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Phase III GALLIUM Results and Maintenance Therapy

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: 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, no, please don’t treat me.” So you have that issue as well. I want to just dive down a little more on the details of the GALLIUM trial. There were data that suggest that the depth of remission, MRD [minimal residual disease] negativity was important with obinutuzumab regimens versus rituximab regimens. Of course, MRD is not really something that you can do in follicular lymphoma outside a clinical trial. But does that validate some of the data at all, John?

John Gribben, MD, DSc: Well, it’s been 30 years since I published my first studies on minimal residual disease in follicular lymphoma, I’m embarrassed to say. Clearly for me, this is an important factor, and it’s 1 of the factors that I use to say I want to give optimal therapy. Driving patients into deep responses as assessed by eradication of minimal residual disease, as an example, is what I’m kind of looking for in my patients with indolent lymphomas. If I’m not looking for cure, I’m at least looking to get a deeper response if I can. Because to me, that translates into the longest progression-free survival [PFS].

I’m personally assessing clinical trial data to be saying, “Where have you got data on MRD?” Every time we’ve got evidence on MRD, we can see that it matters in that particular trial. That is when the patients, as you might expect, got the deepest response and have the longest progression-free survival. It’s true that it has not translated into routine clinical practice, but it’s being adopted more and more and it’s there and it’s available in the clinical trial data, and I use it to assess how I think that therapy compares with another in terms of what I can achieve in a patient in front of me.

John Leonard, MD: I really enjoyed reading your papers while I was in high school.

John Gribben, MD, DSc: I’m amazed you were reading. I was amazed you could read when I was published.

Lori A. Leslie, MD: I won’t comment on how old I was at that time or if I was born or not.

Pier Luigi Zinzani, MD, PhD: John, this is a very important point. I thought that it published to apply these kinds of evaluations in real life.

John Gribben, MD, DSc: Yeah. Well, that’s what I said, Pier Luigi. That’s why I use what comes out of the clinical trials to help guide me. Because you’re right, it’s very difficult to apply in real life what tissue you use or how you evaluate it. But you can critically assess what’s been done and what’s been presented at the meetings. As you’ll see, lots of clinical trials have incorporated assessments of minimal residual disease into lots of treatment approaches to try to get a handle.

What it comes down to, of course, is do you then apply it to do what we call unplanned subgroup analyses, which I always hate in a study? In other words, we’re the group that behaved best; therefore, we’ll do this. The studies often aren’t powered to be making those sorts of decisions. But I think you take all data together, it’s very clear that if you can derive a deep response in a patient, you’re going to have that better progression-free survival that our patients are looking for.

Pier Luigi Zinzani, MD, PhD: Every time there is a patient-to-patient discordance to MRD negativity, there is CT [computed tomography] scan positivity.

John Gribben, MD, DSc: Well, by definition to me, that’s not minimal residual disease.

Pier Luigi Zinzani, MD, PhD: Yeah.

Lori A. Leslie, MD: And I think these novel surrogate end points are so important in the indolent lymphomas, because it takes decades for the data to fully mature. If MRD correlates repeatedly with survival benefit or whatever we’re looking at, that in combination with end-of-treatment PET [positron emission tomography] and a CR [complete response] rate of 30 months in follicular lymphoma, together are emerging as important surrogate end points.

Ian Flinn, MD: It certainly sounds like this is important to incorporate into clinical trials, but on an everyday basis it’s hard to do. But let’s dive down a little. We touched on it but didn’t go into depth: the whole issue of maintenance therapy. Lori, it seems to me, 10 years ago, almost all my patients received maintenance therapy, and then I was really disappointed by the trials that showed a difference in progression-free survival but really no difference in overall survival with giving everyone maintenance therapy. There’s really been a change, in my practice at least. A minority of patients get maintenance therapy. But I think there are differences regionally. What’s your take on this?

