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Immunochemotherapy Decision Factors

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: Friday, Feb 07, 2020



Transcript: 

Ian Flinn, MD: You’ve made the decision to proceed with therapy. There are different comorbidities that might affect treatment decisions. There are now a number of large randomized trials looking at BR [bendamustine, rituximab] versus R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or R-CVP [rituximab, cyclophosphamide, vincristine, prednisone] and other therapies. How do you distill that data down to decide are you using bendamustine-rituximab or are you using R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or even R-CVP [rituximab, cyclophosphamide, vincristine, prednisone]? Pier Luigi?

Pier Luigi Zinzani, MD, PhD: It’s a really different situation according to the GALLIUM study. There was a presentation and a publication with official indications, comparing commercial chemotherapy, CVP [cyclophosphamide, vincristine, prednisone], bendamustine, R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] plus rituximab-obinutuzumab. Anyway, I think at the end of the day, it depends on the background of the different countries.

For example, in Europe, in particular in Italy, Germany, Austria, and the most parts of Spain, we are using bendamustine in frontline. And we continue to use bendamustine with obinutuzumab in high-risk and intermediate-risk patients, according to the FLIPI [Follicular Lymphoma International Prognostic Index] score on the basis of the GALLIUM data. And for the other patient, we are using bendamustine plus rituximab. Sometimes we can use CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] plus rituximab or obinutuzumab in the young patient with a real high tumor burden, but normally we prefer to use bendamustine, with different CD20 according to the different high-risk FLIPI score.

Ian Flinn, MD: John, I think you’re articulating that you’re following guidelines in London, in England, and that that requires obinutuzumab in certain patient populations.

John Gribben, MD, DSc: Yeah, exactly as Pier Luigi said. The guidelines we have established are that we should be giving the optimal therapy to the patient, so when the basis of the clinical trial is available, that would be an obinutuzumab-containing combination for the high-risk FLIPI. We’re following exactly what Pier Luigi says, but we’ve got it written in stone, so to speak.

As far as what you partner it with, I’m finding that people are varying a little. I favor bendamustine, because what I’m looking for—I’m sure we’ll come back to it in a minute—is the longest first remission I can get because everything that happens to the patient after depends on when they relapse. If I can offer a patient what I think is going to be the optimal duration of therapy, that’s why I’m favoring for the high-risk patients a bendamustine-obinutuzumab followed by obinutuzumab maintenance.

I know that the benefit seen in GALLIUM is small, but that’s a big difference for that small number of patients. So it’s about sitting down and discussing the optimal therapy. Then, of course, the comorbidities that Lori talked about obviously factor in. We talked a lot already about how bendamustine is in general well tolerated, but there are patients with whom some alternative would be the case. I personally prefer to keep an anthracycline-containing regimen, so that I’ve got it available at transformation if it occurs. I like to keep CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] for later in the armamentarium if I need it. That’s kind of the way that I think about it.

Ian Flinn, MD: Yeah, you’ve brought up some really important issues about sequencing, which we’re going to spend some time on in a minute. But before we do that, John, I feel like it’s different in the United States in terms of the use of obinutuzumab or rituximab. What’s your take on that?

John Leonard, MD: I would say, yes. I mean, we’re alluding to the fact that the PFS [progression-free survival] difference in GALLIUM is on the order of 5% to 7% or 8%. The toxicity is a little more. You’re committed to using maintenance. You don’t have a subcutaneous option if you’re using obinutuzumab. If there’s not a survival benefit, all those things in my mind make it less compelling. And I don’t use as much maintenance, so I have a little trouble because there’s a lack of overall survival benefit. I have a little trouble applying the GALLIUM data to a maintenance-free approach if that’s what you want to use. I tend to think about maintenance more. I like to decide it at the end rather than the beginning. I want to see how the patient did with their induction therapy. Yeah, I think there’s less of that. I also just want to mention, as an aside, there are still a fair number of patients who get single-agent rituximab in my practice.

John Gribben, MD, DSc: I was going to comment on that because that’s another big difference with Europe. Single-agent rituximab was in a couple of countries. Scandinavia and Switzerland still tend to use it. But apart from that, single-agent rituximab is hardly used in Europe.

Pier Luigi Zinzani, MD, PhD: Absolutely.

