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Follicular Lymphoma: Outcomes After Immunochemotherapy

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: Friday, Jan 05, 2018



Ian W. Flinn, MD, PhD: Hello and thank you for joining this OncLive® Peer Exchange® titled “Refining Therapeutic Strategies for Follicular Lymphoma.” Despite that follicular lymphoma remains an incurable disease, outcomes are good for most patients, with a median overall survival exceeding 12 years. However, for the subgroup of patients who have high-risk disease and who develop early relapse or histologic transformation, clinical outcomes after immunochemotherapy are still poor.

Today I am joined by a group of my colleagues who are renowned experts in the field of lymphoma research. During the next 90 minutes, we will discuss evolving research surrounding the treatment of follicular lymphoma, we’ll talk about how to incorporate newly available agents into your treatment approach, and we’ll highlight the studies from the 2017 ASH Annual Meeting.
I am Dr. Ian Flinn, and I am the director of the blood cancer research program at the Sarah Cannon Research Institute in Nashville, Tennessee.

Participating today on our distinguished panel are Dr. Peter Martin, associate professor of medicine in the Division of Hematology/Oncology at the Weill Cornell Medical College in New York City, New York; Dr. Loretta Nastoupil, assistant professor in the Department of Lymphoma/Myeloma in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas; Dr. Grzegorz Nowakowski, associate professor of medicine and oncology for the Division of Hematology at the Mayo Clinic in Rochester, Minnesota; and Dr. Anas Younes, professor and chief of the Lymphoma Service at the Memorial Sloan Kettering Cancer Center in New York City, New York.

Thank you so much for joining us. Let’s begin. Greg, we’ve come to think of frontline therapy for patients with follicular lymphoma to be chemoimmunotherapy, yet there’s tremendous variation in outcomes for patients. Can you describe, perhaps, how these variations occur and how we might tailor therapy?

Grzegorz S. Nowakowski, MD: Absolutely. If you look at follicular lymphoma, in general, this is a very heterogeneous disease. Even patients with low bulk disease, which does not require treatment, have a very variable prognosis. Some of them can be observed for years, and some of them will have a relatively accelerated disease course and require therapy at some point. Now, for patients who are in need of therapy, after chemoimmunotherapy there is significant heterogeneity of the outcomes. But 20% of the patients or so will relapse early within the first 2 years, and those patients generally do much worse than patients who do not. What’s interesting is that a lot of data, including data from the Mayo Clinic, University of Iowa, Lymphoma SPORE, and a French group, indicate that if you do not relapse within the first 2 years after chemoimmunotherapy in follicular lymphoma, your life expectancy is just like anybody else in that population. A lot of those differences are driven by the biology of follicular lymphoma. We all know that the hallmark of the disease is the presence of translocation IGH and BCL-2, which seem to be driving the disease. However, if you look at the pathology of the disease apart from grading, there is also variability in the presence of microenvironment cells, the immune microenvironment, and genetically the tumor is heterogeneous as well. There are somatic mutations, a number of genes that are being described now, and all of those mutations and heterogeneity of the microenvironment are playing an important role in the differences in outcomes that we see after chemoimmunotherapy.

Ian W. Flinn, MD, PhD: One of the most dreaded issues with follicular lymphoma is perhaps the transformation to an aggressive lymphoma. I think it’s difficult in the clinic to know, when you see patients, who that might be. Is there anything that you use to maybe raise your concern about transformation, especially in that frontline setting?

Grzegorz S. Nowakowski, MD: You’re right. This is a very difficult issue, and I will start by highlighting that lymphoma pathology in general tends to be difficult, so you really need to have an expert pathologist looking at the biopsy throughout transformation and for the grading of follicular lymphoma. One of the clinical factors that we use while looking at a patient in determining risk of transformation at presentation is LDH. High LDH is suggestive of transformation, presence of B symptoms, and rapidly progressive disease. The PET scan tends to be somewhat variable. It’s not always conclusive in regards to a transformation.
However, we do worry about the patients who have high SUV, particularly if there is discordance. Some of the lymph nodes are looking relatively dim, but other groups of the lymph nodes are very bright and hot on the PET scan. You worry about transformation, and typically we’d obtain a biopsy to rule it out. If you look at the results in Rituxan (rituximab), the risk of transformation is about 2% per year and appears to be pretty steady. I think what’s important is that we found that outcomes of patients with transformed lymphoma are actually quite variable as well. So, if you have patients who were previously treated with multiple regimens, particularly containing anthracyclines, the outcome is quite poor.

