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Challenging the Role of Maintenance Therapy in FL

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Peter Martin, MD, MS, Weill Cornell Medicine; Loretta J. Nastoupil, MD, University of Texas MD Anderson Cancer Center; Grzegorz S. Nowakowski, MD, Mayo Clinic; Anas Younes, MD, Memorial Sloan Kettering Cancer Center
Published: Thursday, Jan 11, 2018



Transcript: 

Ian W. Flinn, MD, PhD: I’m going to follow up and ask you about maintenance therapy. We have numerous clinical trials, a decade of experience or more, using rituximab and now other CD20 antibodies as maintenance therapy. Initially there was, I think, a lot of enthusiasm for maintenance therapy with the notion that perhaps a progression-free survival advantage would ultimately translate into an overall survival advantage. That’s been a little bit more elusive than what we originally thought. We now have multiple choices of drugs that we can use, or anti-CD20 antibodies that can be used, as maintenance therapy. What do you tell your patients?

Peter Martin, MD, MS: It’s an important question. I think you’re right, that there were a lot of early adopters of maintenance therapy and then there was some peeling back on that. The PRIMA data were really strong. The PRIMA trial was the trial that added 2 years of rituximab maintenance after 2 years of R-chemotherapy, and it demonstrated a significant progression-free survival benefit without an overall survival benefit. And so, people who wanted to be in a remission for longer were more likely to say, “Please give me the maintenance,” as opposed to other people who maybe wanted to spend a little bit less time in the doctor’s office. They said, “Well, I’ll deal with it and probably another 5 years from now we’ll talk again.” I think like Anas, we at Cornell and myself personally were maybe a little bit less inclined to give maintenance, saying we’ll deal with it when we have to deal with it. But the PRIMA data, now with 10 years of follow-up, remain strong. At 10 years, 51% of patients who got maintenance are still free from progression. So, that’s a clinical trial. We don’t know what that would be like in the real-world setting, and that’s an important point, but it’s basically an extension of the same conversation. It’s still the same conversation that it improves progression-free survival without a difference in overall survival. So, we have the conversation and then we have more data to add to it.

Ian W. Flinn, MD, PhD: Greg, do you agree? What do you do for your patients? And now I think there’s even some discussion about how long you should do maintenance therapy, right? There are data from the StiL group looking at 2 versus 4 years of therapy. What are you telling your patients?

Grzegorz S. Nowakowski, MD: The StiL study showed that there’s advantage in prolonged maintenance, rituximab for 4 years versus 2 years, in terms of progression-free survival. Now most of those differences, as you pointed out, are in progression-free survival. This is a very individualized decision and discussion with the patient, which option one would take. In general, I find that people are falling into 2 categories. There are patients who basically say, “I’m done with the chemotherapy, I completed it, I’m happy to follow up, but I would not necessarily like to pursue additional maintenance.” And there are folks who really feel very strongly about doing everything possible to keep their tumor under control. Then we discuss the data and those folks would select maintenance therapy. The duration after this year at ASH will be another discussion that we’ll have about the potential additional benefit of adding 2 years of Rituxan to maintenance.

Anas Younes, MD: Can I add one more thing? What’s confusing in the field is that there is another trial that was published recently in JCO (Journal of Clinical Oncology), another 10-year follow-up from the Italian group where they used R-chemotherapy versus chemotherapy. In the 10-year follow-up, R-CHOP with no maintenance gave also about 10-year progression-free survival. There are data to support either/or. If you give it, it’s fine. If you don’t give it, it’s not malpractice. And I think that’s a discussion for all of us with the patients, and some of them would want to get Rituxan maintenance or obinutuzumab maintenance, and that’s perfect fine. But if you don’t give it, I think it’s also perfectly fine.

Ian W. Flinn, MD, PhD: How does all this realization about this color your interpretation of the GALLIUM trial, where there was maintenance with obinutuzumab? I find it difficult because I felt like for 10 years, I was telling my patients that I think it’s probably good to have maintenance therapy. Now I’m less sure of that, but when trying to interpret the GALLIUM trial with obinutuzumab maintenance, that certainly was superior.