John Gribben, MD, DSc: That impacts upon what happens later, but it also impacts upon engagement in particular clinical trials. Of course, it might also impact upon something we talked about earlier, that is that trigger to give therapy first. In other words, if you’re giving single-agent rituximab as your therapy, because it’s perceived as being so safe, your threshold for starting it might already be lower. Whereas, if we’re going to be using bendamustine-obinutuzumab, we’re preserving it for when a patient really needs it.

Ian Flinn, MD: Even in older patients, single-agent rituximab is not given?

John Gribben, MD, DSc: It tends to still be given with some degree of chemotherapy. Single-agent rituximab is very seldom used in our practice.

Pier Luigi Zinzani, MD, PhD: For this reason, for European centers to do a trial where there is a standard arm with rituximab as a single agent would be difficult, because it’s difficult to persuade our patients.

Ian Flinn, MD: I think it’s different here.

John Leonard, MD: The classic scenario is a watch-and-wait patient who has a little more going on, maybe something cosmetic, maybe a little discomfort that you’re not sure is from the lymphoma. I don’t think you lose a whole lot by giving them. If you give them 4 doses of rituximab and it doesn’t meet your goal, and 6 months down the line you give them bendamustine-based therapy, you’ve lost that time. But it’s usually a pretty benign time, and it’s not a long time, and I think most people—but it also is how we present it to the patient as well.

Lori A. Leslie, MD: There are also patients who are just panicked by the idea of watch-and-wait. Knowing they have a cancer growing inside them and we’re not doing anything about it, even telling them all the evidence that we don’t have to. That is a significant impact on quality of life. Sometimes, if you can at least justify single-agent Rituxan, even though you may not be doing tons for the lymphoma overall, in terms of their overall quality of life, it can make a dramatic difference.

John Gribben, MD, DSc: I’ve spent half my professional life working in the United States and half in Europe, and I completely agree. Americans hate the concept of doing nothing. They just hate it.

Lori A. Leslie, MD: Yes.

John Gribben, MD, DSc: Europeans love the idea that they don’t need treatment yet. So the patients’ response to watch-and-wait is very different on the 2 continents.

Ian Flinn, MD: Interesting. I know that for many of my patients, it’s a difficult concept when you first introduce it, but after they’ve been doing it for a little while, we have the same issue with chronic lymphocytic leukemia. Then it’s always telling them that you need therapy. They’re like, “No, no, please don’t treat me.” So you have that issue as well.

Transcript Edited for Clarity 

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Transcript: 

Ian Flinn, MD: You’ve made the decision to proceed with therapy. There are different comorbidities that might affect treatment decisions. There are now a number of large randomized trials looking at BR [bendamustine, rituximab] versus R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or R-CVP [rituximab, cyclophosphamide, vincristine, prednisone] and other therapies. How do you distill that data down to decide are you using bendamustine-rituximab or are you using R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or even R-CVP [rituximab, cyclophosphamide, vincristine, prednisone]? Pier Luigi?

Pier Luigi Zinzani, MD, PhD: It’s a really different situation according to the GALLIUM study. There was a presentation and a publication with official indications, comparing commercial chemotherapy, CVP [cyclophosphamide, vincristine, prednisone], bendamustine, R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] plus rituximab-obinutuzumab. Anyway, I think at the end of the day, it depends on the background of the different countries.

For example, in Europe, in particular in Italy, Germany, Austria, and the most parts of Spain, we are using bendamustine in frontline. And we continue to use bendamustine with obinutuzumab in high-risk and intermediate-risk patients, according to the FLIPI [Follicular Lymphoma International Prognostic Index] score on the basis of the GALLIUM data. And for the other patient, we are using bendamustine plus rituximab. Sometimes we can use CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] plus rituximab or obinutuzumab in the young patient with a real high tumor burden, but normally we prefer to use bendamustine, with different CD20 according to the different high-risk FLIPI score.

Ian Flinn, MD: John, I think you’re articulating that you’re following guidelines in London, in England, and that that requires obinutuzumab in certain patient populations.

John Gribben, MD, DSc: Yeah, exactly as Pier Luigi said. The guidelines we have established are that we should be giving the optimal therapy to the patient, so when the basis of the clinical trial is available, that would be an obinutuzumab-containing combination for the high-risk FLIPI. We’re following exactly what Pier Luigi says, but we’ve got it written in stone, so to speak.

As far as what you partner it with, I’m finding that people are varying a little. I favor bendamustine, because what I’m looking for—I’m sure we’ll come back to it in a minute—is the longest first remission I can get because everything that happens to the patient after depends on when they relapse. If I can offer a patient what I think is going to be the optimal duration of therapy, that’s why I’m favoring for the high-risk patients a bendamustine-obinutuzumab followed by obinutuzumab maintenance.

