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Treating Follicular Lymphoma: Addressing Unmet Needs

Insights From: Alexey V. Danilov, MD, PhD, Oregon Health & Science University; Carla Casulo, MD, University of Rochester, Wilmot Cancer Institute
Published: Thursday, Aug 08, 2019



Transcript: 

Carla Casulo, MD: I think the unmet need right now for follicular lymphoma is knowing who to treat and with what, because right now, we blanket-treat everyone the same. We have 2 large, randomized studies, both GALLIUM and RELEVANCE. Both show that chemotherapy is still king—it works for a long time. We can probably do better, but we don’t know who needs what. We don’t know what subsets of patients will benefit from one particular treatment versus another. I think that if you take a population of patients that will normally do very well, it doesn’t make that much sense to treat everyone the same, because some will do very well and some will not do as well. In my opinion, trying to identify patients—those pockets of high-risk patients—is really the next step in trying to treat patients with follicular lymphoma.

Alexey V. Danilov, MD, PhD: As we discussed, the unmet medical need in treatment for frontline follicular lymphoma remains identification of patients who will progress within 24 months, who are the early progressors, and identifying the best therapeutic approach for those patients. It is unclear whether chemoimmunotherapy still should be the best approach for those patients, but that’s what we have now. Again, using current data, I would treat a patient at risk for early progression with a combination of bendamustine and obinutuzumab. A recent study called RELEVANCE tested a combination of lenalidomide and rituximab versus chemotherapy/rituximab, and the primary endpoint of that study was progression-free survival. It actually wasn’t met, so it seems that lenalidomide/rituximab is not better for therapy in all patients with follicular lymphoma compared with chemoimmunotherapy. Again, we don’t actually know if lenalidomide would particularly benefit patients who are at risk for further progression, and that will need to be investigated in the future.

The remaining unmet needs would be patients with multiple relapsed/refractory follicular lymphoma— those patients who progress through a couple of lines of chemoimmunotherapy and have become rituximab-refractory, obinutuzumab-refractory, and refractory to chemotherapy with alkylating agents. The options for those patients are becoming limited. Lenalidomide still remains an option. Phosphoinositide 3-kinase [PI3-kinase] inhibitors, such as duvelisib, idelalisib, and copanlisib have been approved in this setting. However, most of those agents, particularly PI3-kinase inhibitors, will be associated with a fairly limited progression-free survival. They work for about a year. After that, options are even more limited, so relapsed/refractory follicular lymphoma, particularly double-refractory to alkylating agents and CD20 antibodies, is really an unmet medical need.

An interesting field will be the development of CAR [chimeric antigen receptor] T cells in patients with follicular lymphoma. This is a subject of many clinical trials at this stage, and it will be interesting to see what data are generated there. It seems very promising right now, and the CAR T-cell therapy may be a good option for some patients with relapsed/refractory follicular lymphoma. Then, as we discussed previously, identification of those early progressor patients early on is an unmet medical need, as well.

Carla Casulo, MD: Right now, there are a few studies looking at frontline therapy. A lot of them combine bendamustine and rituximab with something else, or they combine R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone] with something else. They’re really looking at triplet treatments. Again, these are sort of unselected populations of patients with follicular lymphoma. I’m not sure yet, at least now, without getting the read-out of what these studies are. We have to see if they’re able to identify those subsets of patients who have higher-risk disease or lower-risk disease. We have lots of great treatments and everybody is excited about putting them all together, but if all of the patients are going to be treated exactly the same, we may end up in the same situation that we currently are in.

Alexey V. Danilov, MD, PhD: In the community practices in the United States, a combination of bendamustine and rituximab is very commonly used in the therapy of follicular lymphoma. I have to say that in my practice, at least half of the patients will be treated with that regimen. In patients who identify as potentially being at risk for early disease progression, I would use a combination of obinutuzumab and bendamustine. For some of those patients where I suspect disease transformation but cannot confirm it, I would use R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone]. I typically would try to perform a biopsy on patients who come with relapsed disease. Excisional biopsy would be advised, but at least a core biopsy at that stage to confirm follicular lymphoma and rule out disease transformation would be critical. In that setting, depending on how much time has passed since the patient was treated the last time, I would entertain chemoimmunotherapy versus lenalidomide/rituximab.

Carla Casulo, MD: What I would suggest is not necessarily using obinutuzumab as the decision point to decide whether this patient is going to progress early, because we don’t really know at the onset who is going to progress early. Outside of the things we have already discussed, there are few biological mechanisms that have been established as standards to tell us who will relapse early.

What I would instead suggest is that you look at the patient and the patient’s comorbidity. Are they an older person? Do they have many other medical conditions? Can they tolerate the risk of infusion-related reaction? Are you planning on using maintenance? In the GALLIUM study, the benefit that we saw was 2 and a half years of treatment—6 cycles of chemotherapy plus 2 years of maintenance. Are you prepared to offer maintenance to your patient, and is that patient going to tolerate some of the higher rate of grades 3 to 5 adverse events that were observed with the obinutuzumab-containing arm?

I think that’s a much more practical approach to deciding between obinutuzumab versus rituximab. Choosing obinutuzumab on the basis only that it’ll decrease early disease-related events wouldn’t necessarily be my choice. If you had someone who you think is very high-risk—for example, male gender, high-risk FLIPI [Follicular Lymphoma International Prognostic Index], higher-grade disease, advanced stage, very symptomatic—I think you might choose obinutuzumab, naturally, regardless of whether you think that patient is more likely to relapse early.