Lori A. Leslie, MD: Compared with some of my colleagues, I’m more of a fan of maintenance. I do offer and discuss maintenance with patients, particularly post the 10-year follow-up of PRIMA. We were talking before about end-of-treatment PET scan positive versus negative. It seems like maintenance may neutralize some of that danger of being PET positive at the end of treatment.

And at 10 years post treatment, R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] like chemotherapy with maintenance, PFS of 51% versus 35% or so in maintenance versus observation is something I definitely discuss with my patients. I have a very low threshold to stop maintenance if patients are having any adverse effects—sinusitis, upper respiratory tract infections that could be from symptomatic hypogammaglobulinemia. If it becomes too inconvenient for a patient, that is not someone I would really push to say this is going to change your overall course if we continue. But in general, if patients have a deep PR [partial response] or even a CR, I do discuss rituximab maintenance. I don’t use obinutuzumab much in the frontline setting, so I think that’s also different. With rituximab there’s not the neutropenia. Infections are typically less and infusion reactions are less, so I think it’s a generally well-tolerated approach.

Ian Flinn, MD: John, earlier you mentioned that you wait to make the decision till after you see how the patient does. Are they still PET positive? What are you referring to when you do that?

John Leonard, MD: It’s funny, because you look at risk-adapted approaches for Hodgkin lymphoma and think about what you’re going to do. I like to see how it plays out. There’s some value in getting to know the patient over their induction treatment. You get a sense they are going to feel better by getting more therapy. Yes, I gauge it a bit on the response as well, but if the patient is having a lot of infections and adverse effects and is very stressed by their treatment, then I want to leave them alone at the end of treatment. I don’t always know that at the very beginning, because you don’t know how they respond, how they tolerate the treatment, what their preferences are, etc.

That’s it. I think the doctor’s influence is huge over billing it to a patient, as if you’ve got to have maintenance or you don’t want maintenance. If you have your biases, I think you—like most things in medicine—can influence the patient. I’m not sure that’s a good thing. Ideally we would have a tool to be able to figure out what patients prefer maintenance or where it works for them in their view on the long-term outlook and the quality of life versus others that prefer to be done with you more or less at least for several years.

John Gribben, MD, DSc: It’s interesting, John, because I would take the entirely opposite approach. If a patient doesn’t tolerate chemotherapy, that’s when I would want to give maintenance to prolong the time they’d have to face chemotherapy again. As Lori has already said, there’s no difference in overall survival, but there’s a clear benefit in progression-free survival. Giving a patient a longer period off-drug is what I think my patients want. And if you’re not tolerating chemotherapy well the first time, the longer you have until you have to have it again—unless they’re very old with comorbidities—there’s the potential they’re going to be in better shape to have it.

John Leonard, MD: I guess that the BR [bendamustine, rituximab] patient who gets a CR is, when they relapse in 5 years or longer, not going to get chemotherapy. They’re going to get something else most likely. So I have a little more optimistic view about the alternatives for better or worse.
 
Pier Luigi Zinzani, MD, PhD: John’s approach we’re using.

John Leonard, MD: Which John?

Pier Luigi Zinzani, MD, PhD: John on my left, UK [United Kingdom] John. Because we are using maintenance with rituximab in all our patients who obtain at least a partial response after the chemoimmunotherapy induction, and also you remember very well 2 years ago at the ASH [American Society of Hematology Annual] Meeting that there was an update after 10 years of follow-up, the progression-free survival was a statistically significant advantage of maintenance treatment. There is no way the data are that interesting in terms of reducing the risk of relapse for the patient who obtains CR. Remember the preliminary data of the French group: at least 50% of the patients who will obtain a PR after the induction, can have an increase of the response until CR.

Ian Flinn, MD: If you started with 1 antibody, do you stick with that antibody?

Pier Luigi Zinzani, MD, PhD: Yeah.

Ian Flinn, MD: Is that what everyone is doing?

Lori A. Leslie, MD: Yeah. I think as we talk about PFS benefit in this rapidly evolving field, a few years—I agree with both Johns—may dramatically change what you give them in the subsequent line.