I know that the benefit seen in GALLIUM is small, but that’s a big difference for that small number of patients. So it’s about sitting down and discussing the optimal therapy. Then, of course, the comorbidities that Lori talked about obviously factor in. We talked a lot already about how bendamustine is in general well tolerated, but there are patients with whom some alternative would be the case. I personally prefer to keep an anthracycline-containing regimen, so that I’ve got it available at transformation if it occurs. I like to keep CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] for later in the armamentarium if I need it. That’s kind of the way that I think about it.

Ian Flinn, MD: Yeah, you’ve brought up some really important issues about sequencing, which we’re going to spend some time on in a minute. But before we do that, John, I feel like it’s different in the United States in terms of the use of obinutuzumab or rituximab. What’s your take on that?

John Leonard, MD: I would say, yes. I mean, we’re alluding to the fact that the PFS [progression-free survival] difference in GALLIUM is on the order of 5% to 7% or 8%. The toxicity is a little more. You’re committed to using maintenance. You don’t have a subcutaneous option if you’re using obinutuzumab. If there’s not a survival benefit, all those things in my mind make it less compelling. And I don’t use as much maintenance, so I have a little trouble because there’s a lack of overall survival benefit. I have a little trouble applying the GALLIUM data to a maintenance-free approach if that’s what you want to use. I tend to think about maintenance more. I like to decide it at the end rather than the beginning. I want to see how the patient did with their induction therapy. Yeah, I think there’s less of that. I also just want to mention, as an aside, there are still a fair number of patients who get single-agent rituximab in my practice.

John Gribben, MD, DSc: I was going to comment on that because that’s another big difference with Europe. Single-agent rituximab was in a couple of countries. Scandinavia and Switzerland still tend to use it. But apart from that, single-agent rituximab is hardly used in Europe.

Pier Luigi Zinzani, MD, PhD: Absolutely.

John Gribben, MD, DSc: That impacts upon what happens later, but it also impacts upon engagement in particular clinical trials. Of course, it might also impact upon something we talked about earlier, that is that trigger to give therapy first. In other words, if you’re giving single-agent rituximab as your therapy, because it’s perceived as being so safe, your threshold for starting it might already be lower. Whereas, if we’re going to be using bendamustine-obinutuzumab, we’re preserving it for when a patient really needs it.

Ian Flinn, MD: Even in older patients, single-agent rituximab is not given?

John Gribben, MD, DSc: It tends to still be given with some degree of chemotherapy. Single-agent rituximab is very seldom used in our practice.

Pier Luigi Zinzani, MD, PhD: For this reason, for European centers to do a trial where there is a standard arm with rituximab as a single agent would be difficult, because it’s difficult to persuade our patients.

Ian Flinn, MD: I think it’s different here.

John Leonard, MD: The classic scenario is a watch-and-wait patient who has a little more going on, maybe something cosmetic, maybe a little discomfort that you’re not sure is from the lymphoma. I don’t think you lose a whole lot by giving them. If you give them 4 doses of rituximab and it doesn’t meet your goal, and 6 months down the line you give them bendamustine-based therapy, you’ve lost that time. But it’s usually a pretty benign time, and it’s not a long time, and I think most people—but it also is how we present it to the patient as well.

Lori A. Leslie, MD: There are also patients who are just panicked by the idea of watch-and-wait. Knowing they have a cancer growing inside them and we’re not doing anything about it, even telling them all the evidence that we don’t have to. That is a significant impact on quality of life. Sometimes, if you can at least justify single-agent Rituxan, even though you may not be doing tons for the lymphoma overall, in terms of their overall quality of life, it can make a dramatic difference.

John Gribben, MD, DSc: I’ve spent half my professional life working in the United States and half in Europe, and I completely agree. Americans hate the concept of doing nothing. They just hate it.

Lori A. Leslie, MD: Yes.

John Gribben, MD, DSc: Europeans love the idea that they don’t need treatment yet. So the patients’ response to watch-and-wait is very different on the 2 continents.

Ian Flinn, MD: Interesting. I know that for many of my patients, it’s a difficult concept when you first introduce it, but after they’ve been doing it for a little while, we have the same issue with chronic lymphocytic leukemia. Then it’s always telling them that you need therapy. They’re like, “No, no, please don’t treat me.” So you have that issue as well.

Transcript Edited for Clarity 
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