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Novel Therapies for the Treatment of Follicular Lymphoma

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Joshua Brody, MD, Icahn School of Medicine at Mount Sanai; Nathan H. Fowler, MD, University of Texas MD Anderson Cancer Center; John P. Leonard, MD, New York Presbyterian/Weill Cornell Medical Center; Matthew Lunning, DO, University of Nebraska Medical Center; Sonali M. Smith, MD, University of Chicago
Published: Friday, Aug 31, 2018



Transcript: 

Ian W. Flinn, MD, PhD: Let’s talk about the bispecifics, because logistically, it’s expensive. They are customized products for each person, unless you’re going to come up with a universal cell. Sonali, bispecifics are attractive because you’re engaging the T cell. You’re bringing it right in juxtaposition to the lymphoma, forming the synapse. What is your take on that?

Sonali M. Smith, MD: Well, I think, intuitively, it makes a lot of sense, particularly if targeting CD3 can activate the T cell. I don’t pretend to think that it’s that simple, but I do think that bringing the cells in proximity, at least, allows a chance for that type of immune attack to occur. Most of the bispecific antibodies have targeted either CD19 or CD20 on the B cell and then CD3 on the T cell. There are some unique toxicities to the bispecific antibodies. The administration route may be a little bit challenging for a low-grade lymphoma. From my perspective, it’s a little early to think about where bispecific antibodies might fit in to an indolent disease.

Nathan H. Fowler, MD: Yes, we definitely need more trials. There was an abstract at ASH looking at some of the early BiTE (bi-specific T cell engager) data in large-cell and in follicular lymphoma. The concerning thing is, as Sonali mentioned, you saw these same toxicity profiles that we see with the CAR T cells. You see cytokine release syndrome, you saw neurotoxicity; I think Josh brought this up. We need to really build a better, safer product before these kinds of drugs can move into a low-grade type disease.

John P. Leonard, MD: Then, in the middle is the antibody-drug conjugates, polatuzumab vedotin. There are several others; you can’t pronounce all of their names, but I think they clearly have activity when you have an antibody-drug conjugate, depending on whether or not there’s an immune effect or if it’s just the drug delivery mechanism with a more targeted chemotherapy. These are all active. Certainly, a number of them have response rates in the 30% to 50% range. They seem to be studied a little bit more in the aggressive lymphomas, but I think more for practicalities that bring them forward. But they’re also active in follicular lymphoma, and we’ll see if they make it get any traction as far as comparative studies there.

Matthew Lunning, DO: I was surprised. I thought the dark horse at ASH, the one that people may have walked by was the POLA/BR (polatuzumab vedotin/bendamustine plus rituximab) versus BR in relapsed/refractory large cell. But then, to see at ASCO this year that the follicular lymphoma didn’t look as good, I was scratching my head when I was reading that abstract. I thought that it would maybe look even better, but I guess it’s going to be in the details.

John P. Leonard, MD: More effective chemotherapy in follicular probably.
Ian W. Flinn, MD, PhD: One of the problems with some of them has been the neuropathy with the polatuzumab vedotin. The alternative dosing scheduling has really made that easier to give in patients with follicular lymphoma. We’ll cut way back on these patients with low-grade malignancies. Of course, you wouldn’t want to leave them with a terrible, devastating neuropathy. But I think that’s gotten a lot better. Nathan, what about some other novel therapies for patients with follicular lymphoma? John touched on ibrutinib in the refractory setting in patients with follicular lymphoma. But you’ve done some work with acalabrutinib in follicular lymphoma. What do you see that looking like?

Nathan H. Fowler, MD: As John mentioned, there have been a couple studies now that have looked at ibrutinib in the relapsed setting in follicular. One recently published showed a response rate of only about 20%. So, I think the drug, at least as a single agent, doesn’t have a lot of activity or a real role, in follicular lymphoma at least, with other agents that are available. But we have seen some preclinical data that ibrutinib may change some of the phenotypes or actually have a switch toward different levels in T cells within the microenvironment. Maybe using a drug like that could help or augment the effect of rituximab. We did a couple of trials with ibrutinib and with acalabrutinib combined with rituximab in the frontline setting. Interestingly, in both of these trials, we saw responses around 80% to 90%. Now, again, this is frontline with rituximab in a patient population and some of these patients did not need treatment. It’s hard to know how much of the effect was just Rituxan alone.

In the ibrutinib trial, we saw a complete response rate of around 50%, and in the acalabrutinib trial we saw a CR rate of around 30%, which again, comparing across trials, the CR rate is maybe a little bit higher than you would expect with Rituxan alone. I think that it’s going to require larger trials to really understand what this means for follicular, and one of those trials is currently enrolling. It’s called the PERSPECTIVE trial, and this is in elderly patients with follicular lymphoma—ibrutinib/rituximab versus rituximab, basically in patients who would not tolerate chemotherapy.

Joshua Brody, MD: I think that it’s at least exciting to be open-minded about the difference between ibrutinib and acalabrutinib there. Ibrutinib, we had a lot of concern in the beginning. It hits ITK and IC50s just above BTK. So, it not only affects T cells, but it certainly hits NK cells which are ITK dependent. So, in theory, there was a concern about worsening the ADCC. The Stanford group published a preclinical paper, on the in vitro effect of ADCC with ibrutinib, but acalabrutinib does not hit ITK at all.

Nathan H. Fowler, MD: It’s interesting. That same group published another paper a year later saying there was synergy between anti-CD20s and ibrutinib.