On the other hand, patients who did not have exposure to anthracycline before do quite well with R-CHOP alone. So, I think that’s encouraging because in the past we used to consider most of those patients to be in quite a difficult situation. But right now, clearly, patients who are not anthracycline exposed do quite well, even with transformed disease, with R-CHOP or similar therapy.

Ian W. Flinn, MD, PhD: Peter, Greg has brought up a number of issues. In clinical trials, we use prognostic indicators such as the FLIPI score and variations of that. Do you use these in your practice? How does that change, perhaps, what you do? We talked about PET scanning and maybe a way of figuring out who’s at risk for transformation, but how about PET scanning after someone has had therapy? Is that useful?

Peter Martin, MD, MS: I think those are great questions, Ian. The FLIPI, FLIPI-2, and m7- FLIPI were all prognostic scores that were effectively developed to be research tools, I think. FLIPI was originally looking retrospectively as existing data. People realized that it had significant prognostic value, but decided that we would like to evaluate it in a group of patients with prospectively collected data. And so, they went to the FLIPI-2, where they had more patients with beta-2 microglobulin available, refining that score a little bit. And later on, eventually people said, “Well, we’re in this next-generation sequencing era. We should look at the actual genetics of the disease.” We did sequencing and found 7 genes had a significant prognostic value and came up with the m7-FLIPI. In all of these cases, l think these are just prognostic tools; they’re not necessarily predictive tools. So, we can report these, and I certainly add the FLIPI score in all of my clinical notes as a reminder to myself of what I’m dealing with. But I’m not necessarily sure that we need to modify therapy based on the FLIPI score. There are certainly people with a low-risk FLIPI score who don’t do all that well, and there are people with a high-risk FLIPI score who do very well. So, it’s hard to say how we should use the FLIPI score to impact management. It’s more a matter of understanding where we’re likely heading when we’re dealing with a patient.

But I think a PET scan is a useful tool as well to assess response at the end of therapy, and certainly there have been studies that have suggested a good response to therapy, defined by a negative PET scan at the end of therapy, is associated with good long-term outcomes. Whether that’s just a marker of a better therapy or whether it’s a marker of a lower risk disease is still unknown. I’m not sure that we should necessarily be increasing the intensity of therapy all the time to try to get to that negative PET scan. But when you see a negative PET scan, it’s certainly encouraging.

Transcript Edited for Clarity 

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Ian W. Flinn, MD, PhD: Hello and thank you for joining this OncLive® Peer Exchange® titled “Refining Therapeutic Strategies for Follicular Lymphoma.” Despite that follicular lymphoma remains an incurable disease, outcomes are good for most patients, with a median overall survival exceeding 12 years. However, for the subgroup of patients who have high-risk disease and who develop early relapse or histologic transformation, clinical outcomes after immunochemotherapy are still poor.

Today I am joined by a group of my colleagues who are renowned experts in the field of lymphoma research. During the next 90 minutes, we will discuss evolving research surrounding the treatment of follicular lymphoma, we’ll talk about how to incorporate newly available agents into your treatment approach, and we’ll highlight the studies from the 2017 ASH Annual Meeting.
I am Dr. Ian Flinn, and I am the director of the blood cancer research program at the Sarah Cannon Research Institute in Nashville, Tennessee.

Participating today on our distinguished panel are Dr. Peter Martin, associate professor of medicine in the Division of Hematology/Oncology at the Weill Cornell Medical College in New York City, New York; Dr. Loretta Nastoupil, assistant professor in the Department of Lymphoma/Myeloma in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas; Dr. Grzegorz Nowakowski, associate professor of medicine and oncology for the Division of Hematology at the Mayo Clinic in Rochester, Minnesota; and Dr. Anas Younes, professor and chief of the Lymphoma Service at the Memorial Sloan Kettering Cancer Center in New York City, New York.

Thank you so much for joining us. Let’s begin. Greg, we’ve come to think of frontline therapy for patients with follicular lymphoma to be chemoimmunotherapy, yet there’s tremendous variation in outcomes for patients. Can you describe, perhaps, how these variations occur and how we might tailor therapy?

