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Determining Second-Line Therapy in FL

Panelists Ian Flinn, MD, Sarah Cannon Research Institute; John Gribben, MD, DSc, Barts Cancer Institute; John Leonard, MD, Weill Cornell Medical College; Lori A. Leslie, MD, John Theurur Cancer Center; Pier Luigi Zinzani, MD, PhD, University of Bologna Institute of Hematology
Published: Thursday, Feb 13, 2020




Transcript: 

Ian Flinn, MD: We’ve talked about a lot of different treatment decisions and initial therapy of patients with follicular lymphoma. Let’s now move to second-line therapy. John, we talked about how sometimes there’s a lot of variability about how to apply the GELF [Groupe l’Etude des Lymphomes Folliculaires] criteria in the initial timing for first-line therapy. What about second-line therapy? Are you theoretically using the same criteria, or do you have a lower threshold to start treatment?

John Leonard, MD: There are some similarities but some differences. First, patients, when they relapse, tend to present with less disease than when they were diagnosed. They know they have lymphoma, so if they feel a lymph node or have a symptom, they’re in your office quicker than they were at the beginning. It’s interesting. When you look at studies that looked at this, the bulk of disease—at the time of second-line presentation, at least—is lower than it is for the average patient at first line. Typically, the patient is coming in with a palpable lymph node or some symptom. What you’re looking for in that scenario is transformation, because roughly half of the earlier progressors and a substantial fraction of later progressors are going to have transformation. And so some of these individuals come in very sick with transformed disease, and that’s often an important scenario.

For the nontransformed patients, because they often present earlier, while the criteria are the same, many of those can watch and wait. And in my mind, there’s even less rush to do a therapy in a relapsed patient because you kind of expect that this is going to be a relapsed lymphoma that you’re going to be dealing with on and off for many years because relapse that’s declared itself. And so yes, I’m using the same criteria, more or less. But we tend to be a little more relaxed as far as rushing to do something. Nonetheless, you still have to kind of counsel the patient, because they’re disappointed. They think they’re the one who was going to be cured, but they’re not. And it’s obviously—I don’t want to say devastating, but it’s concerning for them.

Ian Flinn, MD: Right. John, let’s get beyond the heterogeneity between the different nations on when to start therapy. But let’s agree that you’ve decided to start therapy. We’ve also touched upon your initial decisions, which are really important in subsequent therapy. Maybe you’re not always the person who made the initial decisions, but you’re trying to find a sequence for patients. Talk us through a little about how you approach the second-line therapy for patients with follicular lymphoma, the nontransformed patient.

John Gribben, MD, DSc: Yeah, I completely agree with John. You’re right. You’re talking here about a patient who’s now come to the point at which they’ve relapsed and know either they’ve relapsed, and you feel they need treatment. Or they’ve relapsed and progressed to the point that they need treatment. We’ve got 1 additional piece of information of the relapse that we didn’t have before. That’s the duration of response that they had to the previous therapy and of course what therapy they had before.

The whole sequence of what your first-line therapy has is going to potentially have a major impact, and the duration of response is also going to have a major impact. There are lots of indications where if somebody has had a very long response to therapy and they tolerated it well, you can go back to the same therapy again. You do have to counsel the patient then of course to expect that here you’re going to relapse; the time to relapse is usually shorter with second-line therapy. I think we’ll come back and talk later about some of the more experimental agents that we’re hoping will be able to overcome that barrier. But in general terms, the data are very clear that the duration of second response is usually going to be less than the first.

You’re absolutely right, though. If we’ve had a patient from frontline therapy, we’ve given and delivered the frontline therapy. But we’re all working at major cancer centers, where a lot of our patients are referred in, and you can actually argue we see more relapsed patients than frontline because a lot of frontline patients get treated in the community. Whereas at relapse they’re often sent in at least for an opinion. We’re seeing a lot of these patients, and they may not have had the frontline therapy that you would have delivered, but that can then impact your second-line therapy. Because if you’ve already used bendamustine, and they’ve had a short response, you’re not going to use a bendamustine-containing regimen again. If somebody has not used bendamustine before, you’ve got that available as an option.

You’ve got to take together all the information you have on the patient already, and they may have more comorbidities now because they’re older. But we also have the piece of information of how well they tolerated the therapy before to give you clues as to what kind of therapy, and how aggressive you want to be. So you’ve got a little more than just the comorbidity stuff that we’ve talked about before. You’ve got how well they accepted the therapy.

