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Up-Front Therapy in Follicular Lymphoma

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Nathan H. Fowler, MD, The University of Texas MD Anderson Cancer Center; Ajay K. Gopal, MD, FACP, Seattle Cancer Care Alliance; Scott Huntington, MD, MPH, MSc, Yale University School of Medicine
Published: Monday, Jan 21, 2019



Transcript:

Ian W. Flinn, MD, PhD:
Scott, let’s turn to initial therapy of follicular lymphoma. How do you make the decision about when to start someone? We’ve had watch-and-wait for a number of years, the GELF [Groupe d’Etude des Lymphomes Folliculaires] Criteria about initiation. Is that still relevant today and is that how you’re approaching things?

Scott Huntington, MD, MPH, MSc: The GELF Criteria is helpful for defining who’s entering clinical trials, and so this looks at things like nodal involvement, extra nodal involvement, pleural effusions, ascites, leukemic involvement. So I think it helps define the study population. But in clinical practice there may be people that actually have criteria by GELF that may have a treatment indication but have very slowly progressive disease that you follow for many years, and it may not be urgent to start therapy.

Conversely there are people that effectively don’t have criteria by GELF that may benefit from therapy. So these might be older folks that have comorbidities. You may want to treat them as they have lower volume disease. You might be able to get away with say rituximab monotherapy.

So I think the GELF Criteria is very important for defining who’s entering the trials. But in the real-world practice there’s a spectrum of who you’re starting therapy on in our patients.

Ian W. Flinn, MD, PhD: I know that I tell my patients up front, we’re not going to treat for a while, and most of them think that’s crazy, right? I mean everything they know about cancer is early initiation of treatment is the key to outcome. Once you watched-and-waited them for a while, sometimes it’s hard to get them out.

Scott Huntington, MD, MPH, MSc: Yes.

Ian W. Flinn, MD, PhD: So how does that conversation go and what criteria do you use? And talk a little bit about how you’re deciding what treatments to use in an individual patient.

Scott Huntington, MD, MPH, MSc: Sure. If we think about CLL [chronic lymphocytic leukemia] for instance, the data suggest that really we should be having active surveillance until disease progression, or just before disease progression. We do have data in follicular lymphoma of treating asymptomatic low-volume, and that primarily is using rituximab monotherapy, not a prolonged course but perhaps 8 treatments over 9 months or so.

And so for a select population that has questions about delaying therapy, I think monotherapy rituximab, we have data to support that. The majority of patients if you have a back and forth discussion and you see them, I typically see patients frequently and we go over the diagnosis, bring them back in. And if they feel great and you have a repeat scan, or repeat examination suggesting stability, oftentimes they come around to the idea of active surveillance, and patients can have very normal processes and not require therapy for 10 years in some instances, and very low indolent lymphoma.

In terms of choosing treatment, it really depends on the pace of progression. You know perhaps the histology, so whether someone has a more indolent appearing low-grade versus certainly grade 3b would be treated more like aggressive lymphoma. And it’s really all about comorbidities in selecting toxicity profiles for the individual patient.

Ian W. Flinn, MD, PhD: Ajay, is that similar to your experience? We’ll get into details later about some of the different chemotherapy regimens, but are you using some of these comorbidities, or patient factors or even measurement of disease to determine what your frontline therapy is?

Ajay K. Gopal, MD, FACP: I’d first echo that I think observation, at least in 2 randomized trials, has shown that treating asymptomatic patients doesn’t improve overall survival. And I think as we know that this is a long game disease, I’d sit down with my patients and say, “We’re playing a long game, the 20-year game here.” We can always get people in remission, but that may not be the most important thing. So observation is really key.

However, when patients meet GELF Criteria there’s other reason to treat them. We’ll often stratify them by comorbidities. I think we probably do this a little more informally. There are these comorbidity scores, Charlson Comorbidity Index and scales, but it’s really more informal. And then we look at their disease burden, and typically for those that have high disease burden, it’s more in this day and age a chemoimmunotherapy approach. And for those that have low disease burden, or significant comorbidities, we may try a single-agent rituximab strategy.

Ian W. Flinn, MD, PhD.: So chemoimmunotherapy, do people call you up and say, “What’s your go-to therapy for patients with follicular?” Do you have a go-to therapy or is it different for everybody?

