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Strategies for Sequencing Agents in FL

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Matthew Lunning, DO, University of Nebraska Medical Center; John M. Pagel, MD, PhD, Swedish Cancer Institute; Pier Luigi Zinzani, MD, PhD, University of Bologna
Published: Wednesday, Aug 28, 2019



Transcript: 

Ian W. Flinn, MD, PhD: The next question, no one is going to escape from; it’s a difficult 1. How do you sequence all these different therapies second line, third line, and beyond? I think you can ask probably 4 people and there are 10 opinions. How do you approach this, Matt?

Matthew Lunning, DO: Well, I find it very interesting to see when people actually start therapy in second and third line. I mean, do you wait for GELF [Groupe d’Etude des Lymphomes Folliculaires] criteria before you start second line? Or are you starting when the lymph node goes above 1½ cm? And did you find the relapse based upon CT [computed tomography] surveillance, or because the patient had a symptom or you felt something on physical exam? So, I’m not going to…

Ian W. Flinn, MD, PhD: OK, well what are you doing, what do you do? You brought it up, you’ve got to answer.    

Matthew Lunning, DO: Well, I think in the relapse setting it’s all about duration of remission, and we don’t often do CT surveillance in this population. I use physical exam, how the patient feels, and what their labs are doing. And if I feel something on physical exam, then I may evaluate that via a CT scan and then go from there. If the patient comes in and says that’s been there for 3 months and since the last time you saw it, and you know that may inform the decision.

Often, I’ll let velocity of change dictate how long I let them go. You know we have this notion of the law of diminishing returns, right? Your remission duration from the first line to the second line to the third line, that’s maybe dogma in this era of kind of novel-directed therapies. I do tend to try to get toward GELF criteria before reinstituting a therapy. But again, it’s a discussion, and I think it was there all along, and now they’re progressing, I’m more likely to start therapy earlier.

John M. Pagel, MD, PhD: Yeah, I would also say, again, it comes down to that individual patient and how they’ve done, what their responses have looked like. But in general, the sequencing has been all over the map. You could imagine everybody doing it differently, but I think that time is changing a lot now with the emergence of Revlimid and rituximab in relapsed follicular lymphoma. I’m sure you want to talk about that. But I think that’s becoming much more available for all of us, certainly in the United States, now that it has gained approval. And that’s probably now going to be my second-line treatment in many patients. Very well tolerated, relatively speaking, and outstanding results.

Then I’m thinking about other novel agents, and I think that’s when the PI3 kinase inhibitors come in again. I’m still a BR [bendamustine-rituximab] person, primarily up front. Maybe at relapse it’s going to be R2 [lenalidomide-rituximab], and maybe at subsequent relapse it might be a PI3 kinase inhibitor, and I think duvelisib or all these are reasonable choices.

Pier Luigi Zinzani, MD, PhD: I totally agree with this situation. We are waiting for the EMA [European Medicines Agency] official indication of R2 [lenalidomide-rituximab], probably at the end of this year. But R2 [lenalidomide-rituximab] will be the really good second line for this patient because it’s active, it’s less toxic ,and it’s possible to use in all the different kind of patients, and second line could be for sure R2 [lenalidomide-rituximab]. And we can discuss in the future if you include obinutuzumab instead of rituximab. There was a presentation at the last ASH [American Society of Hematology Annual Meeting & Exposition] from the French group about, at the end of the day as we discussed it before, obinutuzumab is a little bit more toxic. R2 [lenalidomide-rituximab] is really good second-line treatment for a follicular lymphoma patient. Of course, right now the third line is for PI3K inhibitors—duvelisib, idelalisib, copanlisib, and so on.

Matthew Lunning, DO: I think that it’s important to note that it’s in a rituximab-sensitive population in second line. We’ve all been saying relapsed not refractory to first-line therapy from that setting. And that’s where the obinutuzumab-lenalidomide may be interesting and is being studied actually—at least in the United States it’s being studied.

And the other piece that I would say about lenalidomide is you’ve got to measure the creatinine clearance. A lot of these patients with follicular lymphoma will have a creatinine clearance less than 60 [mL/min], and that would lead to an initial starting dose that would be lower than what was in the study, at 10 mg. I think that’s potentially an important point.

Pier Luigi Zinzani, MD, PhD: At the end of the day, lenalidomide is also active if you use a low-dose, 5 mg, 10 mg.

Matthew Lunning, DO: There are so many schedules in relapsed-refractory NHL [non-Hodgkin lymphoma] that 1 was chosen and went forward. But I’m not sure that 15 isn’t just as effective as the dose. I don’t, you know?

John M. Pagel, MD, PhD: Right.

Matthew Lunning, DO: I have very low thresholds to dose reduce lenalidomide if people are responding.

John M. Pagel, MD, PhD: Right. The dose that is recommended, I think is too high, it’s 20 mg a day. And it’s interesting that I find—although I don’t do really much at all in myeloma—that patients with follicular lymphoma don’t seem to tolerate it quite as well at the higher doses as myeloma patients. And I agree completely with you, Pier Luigi, that lower doses can work very well. I’ve had some patients on 5 mg for prolonged periods of time doing extremely well.
 