Anas Younes, MD: It’s certainly in a disease where the median survival now exceeds 18 years. And safety and toxicity become an issue, so you need to make sure that the patients who are treated would also get safe treatment, that we’re not exposing them to toxic treatments that may add subsequent therapies. So, this needs to be factored in. In a perfectly healthy person, I think it’s no problem treating patients with maintenance. Honestly, most of us were shocked when we saw the data from GALLIUM because all of us said, “I never see this in my patients,” but data is data. So, I’m sure some patients may not tolerate this kind of treatment, but it’s rare in clinical practice, at least in some of our experience.

Ian W. Flinn, MD, PhD: Loretta, how about you? Is there any difference, in your opinion, on this subject?

Loretta J. Nastoupil, MD: I think the problem with the GALLIUM study is that it was designed to tell us which CD20 antibody was superior, but it’s a very large prospective study of follicular lymphoma with over 1000 patients. So now we’re learning more in terms of what the toxicity profile is associated with chemotherapy and CD20, and we, for the first time, saw some prospective data looking at CD20 maintenance following bendamustine. We do have the StiL data at this ASH meeting, and your BRIGHT study. There, about half of the patients did receive maintenance, but it wasn’t prospectively built in. So, I think what we’ve learned from this is there are some toxicities that you have to be mindful of after patients complete their chemotherapy. And we’re seeing some subgroup analysis come out of the GALLIUM data, where it looks like particularly some of the CD8 effector cells may be impacted after they stop the bendamustine.

I think this now raises more complexity, and the discussion you have with patients is, “Just because you’re in this maintenance phase and we’re less worried about toxicity associated with chemotherapy, there still are toxicities that you need to be mindful of, including infection.” The other issue is second cancers. Now, we know patients with follicular lymphoma are more prone to second cancers, probably due to failure of immune surveillance. But when you continue these therapies more prolongedly, are you also enhancing that risk? We don’t know the answer.

Peter Martin, MD, MS: I think that’s a great point. Greg made the point earlier as well from the Mayo Clinic, the Matt Maurer data looking at EFS12, where it’s clear that a significant proportion of patients have a survival that’s equivalent to the population without lymphoma. Their life experience is not one of excess mortality, but one of excess morbidity. When we’re managing people with follicular lymphoma, as Loretta says, one of the key points is to minimize morbidity because chances are they’re going to do well regardless of the choices we make.

Transcript Edited for Clarity 

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Transcript: 

Ian W. Flinn, MD, PhD: I’m going to follow up and ask you about maintenance therapy. We have numerous clinical trials, a decade of experience or more, using rituximab and now other CD20 antibodies as maintenance therapy. Initially there was, I think, a lot of enthusiasm for maintenance therapy with the notion that perhaps a progression-free survival advantage would ultimately translate into an overall survival advantage. That’s been a little bit more elusive than what we originally thought. We now have multiple choices of drugs that we can use, or anti-CD20 antibodies that can be used, as maintenance therapy. What do you tell your patients?

Peter Martin, MD, MS: It’s an important question. I think you’re right, that there were a lot of early adopters of maintenance therapy and then there was some peeling back on that. The PRIMA data were really strong. The PRIMA trial was the trial that added 2 years of rituximab maintenance after 2 years of R-chemotherapy, and it demonstrated a significant progression-free survival benefit without an overall survival benefit. And so, people who wanted to be in a remission for longer were more likely to say, “Please give me the maintenance,” as opposed to other people who maybe wanted to spend a little bit less time in the doctor’s office. They said, “Well, I’ll deal with it and probably another 5 years from now we’ll talk again.” I think like Anas, we at Cornell and myself personally were maybe a little bit less inclined to give maintenance, saying we’ll deal with it when we have to deal with it. But the PRIMA data, now with 10 years of follow-up, remain strong. At 10 years, 51% of patients who got maintenance are still free from progression. So, that’s a clinical trial. We don’t know what that would be like in the real-world setting, and that’s an important point, but it’s basically an extension of the same conversation. It’s still the same conversation that it improves progression-free survival without a difference in overall survival. So, we have the conversation and then we have more data to add to it.

Ian W. Flinn, MD, PhD: Greg, do you agree? What do you do for your patients? And now I think there’s even some discussion about how long you should do maintenance therapy, right? There are data from the StiL group looking at 2 versus 4 years of therapy. What are you telling your patients?