Ajay K. Gopal, MD, FACP: Well I think things may change in the future. In general, I still use bendamustine/rituximab frequently. There are data obviously with R-squared [lenalidomide/rituximab] as well for consideration. But bendamustine/rituximab, and it’s important to make sure there’s no transformation. You need to only use it for grades 1 and 2 follicular lymphoma, since the 2 randomized trials excluded grade 3a. So there’s certain criteria where you consider bendamustine/rituximab, but that’s typically what I would go to in those specific situations.

Ian W. Flinn, MD, PhD: We’re going to talk about R-squared regimen in a little bit, but patient selection for different the regimens, is it you sort of follow similar algorithms?

Nathan H. Fowler, MD: Yes. I think the buzzword about newly diagnosed low-grade lymphomas is individualization of therapy. You find some patients that they prefer an IV [intravenous] regimen and they finish quickly. Other patients are looking for some type of immunotherapy. I have many of my young and very active patients who actually opt for R-squared because the quality of life. And many of these patients have almost no symptoms as they’re going through therapy. So I would say, unfortunately I don’t have a real clear answer for that. I use R-squared in some patients, a little bit of bendamustine, and R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone] in patients who I’m going to be a little worried about something bad that’s kind of cooking.

There was an interesting abstract by Dr Emanuele Zucca MD at this ASH[American Society of Hematology meeting] where they had long-term follow up of a SAKK trial where they’re randomizing patients to get 2 or 5 years of rituximab. And although it wasn’t a big difference, one thing I found interesting in that abstract, they look at the long-term survival of these patients who were started on rituximab as a single agent; it was 80% to 10 years. And that’s very similar to the PRIMA trial and some of these others trials that started with chemotherapy. And so it brings up to me a very interesting question of, if we start with milder therapy first and only use more aggressive regimens like chemotherapy regimens in those patients where single-agent rituximab did not work, you know we may be having the same long-term outcomes.

And, again, I think in the United States we don’t use a lot single-agent rituximab as a frontline, and I think in Europe they’re more used to using that, and it may be just as good.

Ajay K. Gopal, MD, FACP: Right. I think this is maybe a situation where the community doctors are actually ahead of the curve compared to us academicians, because I think the community, even if you have high-burden disease, single-agent rituximab is often employed because of the toxicity profile, and people see how much mileage they can get out of that knowing you could always add in lenalidomide or bendamustine later.

Transcript edited for clarity.
 

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Transcript:

Ian W. Flinn, MD, PhD:
Scott, let’s turn to initial therapy of follicular lymphoma. How do you make the decision about when to start someone? We’ve had watch-and-wait for a number of years, the GELF [Groupe d’Etude des Lymphomes Folliculaires] Criteria about initiation. Is that still relevant today and is that how you’re approaching things?

Scott Huntington, MD, MPH, MSc: The GELF Criteria is helpful for defining who’s entering clinical trials, and so this looks at things like nodal involvement, extra nodal involvement, pleural effusions, ascites, leukemic involvement. So I think it helps define the study population. But in clinical practice there may be people that actually have criteria by GELF that may have a treatment indication but have very slowly progressive disease that you follow for many years, and it may not be urgent to start therapy.

Conversely there are people that effectively don’t have criteria by GELF that may benefit from therapy. So these might be older folks that have comorbidities. You may want to treat them as they have lower volume disease. You might be able to get away with say rituximab monotherapy.

So I think the GELF Criteria is very important for defining who’s entering the trials. But in the real-world practice there’s a spectrum of who you’re starting therapy on in our patients.

Ian W. Flinn, MD, PhD: I know that I tell my patients up front, we’re not going to treat for a while, and most of them think that’s crazy, right? I mean everything they know about cancer is early initiation of treatment is the key to outcome. Once you watched-and-waited them for a while, sometimes it’s hard to get them out.

Scott Huntington, MD, MPH, MSc: Yes.

Ian W. Flinn, MD, PhD: So how does that conversation go and what criteria do you use? And talk a little bit about how you’re deciding what treatments to use in an individual patient.

Scott Huntington, MD, MPH, MSc: Sure. If we think about CLL [chronic lymphocytic leukemia] for instance, the data suggest that really we should be having active surveillance until disease progression, or just before disease progression. We do have data in follicular lymphoma of treating asymptomatic low-volume, and that primarily is using rituximab monotherapy, not a prolonged course but perhaps 8 treatments over 9 months or so.

