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Optimizing Frontline Therapy and Maintenance in FL

Insights From: Carla Casulo, MD, University of Rochester Medical Center; Nathan H. Fowler, MD, University of Texas MD Anderson Cancer Center
Published: Friday, Mar 02, 2018



Transcript: 

Nathan H. Fowler, MD: Rituximab maintenance has been shown to extend progression-free survival following several different induction regimens. At this 2017 American Society of Hematology meeting, there was a long-term follow-up of the PRIMA trial of frontline rituximab plus chemotherapy followed by one of 2 arms. It’s a randomized trial, where patients who responded to induction chemotherapy with rituximab were randomized to receive rituximab maintenance for 2 years versus observation. Dr. Gilles Salles showed that there was a significant prolongation in progression-free survival with rituximab maintenance.

Now at this meeting, we saw an extended follow-up of that trial where they presented 10-year data showing that patients who were on the rituximab maintenance arm, about half of them, actually remain in remission, which is pretty exciting. It shows that by using an induction regimen followed by a fairly short maintenance schedule, 2 years, about half of patients can attain very durable remissions. We also saw at this meeting data from maintenance rituximab studies following bendamustine-containing induction regimens. This is very relevant, because in the United States we’ve seen bendamustine really become a major player in frontline follicular lymphoma. In the past, there were not a lot of data to show outcomes of patients who received this newer induction regimen, bendamustine, with maintenance therapy.

At this meeting, we saw several different abstracts. One abstract from a subset analysis of the BRIGHT study was presented by Brad Kahl, where they looked at a subset of patients. The BRIGHT trial was a randomization trial between bendamustine-rituximab versus R [rituximab]-CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone], and they looked at patients who received maintenance rituximab, including a large portion of patients who had received bendamustine rituximab.

In that study, as no surprise, they showed a prolongation in progression-free survival. We also saw data from the German StiL Group, which is a German low-grade lymphoma group. The trial was presented by Mathias Rummel, and this study looked at bendamustine-rituximab with 2 different maintenance rituximab schedules. One was 2 years of rituximab and the other was 4 years of rituximab, following rituximab induction. In this study, they also showed prolongation in progression-free survival with both arms compared to historical bendamustine-rituximab reduction regimens, and a slight prolongation in progression-free survival with 4 years of rituximab versus 2 years.

Most importantly, to me this whole group of data suggests that maintenance rituximab following bendamustine didn’t appear to be significantly more toxic. So, we didn’t see a very high infection rate. We didn’t appear to see any or dramatic increase in death rates with maintenance rituximab following bendamustine. I do think that, at least with the studies that were presented at this meeting, bendamustine-rituximab followed by rituximab maintenance appeared to be safe in the vast majority of patients.

Carla Casulo, MD: The phase III GALLIUM study has been a very impactful study in follicular lymphoma because it demonstrates that in using obinutuzumab-based induction therapy compared to rituximab-based therapy, there is a progression-free survival benefit for patients. I think that the issue with obinutuzumab is that it has been shown to be slightly more toxic. So, patients had more infection-related complications and there were more deaths related to that in the obinutuzumab arm.

But I think it makes an important point that there was a progression-free survival benefit demonstrated. That will likely change the standard of care for patients with follicular lymphoma. The aspect of maintenance is an interesting one because we know rituximab maintenance has a progression-free survival benefit, and we’re seeing that with obinutuzumab. The progression-free survival benefit is there as well. So, I suspect that this will be practice changing for most patients with follicular lymphoma.

Nathan H. Fowler, MD: There were some data from the GADOLIN trial. This was a trial that looked at obinutuzumab versus rituximab with induction therapy. In this trial, one arm received rituximab plus chemotherapy followed by rituximab maintenance. The other arm received obinutuzumab plus chemotherapy followed by obinutuzumab maintenance.

A subset analysis looking at the bendamustine arms showed an increase in late mortality, late deaths, during maintenance therapy with bendamustine with obinutuzumab or rituximab. This was not part of the primary objective of the trial, but a subset analysis suggested that there could potentially be an increased infection rate, increased death rate, in bendamustine followed by maintenance obinutuzumab or rituximab. So, a lot of us were waiting to see other trials with rituximab maintenance following bendamustine to see if this signal persisted in other studies. The good news, at least in the trials that were presented at this ASH, was that we didn’t see that increased safety signal.