Grzegorz S. Nowakowski, MD: The StiL study showed that there’s advantage in prolonged maintenance, rituximab for 4 years versus 2 years, in terms of progression-free survival. Now most of those differences, as you pointed out, are in progression-free survival. This is a very individualized decision and discussion with the patient, which option one would take. In general, I find that people are falling into 2 categories. There are patients who basically say, “I’m done with the chemotherapy, I completed it, I’m happy to follow up, but I would not necessarily like to pursue additional maintenance.” And there are folks who really feel very strongly about doing everything possible to keep their tumor under control. Then we discuss the data and those folks would select maintenance therapy. The duration after this year at ASH will be another discussion that we’ll have about the potential additional benefit of adding 2 years of Rituxan to maintenance.

Anas Younes, MD: Can I add one more thing? What’s confusing in the field is that there is another trial that was published recently in JCO (Journal of Clinical Oncology), another 10-year follow-up from the Italian group where they used R-chemotherapy versus chemotherapy. In the 10-year follow-up, R-CHOP with no maintenance gave also about 10-year progression-free survival. There are data to support either/or. If you give it, it’s fine. If you don’t give it, it’s not malpractice. And I think that’s a discussion for all of us with the patients, and some of them would want to get Rituxan maintenance or obinutuzumab maintenance, and that’s perfect fine. But if you don’t give it, I think it’s also perfectly fine.

Ian W. Flinn, MD, PhD: How does all this realization about this color your interpretation of the GALLIUM trial, where there was maintenance with obinutuzumab? I find it difficult because I felt like for 10 years, I was telling my patients that I think it’s probably good to have maintenance therapy. Now I’m less sure of that, but when trying to interpret the GALLIUM trial with obinutuzumab maintenance, that certainly was superior.

Anas Younes, MD: It’s certainly in a disease where the median survival now exceeds 18 years. And safety and toxicity become an issue, so you need to make sure that the patients who are treated would also get safe treatment, that we’re not exposing them to toxic treatments that may add subsequent therapies. So, this needs to be factored in. In a perfectly healthy person, I think it’s no problem treating patients with maintenance. Honestly, most of us were shocked when we saw the data from GALLIUM because all of us said, “I never see this in my patients,” but data is data. So, I’m sure some patients may not tolerate this kind of treatment, but it’s rare in clinical practice, at least in some of our experience.

Ian W. Flinn, MD, PhD: Loretta, how about you? Is there any difference, in your opinion, on this subject?

Loretta J. Nastoupil, MD: I think the problem with the GALLIUM study is that it was designed to tell us which CD20 antibody was superior, but it’s a very large prospective study of follicular lymphoma with over 1000 patients. So now we’re learning more in terms of what the toxicity profile is associated with chemotherapy and CD20, and we, for the first time, saw some prospective data looking at CD20 maintenance following bendamustine. We do have the StiL data at this ASH meeting, and your BRIGHT study. There, about half of the patients did receive maintenance, but it wasn’t prospectively built in. So, I think what we’ve learned from this is there are some toxicities that you have to be mindful of after patients complete their chemotherapy. And we’re seeing some subgroup analysis come out of the GALLIUM data, where it looks like particularly some of the CD8 effector cells may be impacted after they stop the bendamustine.

I think this now raises more complexity, and the discussion you have with patients is, “Just because you’re in this maintenance phase and we’re less worried about toxicity associated with chemotherapy, there still are toxicities that you need to be mindful of, including infection.” The other issue is second cancers. Now, we know patients with follicular lymphoma are more prone to second cancers, probably due to failure of immune surveillance. But when you continue these therapies more prolongedly, are you also enhancing that risk? We don’t know the answer.

Peter Martin, MD, MS: I think that’s a great point. Greg made the point earlier as well from the Mayo Clinic, the Matt Maurer data looking at EFS12, where it’s clear that a significant proportion of patients have a survival that’s equivalent to the population without lymphoma. Their life experience is not one of excess mortality, but one of excess morbidity. When we’re managing people with follicular lymphoma, as Loretta says, one of the key points is to minimize morbidity because chances are they’re going to do well regardless of the choices we make.

Transcript Edited for Clarity 
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