What I’m saying is, that’s not the only parameter I would use. I think that’s something to be taken into consideration, but it’s not the only parameter that should be used in selecting first-line treatment.

Transcript Edited for Clarity
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Transcript: 

Carla Casulo, MD: I think the unmet need right now for follicular lymphoma is knowing who to treat and with what, because right now, we blanket-treat everyone the same. We have 2 large, randomized studies, both GALLIUM and RELEVANCE. Both show that chemotherapy is still king—it works for a long time. We can probably do better, but we don’t know who needs what. We don’t know what subsets of patients will benefit from one particular treatment versus another. I think that if you take a population of patients that will normally do very well, it doesn’t make that much sense to treat everyone the same, because some will do very well and some will not do as well. In my opinion, trying to identify patients—those pockets of high-risk patients—is really the next step in trying to treat patients with follicular lymphoma.

Alexey V. Danilov, MD, PhD: As we discussed, the unmet medical need in treatment for frontline follicular lymphoma remains identification of patients who will progress within 24 months, who are the early progressors, and identifying the best therapeutic approach for those patients. It is unclear whether chemoimmunotherapy still should be the best approach for those patients, but that’s what we have now. Again, using current data, I would treat a patient at risk for early progression with a combination of bendamustine and obinutuzumab. A recent study called RELEVANCE tested a combination of lenalidomide and rituximab versus chemotherapy/rituximab, and the primary endpoint of that study was progression-free survival. It actually wasn’t met, so it seems that lenalidomide/rituximab is not better for therapy in all patients with follicular lymphoma compared with chemoimmunotherapy. Again, we don’t actually know if lenalidomide would particularly benefit patients who are at risk for further progression, and that will need to be investigated in the future.

The remaining unmet needs would be patients with multiple relapsed/refractory follicular lymphoma— those patients who progress through a couple of lines of chemoimmunotherapy and have become rituximab-refractory, obinutuzumab-refractory, and refractory to chemotherapy with alkylating agents. The options for those patients are becoming limited. Lenalidomide still remains an option. Phosphoinositide 3-kinase [PI3-kinase] inhibitors, such as duvelisib, idelalisib, and copanlisib have been approved in this setting. However, most of those agents, particularly PI3-kinase inhibitors, will be associated with a fairly limited progression-free survival. They work for about a year. After that, options are even more limited, so relapsed/refractory follicular lymphoma, particularly double-refractory to alkylating agents and CD20 antibodies, is really an unmet medical need.

An interesting field will be the development of CAR [chimeric antigen receptor] T cells in patients with follicular lymphoma. This is a subject of many clinical trials at this stage, and it will be interesting to see what data are generated there. It seems very promising right now, and the CAR T-cell therapy may be a good option for some patients with relapsed/refractory follicular lymphoma. Then, as we discussed previously, identification of those early progressor patients early on is an unmet medical need, as well.

Carla Casulo, MD: Right now, there are a few studies looking at frontline therapy. A lot of them combine bendamustine and rituximab with something else, or they combine R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone] with something else. They’re really looking at triplet treatments. Again, these are sort of unselected populations of patients with follicular lymphoma. I’m not sure yet, at least now, without getting the read-out of what these studies are. We have to see if they’re able to identify those subsets of patients who have higher-risk disease or lower-risk disease. We have lots of great treatments and everybody is excited about putting them all together, but if all of the patients are going to be treated exactly the same, we may end up in the same situation that we currently are in.

Alexey V. Danilov, MD, PhD: In the community practices in the United States, a combination of bendamustine and rituximab is very commonly used in the therapy of follicular lymphoma. I have to say that in my practice, at least half of the patients will be treated with that regimen. In patients who identify as potentially being at risk for early disease progression, I would use a combination of obinutuzumab and bendamustine. For some of those patients where I suspect disease transformation but cannot confirm it, I would use R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone]. I typically would try to perform a biopsy on patients who come with relapsed disease. Excisional biopsy would be advised, but at least a core biopsy at that stage to confirm follicular lymphoma and rule out disease transformation would be critical. In that setting, depending on how much time has passed since the patient was treated the last time, I would entertain chemoimmunotherapy versus lenalidomide/rituximab.

Carla Casulo, MD: What I would suggest is not necessarily using obinutuzumab as the decision point to decide whether this patient is going to progress early, because we don’t really know at the onset who is going to progress early. Outside of the things we have already discussed, there are few biological mechanisms that have been established as standards to tell us who will relapse early.

What I would instead suggest is that you look at the patient and the patient’s comorbidity. Are they an older person? Do they have many other medical conditions? Can they tolerate the risk of infusion-related reaction? Are you planning on using maintenance? In the GALLIUM study, the benefit that we saw was 2 and a half years of treatment—6 cycles of chemotherapy plus 2 years of maintenance. Are you prepared to offer maintenance to your patient, and is that patient going to tolerate some of the higher rate of grades 3 to 5 adverse events that were observed with the obinutuzumab-containing arm?

I think that’s a much more practical approach to deciding between obinutuzumab versus rituximab. Choosing obinutuzumab on the basis only that it’ll decrease early disease-related events wouldn’t necessarily be my choice. If you had someone who you think is very high-risk—for example, male gender, high-risk FLIPI [Follicular Lymphoma International Prognostic Index], higher-grade disease, advanced stage, very symptomatic—I think you might choose obinutuzumab, naturally, regardless of whether you think that patient is more likely to relapse early.

What I’m saying is, that’s not the only parameter I would use. I think that’s something to be taken into consideration, but it’s not the only parameter that should be used in selecting first-line treatment.

Transcript Edited for Clarity
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