Joshua Brody, MD: Let’s agree it’s an excellent group.

Nathan H. Fowler, MD: Yes. Well, what that tells me is that the field is in flux and we’re still learning about how these drugs work.

Transcript Edited for Clarity 

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Transcript: 

Ian W. Flinn, MD, PhD: Let’s talk about the bispecifics, because logistically, it’s expensive. They are customized products for each person, unless you’re going to come up with a universal cell. Sonali, bispecifics are attractive because you’re engaging the T cell. You’re bringing it right in juxtaposition to the lymphoma, forming the synapse. What is your take on that?

Sonali M. Smith, MD: Well, I think, intuitively, it makes a lot of sense, particularly if targeting CD3 can activate the T cell. I don’t pretend to think that it’s that simple, but I do think that bringing the cells in proximity, at least, allows a chance for that type of immune attack to occur. Most of the bispecific antibodies have targeted either CD19 or CD20 on the B cell and then CD3 on the T cell. There are some unique toxicities to the bispecific antibodies. The administration route may be a little bit challenging for a low-grade lymphoma. From my perspective, it’s a little early to think about where bispecific antibodies might fit in to an indolent disease.

Nathan H. Fowler, MD: Yes, we definitely need more trials. There was an abstract at ASH looking at some of the early BiTE (bi-specific T cell engager) data in large-cell and in follicular lymphoma. The concerning thing is, as Sonali mentioned, you saw these same toxicity profiles that we see with the CAR T cells. You see cytokine release syndrome, you saw neurotoxicity; I think Josh brought this up. We need to really build a better, safer product before these kinds of drugs can move into a low-grade type disease.

John P. Leonard, MD: Then, in the middle is the antibody-drug conjugates, polatuzumab vedotin. There are several others; you can’t pronounce all of their names, but I think they clearly have activity when you have an antibody-drug conjugate, depending on whether or not there’s an immune effect or if it’s just the drug delivery mechanism with a more targeted chemotherapy. These are all active. Certainly, a number of them have response rates in the 30% to 50% range. They seem to be studied a little bit more in the aggressive lymphomas, but I think more for practicalities that bring them forward. But they’re also active in follicular lymphoma, and we’ll see if they make it get any traction as far as comparative studies there.

Matthew Lunning, DO: I was surprised. I thought the dark horse at ASH, the one that people may have walked by was the POLA/BR (polatuzumab vedotin/bendamustine plus rituximab) versus BR in relapsed/refractory large cell. But then, to see at ASCO this year that the follicular lymphoma didn’t look as good, I was scratching my head when I was reading that abstract. I thought that it would maybe look even better, but I guess it’s going to be in the details.

John P. Leonard, MD: More effective chemotherapy in follicular probably.
Ian W. Flinn, MD, PhD: One of the problems with some of them has been the neuropathy with the polatuzumab vedotin. The alternative dosing scheduling has really made that easier to give in patients with follicular lymphoma. We’ll cut way back on these patients with low-grade malignancies. Of course, you wouldn’t want to leave them with a terrible, devastating neuropathy. But I think that’s gotten a lot better. Nathan, what about some other novel therapies for patients with follicular lymphoma? John touched on ibrutinib in the refractory setting in patients with follicular lymphoma. But you’ve done some work with acalabrutinib in follicular lymphoma. What do you see that looking like?

Nathan H. Fowler, MD: As John mentioned, there have been a couple studies now that have looked at ibrutinib in the relapsed setting in follicular. One recently published showed a response rate of only about 20%. So, I think the drug, at least as a single agent, doesn’t have a lot of activity or a real role, in follicular lymphoma at least, with other agents that are available. But we have seen some preclinical data that ibrutinib may change some of the phenotypes or actually have a switch toward different levels in T cells within the microenvironment. Maybe using a drug like that could help or augment the effect of rituximab. We did a couple of trials with ibrutinib and with acalabrutinib combined with rituximab in the frontline setting. Interestingly, in both of these trials, we saw responses around 80% to 90%. Now, again, this is frontline with rituximab in a patient population and some of these patients did not need treatment. It’s hard to know how much of the effect was just Rituxan alone.

In the ibrutinib trial, we saw a complete response rate of around 50%, and in the acalabrutinib trial we saw a CR rate of around 30%, which again, comparing across trials, the CR rate is maybe a little bit higher than you would expect with Rituxan alone. I think that it’s going to require larger trials to really understand what this means for follicular, and one of those trials is currently enrolling. It’s called the PERSPECTIVE trial, and this is in elderly patients with follicular lymphoma—ibrutinib/rituximab versus rituximab, basically in patients who would not tolerate chemotherapy.

Joshua Brody, MD: I think that it’s at least exciting to be open-minded about the difference between ibrutinib and acalabrutinib there. Ibrutinib, we had a lot of concern in the beginning. It hits ITK and IC50s just above BTK. So, it not only affects T cells, but it certainly hits NK cells which are ITK dependent. So, in theory, there was a concern about worsening the ADCC. The Stanford group published a preclinical paper, on the in vitro effect of ADCC with ibrutinib, but acalabrutinib does not hit ITK at all.

Nathan H. Fowler, MD: It’s interesting. That same group published another paper a year later saying there was synergy between anti-CD20s and ibrutinib.

Joshua Brody, MD: Let’s agree it’s an excellent group.

Nathan H. Fowler, MD: Yes. Well, what that tells me is that the field is in flux and we’re still learning about how these drugs work.

Transcript Edited for Clarity 
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