Grzegorz S. Nowakowski, MD: Absolutely. If you look at follicular lymphoma, in general, this is a very heterogeneous disease. Even patients with low bulk disease, which does not require treatment, have a very variable prognosis. Some of them can be observed for years, and some of them will have a relatively accelerated disease course and require therapy at some point. Now, for patients who are in need of therapy, after chemoimmunotherapy there is significant heterogeneity of the outcomes. But 20% of the patients or so will relapse early within the first 2 years, and those patients generally do much worse than patients who do not. What’s interesting is that a lot of data, including data from the Mayo Clinic, University of Iowa, Lymphoma SPORE, and a French group, indicate that if you do not relapse within the first 2 years after chemoimmunotherapy in follicular lymphoma, your life expectancy is just like anybody else in that population. A lot of those differences are driven by the biology of follicular lymphoma. We all know that the hallmark of the disease is the presence of translocation IGH and BCL-2, which seem to be driving the disease. However, if you look at the pathology of the disease apart from grading, there is also variability in the presence of microenvironment cells, the immune microenvironment, and genetically the tumor is heterogeneous as well. There are somatic mutations, a number of genes that are being described now, and all of those mutations and heterogeneity of the microenvironment are playing an important role in the differences in outcomes that we see after chemoimmunotherapy.

Ian W. Flinn, MD, PhD: One of the most dreaded issues with follicular lymphoma is perhaps the transformation to an aggressive lymphoma. I think it’s difficult in the clinic to know, when you see patients, who that might be. Is there anything that you use to maybe raise your concern about transformation, especially in that frontline setting?

Grzegorz S. Nowakowski, MD: You’re right. This is a very difficult issue, and I will start by highlighting that lymphoma pathology in general tends to be difficult, so you really need to have an expert pathologist looking at the biopsy throughout transformation and for the grading of follicular lymphoma. One of the clinical factors that we use while looking at a patient in determining risk of transformation at presentation is LDH. High LDH is suggestive of transformation, presence of B symptoms, and rapidly progressive disease. The PET scan tends to be somewhat variable. It’s not always conclusive in regards to a transformation.
However, we do worry about the patients who have high SUV, particularly if there is discordance. Some of the lymph nodes are looking relatively dim, but other groups of the lymph nodes are very bright and hot on the PET scan. You worry about transformation, and typically we’d obtain a biopsy to rule it out. If you look at the results in Rituxan (rituximab), the risk of transformation is about 2% per year and appears to be pretty steady. I think what’s important is that we found that outcomes of patients with transformed lymphoma are actually quite variable as well. So, if you have patients who were previously treated with multiple regimens, particularly containing anthracyclines, the outcome is quite poor.

On the other hand, patients who did not have exposure to anthracycline before do quite well with R-CHOP alone. So, I think that’s encouraging because in the past we used to consider most of those patients to be in quite a difficult situation. But right now, clearly, patients who are not anthracycline exposed do quite well, even with transformed disease, with R-CHOP or similar therapy.

Ian W. Flinn, MD, PhD: Peter, Greg has brought up a number of issues. In clinical trials, we use prognostic indicators such as the FLIPI score and variations of that. Do you use these in your practice? How does that change, perhaps, what you do? We talked about PET scanning and maybe a way of figuring out who’s at risk for transformation, but how about PET scanning after someone has had therapy? Is that useful?

Peter Martin, MD, MS: I think those are great questions, Ian. The FLIPI, FLIPI-2, and m7- FLIPI were all prognostic scores that were effectively developed to be research tools, I think. FLIPI was originally looking retrospectively as existing data. People realized that it had significant prognostic value, but decided that we would like to evaluate it in a group of patients with prospectively collected data. And so, they went to the FLIPI-2, where they had more patients with beta-2 microglobulin available, refining that score a little bit. And later on, eventually people said, “Well, we’re in this next-generation sequencing era. We should look at the actual genetics of the disease.” We did sequencing and found 7 genes had a significant prognostic value and came up with the m7-FLIPI. In all of these cases, l think these are just prognostic tools; they’re not necessarily predictive tools. So, we can report these, and I certainly add the FLIPI score in all of my clinical notes as a reminder to myself of what I’m dealing with. But I’m not necessarily sure that we need to modify therapy based on the FLIPI score. There are certainly people with a low-risk FLIPI score who don’t do all that well, and there are people with a high-risk FLIPI score who do very well. So, it’s hard to say how we should use the FLIPI score to impact management. It’s more a matter of understanding where we’re likely heading when we’re dealing with a patient.

But I think a PET scan is a useful tool as well to assess response at the end of therapy, and certainly there have been studies that have suggested a good response to therapy, defined by a negative PET scan at the end of therapy, is associated with good long-term outcomes. Whether that’s just a marker of a better therapy or whether it’s a marker of a lower risk disease is still unknown. I’m not sure that we should necessarily be increasing the intensity of therapy all the time to try to get to that negative PET scan. But when you see a negative PET scan, it’s certainly encouraging.

Transcript Edited for Clarity 
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