Transcript Edited for Clarity

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Transcript: 

Ian Flinn, MD: 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, no, please don’t treat me.” So you have that issue as well. I want to just dive down a little more on the details of the GALLIUM trial. There were data that suggest that the depth of remission, MRD [minimal residual disease] negativity was important with obinutuzumab regimens versus rituximab regimens. Of course, MRD is not really something that you can do in follicular lymphoma outside a clinical trial. But does that validate some of the data at all, John?

John Gribben, MD, DSc: Well, it’s been 30 years since I published my first studies on minimal residual disease in follicular lymphoma, I’m embarrassed to say. Clearly for me, this is an important factor, and it’s 1 of the factors that I use to say I want to give optimal therapy. Driving patients into deep responses as assessed by eradication of minimal residual disease, as an example, is what I’m kind of looking for in my patients with indolent lymphomas. If I’m not looking for cure, I’m at least looking to get a deeper response if I can. Because to me, that translates into the longest progression-free survival [PFS].

I’m personally assessing clinical trial data to be saying, “Where have you got data on MRD?” Every time we’ve got evidence on MRD, we can see that it matters in that particular trial. That is when the patients, as you might expect, got the deepest response and have the longest progression-free survival. It’s true that it has not translated into routine clinical practice, but it’s being adopted more and more and it’s there and it’s available in the clinical trial data, and I use it to assess how I think that therapy compares with another in terms of what I can achieve in a patient in front of me.

John Leonard, MD: I really enjoyed reading your papers while I was in high school.

John Gribben, MD, DSc: I’m amazed you were reading. I was amazed you could read when I was published.

Lori A. Leslie, MD: I won’t comment on how old I was at that time or if I was born or not.

Pier Luigi Zinzani, MD, PhD: John, this is a very important point. I thought that it published to apply these kinds of evaluations in real life.

John Gribben, MD, DSc: Yeah. Well, that’s what I said, Pier Luigi. That’s why I use what comes out of the clinical trials to help guide me. Because you’re right, it’s very difficult to apply in real life what tissue you use or how you evaluate it. But you can critically assess what’s been done and what’s been presented at the meetings. As you’ll see, lots of clinical trials have incorporated assessments of minimal residual disease into lots of treatment approaches to try to get a handle.

What it comes down to, of course, is do you then apply it to do what we call unplanned subgroup analyses, which I always hate in a study? In other words, we’re the group that behaved best; therefore, we’ll do this. The studies often aren’t powered to be making those sorts of decisions. But I think you take all data together, it’s very clear that if you can derive a deep response in a patient, you’re going to have that better progression-free survival that our patients are looking for.

Pier Luigi Zinzani, MD, PhD: Every time there is a patient-to-patient discordance to MRD negativity, there is CT [computed tomography] scan positivity.

John Gribben, MD, DSc: Well, by definition to me, that’s not minimal residual disease.

Pier Luigi Zinzani, MD, PhD: Yeah.

Lori A. Leslie, MD: And I think these novel surrogate end points are so important in the indolent lymphomas, because it takes decades for the data to fully mature. If MRD correlates repeatedly with survival benefit or whatever we’re looking at, that in combination with end-of-treatment PET [positron emission tomography] and a CR [complete response] rate of 30 months in follicular lymphoma, together are emerging as important surrogate end points.

Ian Flinn, MD: It certainly sounds like this is important to incorporate into clinical trials, but on an everyday basis it’s hard to do. But let’s dive down a little. We touched on it but didn’t go into depth: the whole issue of maintenance therapy. Lori, it seems to me, 10 years ago, almost all my patients received maintenance therapy, and then I was really disappointed by the trials that showed a difference in progression-free survival but really no difference in overall survival with giving everyone maintenance therapy. There’s really been a change, in my practice at least. A minority of patients get maintenance therapy. But I think there are differences regionally. What’s your take on this?