Transcript Edited for Clarity 
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Transcript: 

Nathan H. Fowler, MD: Rituximab maintenance has been shown to extend progression-free survival following several different induction regimens. At this 2017 American Society of Hematology meeting, there was a long-term follow-up of the PRIMA trial of frontline rituximab plus chemotherapy followed by one of 2 arms. It’s a randomized trial, where patients who responded to induction chemotherapy with rituximab were randomized to receive rituximab maintenance for 2 years versus observation. Dr. Gilles Salles showed that there was a significant prolongation in progression-free survival with rituximab maintenance.

Now at this meeting, we saw an extended follow-up of that trial where they presented 10-year data showing that patients who were on the rituximab maintenance arm, about half of them, actually remain in remission, which is pretty exciting. It shows that by using an induction regimen followed by a fairly short maintenance schedule, 2 years, about half of patients can attain very durable remissions. We also saw at this meeting data from maintenance rituximab studies following bendamustine-containing induction regimens. This is very relevant, because in the United States we’ve seen bendamustine really become a major player in frontline follicular lymphoma. In the past, there were not a lot of data to show outcomes of patients who received this newer induction regimen, bendamustine, with maintenance therapy.

At this meeting, we saw several different abstracts. One abstract from a subset analysis of the BRIGHT study was presented by Brad Kahl, where they looked at a subset of patients. The BRIGHT trial was a randomization trial between bendamustine-rituximab versus R [rituximab]-CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone], and they looked at patients who received maintenance rituximab, including a large portion of patients who had received bendamustine rituximab.

In that study, as no surprise, they showed a prolongation in progression-free survival. We also saw data from the German StiL Group, which is a German low-grade lymphoma group. The trial was presented by Mathias Rummel, and this study looked at bendamustine-rituximab with 2 different maintenance rituximab schedules. One was 2 years of rituximab and the other was 4 years of rituximab, following rituximab induction. In this study, they also showed prolongation in progression-free survival with both arms compared to historical bendamustine-rituximab reduction regimens, and a slight prolongation in progression-free survival with 4 years of rituximab versus 2 years.

Most importantly, to me this whole group of data suggests that maintenance rituximab following bendamustine didn’t appear to be significantly more toxic. So, we didn’t see a very high infection rate. We didn’t appear to see any or dramatic increase in death rates with maintenance rituximab following bendamustine. I do think that, at least with the studies that were presented at this meeting, bendamustine-rituximab followed by rituximab maintenance appeared to be safe in the vast majority of patients.

Carla Casulo, MD: The phase III GALLIUM study has been a very impactful study in follicular lymphoma because it demonstrates that in using obinutuzumab-based induction therapy compared to rituximab-based therapy, there is a progression-free survival benefit for patients. I think that the issue with obinutuzumab is that it has been shown to be slightly more toxic. So, patients had more infection-related complications and there were more deaths related to that in the obinutuzumab arm.

But I think it makes an important point that there was a progression-free survival benefit demonstrated. That will likely change the standard of care for patients with follicular lymphoma. The aspect of maintenance is an interesting one because we know rituximab maintenance has a progression-free survival benefit, and we’re seeing that with obinutuzumab. The progression-free survival benefit is there as well. So, I suspect that this will be practice changing for most patients with follicular lymphoma.

Nathan H. Fowler, MD: There were some data from the GADOLIN trial. This was a trial that looked at obinutuzumab versus rituximab with induction therapy. In this trial, one arm received rituximab plus chemotherapy followed by rituximab maintenance. The other arm received obinutuzumab plus chemotherapy followed by obinutuzumab maintenance.

A subset analysis looking at the bendamustine arms showed an increase in late mortality, late deaths, during maintenance therapy with bendamustine with obinutuzumab or rituximab. This was not part of the primary objective of the trial, but a subset analysis suggested that there could potentially be an increased infection rate, increased death rate, in bendamustine followed by maintenance obinutuzumab or rituximab. So, a lot of us were waiting to see other trials with rituximab maintenance following bendamustine to see if this signal persisted in other studies. The good news, at least in the trials that were presented at this ASH, was that we didn’t see that increased safety signal.

Transcript Edited for Clarity 
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