treatments. It was very interesting to listen to this case. Thank you for asking your question, Dr. Smith.

I'm going to ask your opinion now about a second case. This is a 67-year-old man with diabetes that has a long-lasting history of rectal bleeding, for which he underwent a colonoscopy in 2016 that revealed hemorrhoids and scattered polyps that were not malignant on biopsy. However, as part of routine follow-up, a colonoscopy was repeated five years later, and this, unfortunately, showed diffuse nodularity of the colon with several areas of ulceration. Biopsy of the nodules showed a mature B-cell lymphoma, CD20 positive, CD5 positive, BCL2 positive, SOX11 positive, but negative for CD10.

FISH testing confirmed a translocation 11;14. There was no evidence of TP53 mutation, and Ki-67 was 40%. So Dr. Smith, what do you think about the overall potential histological diagnosis? And how do you approach this patient in terms of staging and prognosis discussion?

SONALI SMITH: Yes, so this poor patient, with long-standing rectal bleeding-- I mean, this can happen. It's not a very common presentation for mantle cell lymphoma, but we know that mantle cell lymphoma is very likely to involve the GI tract and can often be extranodal.

In terms of the histology itself, this is very classic. The co-expression of CD20 along with CD5 is only seen in CLL and mantle cell lymphoma. And in this case, the mantle cell lymphoma's confirmed by SOX11 positivity, CD10 negativity, and then, also, of course, the FISH [INAUDIBLE] translocation of 11;14 with a cyclin-D1 overexpression.

When it comes to prognosis in mantle cell lymphoma, there's a number of different prognostic indices, but the two biologic features that I think are most important are P53 status, as well as the proliferation rate. Patients who have a TP53 mutation typically have chemo-resistant disease. And we have no really good approach in terms of how to treat these patients the best.

PAOLO STRATI: Thank you, Dr. Smith, for outlining the diagnostic and prognostic approach to patients with mantle cell lymphoma. You alluded in your answer about the regenerative treatments, so I wanted to ask you, how do you, in general, treat patients with mantle cell lymphoma and, more specifically, this case. And also, we keep dividing patients with mantle cell lymphoma in transplant-eligible and ineligible, but the big question is, do all patients who are transplant-eligible need transplant? And what's year overall approach to this major dilemma?

SONALI SMITH: Yes. That's a really good question. The general approach to treatment for mantle cell lymphoma is based on the concept of fitness and age. So we end up dichotomozing patients into one of two groups. They are either young and fit, or they are older and unfit.

And, of course, this is somewhat controversial because age itself is just a number, and there is significant variability based on function and other medical conditions. Complicating that further is that many clinical trials have used 65 as the arbitrary cutoff between young and old, whereas some transplant studies have actually gone all the way up to age 70. So if I focus on the fact that this is a 67-year-old man who has no real significant history and clearly has a disease that needs treatment, my general approach has been to follow the younger-and-fit approach.

And as you mentioned, the historical approach to this has been to think of treatment in three phases. There is induction, there's consolidation with a high-dose chemotherapy and autologous stem-cell transplant, and then there is maintenance rituximab for three years, which has been shown to have a survival advantage. But your question-- I think there are many unanswered areas when it comes to approaching a patient who is going to be treated with an aggressive multimodality approach.

So first, in terms of the induction itself, there is data that cytarabine-based regimens likely achieve a deeper minimal residual disease state than aklylator-based therapy. And so cytarabine-containing regimens have really become the standard of care against which other regimens are compared. That being said, there was at least a SWOG study that randomized patients between BR and hyper-CVAD and found that BR was a sufficient type of induction.

And some of this controversy led to an ongoing Intergroup trial, which is EA4181, that takes patients with newly diagnosed mantle cell lymphoma, previously untreated, like our patient, and randomizes them to bendamustine, rituximab with or without cytarabine and with or without a BTK inhibitor, in this case, acalabrutinib. So outside of a clinical trial, I would use a h based induction regimen, but I have preferred to put most patients onto that.

But your second question, which is, do all patients need high-dose chemotherapy and autologous stem-cell transplant, is really important. This is associated with a need for inpatient admission, high-dose chemotherapy with subsequent late toxicity. And remembering that mantle cell lymphoma remains an incurable disease, the question is whether or not all patients should get this.

So to address this, there is the EA4151 trial, which is also being done through the United States Intergroup. And this is using a very unique minimal residual-disease assay to randomize patients to either transplant plus maintenance or maintenance alone. And so this is a next-generation sequencing test. And if patients have a negative MRD status at a very deep level, then patients will get randomized to one of those two arms, whereas if they have minimal residual disease that is detectable, then they will go ahead and get the standard of care.

So for this patient, he opted to be on the clinical trial and was randomized to BR, plus cytarabine, plus acalabrutinib. But outside of a trial, I really would have considered intensive induction, including the Nordic regimen that includes high-dose cytarabine, followed by transplant and maintenance rituximab.

Now some may argue with me that this person is 67 years old, and the Nordic regimen is quite intense. And I think this is where some of the art of medicine may come in. And, hopefully, we can have some type of assessment tools to better predict who can tolerate intensive induction. But I'm quite impressed by some of the transplant data that do lead to seven- and 10-year remissions in some cases. Of course, this new trial will tell us whether or not we're overtreating many of the patients, particularly based on their MRD status.

PAOLO STRATI: Thank you, Dr. Smith. It was very helpful. I think you outlined really well how challenging it can be to treat patients with mantle cell lymphoma and how important it is to tailor treatment based on biological but also, patient-related data.

This is all that we have for today. Thank you, Dr. Smith, for a very delightful conversation. It's been very helpful to review together today the treatment of patients with follicular lymphoma, and mantle-cell lymphoma, and safety and efficacy of novel therapies for these patients.

Thanks, everybody. And, particularly, thank you to all the listeners who tune in to this episode of the ASCO Education Podcast. And thank you, Dr. Smith, for your time.

SONALI SMITH: Thank you. It was such a pleasure to have this conversation today.

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