Ian Flinn, MD: How about also the comorbidities? We talked about the age. You told us that in your world, no one uses single-agent rituximab on the frontline setting. But what about in the relapsed setting? Now that the 80-year-old person you’ve managed so well for 10 years needs something, do you use single agent, or are you back with chemoimmunotherapy?

John Gribben, MD, DSc: You’re raising very good issues. I work in a large cancer center in the middle of London, England. It’s quite difficult for 80-year-olds to make it, almost by definition if you can make it into central London through rush hour traffic, you don’t have high comorbidities. So you’ve got to remember the patient is going to be treated in different settings and in different environments. And you’re right, so in that setting there are patients in whom I would consider rituximab monotherapy to be an appropriate treatment, based upon your expectation that they would not tolerate anything else. And I think that’s appropriate.

Because here we’re always talking in follicular lymphoma potentially about palliating because we’re not offering the treatment with curative intent. But as John has already alluded to, once somebody has relapsed, you’re really talking about palliation. You’re talking about getting the disease away with the lowest morbidity you can for as long as you can. So yeah, I think there is still a place for single-agent rituximab, or there used to be a place for single-agent rituximab, whether we add it with some of the other agents we now have available to add to it. And as we were already hearing, what you’re also hoping to do is if we can just keep patients going that little bit longer, there are new things coming that may be available for them in the future.

Ian Flinn, MD: I’m going to continue to pick on you because you published it when John Leonard was in high school reading your paper. The use of transplant in follicular lymphoma, is that dead?

John Gribben, MD, DSc: Well, it’s not dead, but it’s certainly true that it’s done. If you look at the registry data, there are many fewer autologous transplants being done. I think it still has a place. Where its place is and in which patient? Clearly it’s much less done. The data would suggest that if you’re going to do it, identifying a patient who’s got higher-risk disease, doing it earlier in their treatment course makes sense. But of course, it comes with very significant morbidity. I’ve got patients still alive that I transplanted 30 years ago, before you were born.

Lori A. Leslie, MD: I was born.

John Gribben, MD, DSc: Yeah, I think it still has a role. But you’ve really got to think carefully and select the right patient for it.

Pier Luigi Zinzani, MD, PhD: I totally agree. I continue to use consolidation with transplantation in the second line for young patients, for select patients with very good results.

Ian Flinn, MD: Very good.

Transcript Edited for Clarity

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Transcript: 

Ian Flinn, MD: We’ve talked about a lot of different treatment decisions and initial therapy of patients with follicular lymphoma. Let’s now move to second-line therapy. John, we talked about how sometimes there’s a lot of variability about how to apply the GELF [Groupe l’Etude des Lymphomes Folliculaires] criteria in the initial timing for first-line therapy. What about second-line therapy? Are you theoretically using the same criteria, or do you have a lower threshold to start treatment?

John Leonard, MD: There are some similarities but some differences. First, patients, when they relapse, tend to present with less disease than when they were diagnosed. They know they have lymphoma, so if they feel a lymph node or have a symptom, they’re in your office quicker than they were at the beginning. It’s interesting. When you look at studies that looked at this, the bulk of disease—at the time of second-line presentation, at least—is lower than it is for the average patient at first line. Typically, the patient is coming in with a palpable lymph node or some symptom. What you’re looking for in that scenario is transformation, because roughly half of the earlier progressors and a substantial fraction of later progressors are going to have transformation. And so some of these individuals come in very sick with transformed disease, and that’s often an important scenario.

For the nontransformed patients, because they often present earlier, while the criteria are the same, many of those can watch and wait. And in my mind, there’s even less rush to do a therapy in a relapsed patient because you kind of expect that this is going to be a relapsed lymphoma that you’re going to be dealing with on and off for many years because relapse that’s declared itself. And so yes, I’m using the same criteria, more or less. But we tend to be a little more relaxed as far as rushing to do something. Nonetheless, you still have to kind of counsel the patient, because they’re disappointed. They think they’re the one who was going to be cured, but they’re not. And it’s obviously—I don’t want to say devastating, but it’s concerning for them.

Ian Flinn, MD: Right. John, let’s get beyond the heterogeneity between the different nations on when to start therapy. But let’s agree that you’ve decided to start therapy. We’ve also touched upon your initial decisions, which are really important in subsequent therapy. Maybe you’re not always the person who made the initial decisions, but you’re trying to find a sequence for patients. Talk us through a little about how you approach the second-line therapy for patients with follicular lymphoma, the nontransformed patient.