Ian W. Flinn, MD, PhD: We’ve had some bad rash, cutaneous issues, with that. And you know you see it in myeloma patients, but it’s different when you’re combining with rituximab in B-cell malignancy patients.

Transcript Edited for Clarity

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Transcript: 

Ian W. Flinn, MD, PhD: The next question, no one is going to escape from; it’s a difficult 1. How do you sequence all these different therapies second line, third line, and beyond? I think you can ask probably 4 people and there are 10 opinions. How do you approach this, Matt?

Matthew Lunning, DO: Well, I find it very interesting to see when people actually start therapy in second and third line. I mean, do you wait for GELF [Groupe d’Etude des Lymphomes Folliculaires] criteria before you start second line? Or are you starting when the lymph node goes above 1½ cm? And did you find the relapse based upon CT [computed tomography] surveillance, or because the patient had a symptom or you felt something on physical exam? So, I’m not going to…

Ian W. Flinn, MD, PhD: OK, well what are you doing, what do you do? You brought it up, you’ve got to answer.    

Matthew Lunning, DO: Well, I think in the relapse setting it’s all about duration of remission, and we don’t often do CT surveillance in this population. I use physical exam, how the patient feels, and what their labs are doing. And if I feel something on physical exam, then I may evaluate that via a CT scan and then go from there. If the patient comes in and says that’s been there for 3 months and since the last time you saw it, and you know that may inform the decision.

Often, I’ll let velocity of change dictate how long I let them go. You know we have this notion of the law of diminishing returns, right? Your remission duration from the first line to the second line to the third line, that’s maybe dogma in this era of kind of novel-directed therapies. I do tend to try to get toward GELF criteria before reinstituting a therapy. But again, it’s a discussion, and I think it was there all along, and now they’re progressing, I’m more likely to start therapy earlier.

John M. Pagel, MD, PhD: Yeah, I would also say, again, it comes down to that individual patient and how they’ve done, what their responses have looked like. But in general, the sequencing has been all over the map. You could imagine everybody doing it differently, but I think that time is changing a lot now with the emergence of Revlimid and rituximab in relapsed follicular lymphoma. I’m sure you want to talk about that. But I think that’s becoming much more available for all of us, certainly in the United States, now that it has gained approval. And that’s probably now going to be my second-line treatment in many patients. Very well tolerated, relatively speaking, and outstanding results.

Then I’m thinking about other novel agents, and I think that’s when the PI3 kinase inhibitors come in again. I’m still a BR [bendamustine-rituximab] person, primarily up front. Maybe at relapse it’s going to be R2 [lenalidomide-rituximab], and maybe at subsequent relapse it might be a PI3 kinase inhibitor, and I think duvelisib or all these are reasonable choices.

Pier Luigi Zinzani, MD, PhD: I totally agree with this situation. We are waiting for the EMA [European Medicines Agency] official indication of R2 [lenalidomide-rituximab], probably at the end of this year. But R2 [lenalidomide-rituximab] will be the really good second line for this patient because it’s active, it’s less toxic ,and it’s possible to use in all the different kind of patients, and second line could be for sure R2 [lenalidomide-rituximab]. And we can discuss in the future if you include obinutuzumab instead of rituximab. There was a presentation at the last ASH [American Society of Hematology Annual Meeting & Exposition] from the French group about, at the end of the day as we discussed it before, obinutuzumab is a little bit more toxic. R2 [lenalidomide-rituximab] is really good second-line treatment for a follicular lymphoma patient. Of course, right now the third line is for PI3K inhibitors—duvelisib, idelalisib, copanlisib, and so on.

Matthew Lunning, DO: I think that it’s important to note that it’s in a rituximab-sensitive population in second line. We’ve all been saying relapsed not refractory to first-line therapy from that setting. And that’s where the obinutuzumab-lenalidomide may be interesting and is being studied actually—at least in the United States it’s being studied.

And the other piece that I would say about lenalidomide is you’ve got to measure the creatinine clearance. A lot of these patients with follicular lymphoma will have a creatinine clearance less than 60 [mL/min], and that would lead to an initial starting dose that would be lower than what was in the study, at 10 mg. I think that’s potentially an important point.

Pier Luigi Zinzani, MD, PhD: At the end of the day, lenalidomide is also active if you use a low-dose, 5 mg, 10 mg.

Matthew Lunning, DO: There are so many schedules in relapsed-refractory NHL [non-Hodgkin lymphoma] that 1 was chosen and went forward. But I’m not sure that 15 isn’t just as effective as the dose. I don’t, you know?

John M. Pagel, MD, PhD: Right.

Matthew Lunning, DO: I have very low thresholds to dose reduce lenalidomide if people are responding.

John M. Pagel, MD, PhD: Right. The dose that is recommended, I think is too high, it’s 20 mg a day. And it’s interesting that I find—although I don’t do really much at all in myeloma—that patients with follicular lymphoma don’t seem to tolerate it quite as well at the higher doses as myeloma patients. And I agree completely with you, Pier Luigi, that lower doses can work very well. I’ve had some patients on 5 mg for prolonged periods of time doing extremely well.
 
Ian W. Flinn, MD, PhD: We’ve had some bad rash, cutaneous issues, with that. And you know you see it in myeloma patients, but it’s different when you’re combining with rituximab in B-cell malignancy patients.

Transcript Edited for Clarity
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