Lori A. Leslie, MD: Compared with some of my colleagues, I’m more of a fan of maintenance. I do offer and discuss maintenance with patients, particularly post the 10-year follow-up of PRIMA. We were talking before about end-of-treatment PET scan positive versus negative. It seems like maintenance may neutralize some of that danger of being PET positive at the end of treatment.

And at 10 years post treatment, R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] like chemotherapy with maintenance, PFS of 51% versus 35% or so in maintenance versus observation is something I definitely discuss with my patients. I have a very low threshold to stop maintenance if patients are having any adverse effects—sinusitis, upper respiratory tract infections that could be from symptomatic hypogammaglobulinemia. If it becomes too inconvenient for a patient, that is not someone I would really push to say this is going to change your overall course if we continue. But in general, if patients have a deep PR [partial response] or even a CR, I do discuss rituximab maintenance. I don’t use obinutuzumab much in the frontline setting, so I think that’s also different. With rituximab there’s not the neutropenia. Infections are typically less and infusion reactions are less, so I think it’s a generally well-tolerated approach.

Ian Flinn, MD: John, earlier you mentioned that you wait to make the decision till after you see how the patient does. Are they still PET positive? What are you referring to when you do that?

John Leonard, MD: It’s funny, because you look at risk-adapted approaches for Hodgkin lymphoma and think about what you’re going to do. I like to see how it plays out. There’s some value in getting to know the patient over their induction treatment. You get a sense they are going to feel better by getting more therapy. Yes, I gauge it a bit on the response as well, but if the patient is having a lot of infections and adverse effects and is very stressed by their treatment, then I want to leave them alone at the end of treatment. I don’t always know that at the very beginning, because you don’t know how they respond, how they tolerate the treatment, what their preferences are, etc.

That’s it. I think the doctor’s influence is huge over billing it to a patient, as if you’ve got to have maintenance or you don’t want maintenance. If you have your biases, I think you—like most things in medicine—can influence the patient. I’m not sure that’s a good thing. Ideally we would have a tool to be able to figure out what patients prefer maintenance or where it works for them in their view on the long-term outlook and the quality of life versus others that prefer to be done with you more or less at least for several years.

John Gribben, MD, DSc: It’s interesting, John, because I would take the entirely opposite approach. If a patient doesn’t tolerate chemotherapy, that’s when I would want to give maintenance to prolong the time they’d have to face chemotherapy again. As Lori has already said, there’s no difference in overall survival, but there’s a clear benefit in progression-free survival. Giving a patient a longer period off-drug is what I think my patients want. And if you’re not tolerating chemotherapy well the first time, the longer you have until you have to have it again—unless they’re very old with comorbidities—there’s the potential they’re going to be in better shape to have it.

John Leonard, MD: I guess that the BR [bendamustine, rituximab] patient who gets a CR is, when they relapse in 5 years or longer, not going to get chemotherapy. They’re going to get something else most likely. So I have a little more optimistic view about the alternatives for better or worse.
 
Pier Luigi Zinzani, MD, PhD: John’s approach we’re using.

John Leonard, MD: Which John?

Pier Luigi Zinzani, MD, PhD: John on my left, UK [United Kingdom] John. Because we are using maintenance with rituximab in all our patients who obtain at least a partial response after the chemoimmunotherapy induction, and also you remember very well 2 years ago at the ASH [American Society of Hematology Annual] Meeting that there was an update after 10 years of follow-up, the progression-free survival was a statistically significant advantage of maintenance treatment. There is no way the data are that interesting in terms of reducing the risk of relapse for the patient who obtains CR. Remember the preliminary data of the French group: at least 50% of the patients who will obtain a PR after the induction, can have an increase of the response until CR.

Ian Flinn, MD: If you started with 1 antibody, do you stick with that antibody?

Pier Luigi Zinzani, MD, PhD: Yeah.

Ian Flinn, MD: Is that what everyone is doing?

Lori A. Leslie, MD: Yeah. I think as we talk about PFS benefit in this rapidly evolving field, a few years—I agree with both Johns—may dramatically change what you give them in the subsequent line.

Transcript Edited for Clarity
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