John Gribben, MD, DSc: Yeah, I completely agree with John. You’re right. You’re talking here about a patient who’s now come to the point at which they’ve relapsed and know either they’ve relapsed, and you feel they need treatment. Or they’ve relapsed and progressed to the point that they need treatment. We’ve got 1 additional piece of information of the relapse that we didn’t have before. That’s the duration of response that they had to the previous therapy and of course what therapy they had before.

The whole sequence of what your first-line therapy has is going to potentially have a major impact, and the duration of response is also going to have a major impact. There are lots of indications where if somebody has had a very long response to therapy and they tolerated it well, you can go back to the same therapy again. You do have to counsel the patient then of course to expect that here you’re going to relapse; the time to relapse is usually shorter with second-line therapy. I think we’ll come back and talk later about some of the more experimental agents that we’re hoping will be able to overcome that barrier. But in general terms, the data are very clear that the duration of second response is usually going to be less than the first.

You’re absolutely right, though. If we’ve had a patient from frontline therapy, we’ve given and delivered the frontline therapy. But we’re all working at major cancer centers, where a lot of our patients are referred in, and you can actually argue we see more relapsed patients than frontline because a lot of frontline patients get treated in the community. Whereas at relapse they’re often sent in at least for an opinion. We’re seeing a lot of these patients, and they may not have had the frontline therapy that you would have delivered, but that can then impact your second-line therapy. Because if you’ve already used bendamustine, and they’ve had a short response, you’re not going to use a bendamustine-containing regimen again. If somebody has not used bendamustine before, you’ve got that available as an option.

You’ve got to take together all the information you have on the patient already, and they may have more comorbidities now because they’re older. But we also have the piece of information of how well they tolerated the therapy before to give you clues as to what kind of therapy, and how aggressive you want to be. So you’ve got a little more than just the comorbidity stuff that we’ve talked about before. You’ve got how well they accepted the therapy.

Ian Flinn, MD: How about also the comorbidities? We talked about the age. You told us that in your world, no one uses single-agent rituximab on the frontline setting. But what about in the relapsed setting? Now that the 80-year-old person you’ve managed so well for 10 years needs something, do you use single agent, or are you back with chemoimmunotherapy?

John Gribben, MD, DSc: You’re raising very good issues. I work in a large cancer center in the middle of London, England. It’s quite difficult for 80-year-olds to make it, almost by definition if you can make it into central London through rush hour traffic, you don’t have high comorbidities. So you’ve got to remember the patient is going to be treated in different settings and in different environments. And you’re right, so in that setting there are patients in whom I would consider rituximab monotherapy to be an appropriate treatment, based upon your expectation that they would not tolerate anything else. And I think that’s appropriate.

Because here we’re always talking in follicular lymphoma potentially about palliating because we’re not offering the treatment with curative intent. But as John has already alluded to, once somebody has relapsed, you’re really talking about palliation. You’re talking about getting the disease away with the lowest morbidity you can for as long as you can. So yeah, I think there is still a place for single-agent rituximab, or there used to be a place for single-agent rituximab, whether we add it with some of the other agents we now have available to add to it. And as we were already hearing, what you’re also hoping to do is if we can just keep patients going that little bit longer, there are new things coming that may be available for them in the future.

Ian Flinn, MD: I’m going to continue to pick on you because you published it when John Leonard was in high school reading your paper. The use of transplant in follicular lymphoma, is that dead?

John Gribben, MD, DSc: Well, it’s not dead, but it’s certainly true that it’s done. If you look at the registry data, there are many fewer autologous transplants being done. I think it still has a place. Where its place is and in which patient? Clearly it’s much less done. The data would suggest that if you’re going to do it, identifying a patient who’s got higher-risk disease, doing it earlier in their treatment course makes sense. But of course, it comes with very significant morbidity. I’ve got patients still alive that I transplanted 30 years ago, before you were born.

Lori A. Leslie, MD: I was born.

John Gribben, MD, DSc: Yeah, I think it still has a role. But you’ve really got to think carefully and select the right patient for it.

Pier Luigi Zinzani, MD, PhD: I totally agree. I continue to use consolidation with transplantation in the second line for young patients, for select patients with very good results.

Ian Flinn, MD: Very good.

Transcript Edited for Clarity
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