And so for a select population that has questions about delaying therapy, I think monotherapy rituximab, we have data to support that. The majority of patients if you have a back and forth discussion and you see them, I typically see patients frequently and we go over the diagnosis, bring them back in. And if they feel great and you have a repeat scan, or repeat examination suggesting stability, oftentimes they come around to the idea of active surveillance, and patients can have very normal processes and not require therapy for 10 years in some instances, and very low indolent lymphoma.

In terms of choosing treatment, it really depends on the pace of progression. You know perhaps the histology, so whether someone has a more indolent appearing low-grade versus certainly grade 3b would be treated more like aggressive lymphoma. And it’s really all about comorbidities in selecting toxicity profiles for the individual patient.

Ian W. Flinn, MD, PhD: Ajay, is that similar to your experience? We’ll get into details later about some of the different chemotherapy regimens, but are you using some of these comorbidities, or patient factors or even measurement of disease to determine what your frontline therapy is?

Ajay K. Gopal, MD, FACP: I’d first echo that I think observation, at least in 2 randomized trials, has shown that treating asymptomatic patients doesn’t improve overall survival. And I think as we know that this is a long game disease, I’d sit down with my patients and say, “We’re playing a long game, the 20-year game here.” We can always get people in remission, but that may not be the most important thing. So observation is really key.

However, when patients meet GELF Criteria there’s other reason to treat them. We’ll often stratify them by comorbidities. I think we probably do this a little more informally. There are these comorbidity scores, Charlson Comorbidity Index and scales, but it’s really more informal. And then we look at their disease burden, and typically for those that have high disease burden, it’s more in this day and age a chemoimmunotherapy approach. And for those that have low disease burden, or significant comorbidities, we may try a single-agent rituximab strategy.

Ian W. Flinn, MD, PhD.: So chemoimmunotherapy, do people call you up and say, “What’s your go-to therapy for patients with follicular?” Do you have a go-to therapy or is it different for everybody?

Ajay K. Gopal, MD, FACP: Well I think things may change in the future. In general, I still use bendamustine/rituximab frequently. There are data obviously with R-squared [lenalidomide/rituximab] as well for consideration. But bendamustine/rituximab, and it’s important to make sure there’s no transformation. You need to only use it for grades 1 and 2 follicular lymphoma, since the 2 randomized trials excluded grade 3a. So there’s certain criteria where you consider bendamustine/rituximab, but that’s typically what I would go to in those specific situations.

Ian W. Flinn, MD, PhD: We’re going to talk about R-squared regimen in a little bit, but patient selection for different the regimens, is it you sort of follow similar algorithms?

Nathan H. Fowler, MD: Yes. I think the buzzword about newly diagnosed low-grade lymphomas is individualization of therapy. You find some patients that they prefer an IV [intravenous] regimen and they finish quickly. Other patients are looking for some type of immunotherapy. I have many of my young and very active patients who actually opt for R-squared because the quality of life. And many of these patients have almost no symptoms as they’re going through therapy. So I would say, unfortunately I don’t have a real clear answer for that. I use R-squared in some patients, a little bit of bendamustine, and R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone] in patients who I’m going to be a little worried about something bad that’s kind of cooking.

There was an interesting abstract by Dr Emanuele Zucca MD at this ASH[American Society of Hematology meeting] where they had long-term follow up of a SAKK trial where they’re randomizing patients to get 2 or 5 years of rituximab. And although it wasn’t a big difference, one thing I found interesting in that abstract, they look at the long-term survival of these patients who were started on rituximab as a single agent; it was 80% to 10 years. And that’s very similar to the PRIMA trial and some of these others trials that started with chemotherapy. And so it brings up to me a very interesting question of, if we start with milder therapy first and only use more aggressive regimens like chemotherapy regimens in those patients where single-agent rituximab did not work, you know we may be having the same long-term outcomes.

And, again, I think in the United States we don’t use a lot single-agent rituximab as a frontline, and I think in Europe they’re more used to using that, and it may be just as good.

Ajay K. Gopal, MD, FACP: Right. I think this is maybe a situation where the community doctors are actually ahead of the curve compared to us academicians, because I think the community, even if you have high-burden disease, single-agent rituximab is often employed because of the toxicity profile, and people see how much mileage they can get out of that knowing you could always add in lenalidomide or bendamustine later.

Transcript edited for clarity.
 
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