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Sequencing Therapies for Follicular Lymphoma

Panelists: Krishna V. Komanduri, MD, Sylvester Comprehensive Cancer Center; Leo I. Gordon, MD, Robert H. Lurie Comprehensive Cancer Center; John Byrd, MD, Ohio State University; Michael Keating, MB, BS, University of Texas MD Anderson Cancer Center; John Leonard, MD, New York-Presbyterian Hospital
Published: Thursday, Jan 19, 2017


Transcript:

Krishna V. Komanduri, MD:
As you said, it’s great to have new options, and now we have a number of different options in addition to obinutuzumab. We’ve had studies that have looked at idelalisib, ibrutinib, and combinations of both traditional and newer agents. I want to get to the question of sequencing as we think about patients who will have relapses. And, of course, the nature of these diseases is that we don’t cure patients and that they have multiple relapses. How do we sort through the data? Let’s talk about some of the combinations, like, for example, the combination of obinutuzumab with bendamustine, as you just talked about.

Leo I. Gordon, MD: Right. So, there are a couple things. First of all, I think in terms of thinking about second treatment after recurrences, it’s important to keep in mind that we’ve now been able to identify groups of patients with follicular lymphoma that might behave in a little bit more aggressive way, even looking for clinical factors. There’s the FLIPI-1 and the FLIPI-2 score to help us make predictions. There’s recently molecular analysis looking at a number of genes plus FLIPI. Those are important criteria, but there’s an important paper that was published by Carla Casulo looking at one major risk factor, and that was recurrence of disease within a 24-month period. And there are some studies looking at 12 months. But, it looks as though if you do treatment and the disease recurs relatively early, that’s a group of patients who may not do as well with any of the sequences that we’re talking about. And, I think, those are patients whom one might at least begin thinking about more novel therapies or possibly transplant, either autologous or even allogeneic transplant in younger, fit patients.

We’ll talk mostly then about patients that are recurring after a 24-month period. In that group of patients, there was a study. Laurie Sehn did the so-called GADOLIN study, and that basically looked at obinutuzumab and bendamustine versus bendamustine alone in patients that were refractory. A significant number of those patients had already had bendamustine, so we’re asking patients to now get not only 6 cycles of bendamustine but 12 cycles of bendamustine, which I think is problematic. I have trouble getting 4 cycles of bendamustine in patients sometimes. That’s one thing.

The other thing is that was randomized. So, if this study were going to be positive for bendamustine alone without a CD20 antibody, I think it would be the first study that I’m aware of in B-cell malignancies where an antibody didn’t improve the outcome. And so, I think the data suggest that that’s an active agent, but my caveat there, I’m not sure about the comparator. I have some problem with the comparator arm in that study, but I think it suggests that obinutuzumab/bendamustine is an active agent.

Let me skip to idelalisib and ibrutinib. Certainly, there are data looking at idelalisib with or without bendamustine and Rituxan. It’s an active agent. It’s approved for refractory or recurrent follicular lymphoma. There was a dear doctor note that was written by the company, and the FDA got very much involved in toxicity in that study. Patients were getting what looked like a higher incidence of bacteremia or neutropenic fevers, and, importantly, CMV reactivation and pneumocystis. This is a group of patients that has been heavily treated. I think the data are just sorting out now, but I think the caution if we’re going to use idelalisib, especially in patients that have had prior extensive therapy, is that they’re immunosuppressed. T-cell function we haven’t looked at. We’ve looked at T-cell numbers, and almost every patient that’s had a course of bendamustine has T-cell counts, they’re 100 or less. And so, those are patients whom we routinely put on PCP prophylaxis, antiviral prophylaxis, and antifungal prophylaxis actually, and monitor CMV status on a monthly basis. That’s what’s now required by the FDA. So, if we’re going to look at idelalisib, it has to be with some caution, number 1, at least in lymphoma patients, and number 2, the other toxicities are something that people should become comfortable with managing, the colitis and the pneumonitis that tends to occur.

I think those are some of the second- and third-line agents. One thing that maybe we haven’t talked about much, that historically has been active, is radioimmunotherapy. There are plenty of data, and we’re still following patients 15, 16, 17 years out after 1 dose of Zevalin who are still in complete remission. So, I think it’s an agent that’s been forgotten about a little bit, but I think it shouldn’t be forgotten when we think about options for second- and third-line treatment for patients with follicular lymphoma.

Transcript Edited for Clarity
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Transcript:

Krishna V. Komanduri, MD:
As you said, it’s great to have new options, and now we have a number of different options in addition to obinutuzumab. We’ve had studies that have looked at idelalisib, ibrutinib, and combinations of both traditional and newer agents. I want to get to the question of sequencing as we think about patients who will have relapses. And, of course, the nature of these diseases is that we don’t cure patients and that they have multiple relapses. How do we sort through the data? Let’s talk about some of the combinations, like, for example, the combination of obinutuzumab with bendamustine, as you just talked about.

Leo I. Gordon, MD: Right. So, there are a couple things. First of all, I think in terms of thinking about second treatment after recurrences, it’s important to keep in mind that we’ve now been able to identify groups of patients with follicular lymphoma that might behave in a little bit more aggressive way, even looking for clinical factors. There’s the FLIPI-1 and the FLIPI-2 score to help us make predictions. There’s recently molecular analysis looking at a number of genes plus FLIPI. Those are important criteria, but there’s an important paper that was published by Carla Casulo looking at one major risk factor, and that was recurrence of disease within a 24-month period. And there are some studies looking at 12 months. But, it looks as though if you do treatment and the disease recurs relatively early, that’s a group of patients who may not do as well with any of the sequences that we’re talking about. And, I think, those are patients whom one might at least begin thinking about more novel therapies or possibly transplant, either autologous or even allogeneic transplant in younger, fit patients.

We’ll talk mostly then about patients that are recurring after a 24-month period. In that group of patients, there was a study. Laurie Sehn did the so-called GADOLIN study, and that basically looked at obinutuzumab and bendamustine versus bendamustine alone in patients that were refractory. A significant number of those patients had already had bendamustine, so we’re asking patients to now get not only 6 cycles of bendamustine but 12 cycles of bendamustine, which I think is problematic. I have trouble getting 4 cycles of bendamustine in patients sometimes. That’s one thing.

The other thing is that was randomized. So, if this study were going to be positive for bendamustine alone without a CD20 antibody, I think it would be the first study that I’m aware of in B-cell malignancies where an antibody didn’t improve the outcome. And so, I think the data suggest that that’s an active agent, but my caveat there, I’m not sure about the comparator. I have some problem with the comparator arm in that study, but I think it suggests that obinutuzumab/bendamustine is an active agent.

Let me skip to idelalisib and ibrutinib. Certainly, there are data looking at idelalisib with or without bendamustine and Rituxan. It’s an active agent. It’s approved for refractory or recurrent follicular lymphoma. There was a dear doctor note that was written by the company, and the FDA got very much involved in toxicity in that study. Patients were getting what looked like a higher incidence of bacteremia or neutropenic fevers, and, importantly, CMV reactivation and pneumocystis. This is a group of patients that has been heavily treated. I think the data are just sorting out now, but I think the caution if we’re going to use idelalisib, especially in patients that have had prior extensive therapy, is that they’re immunosuppressed. T-cell function we haven’t looked at. We’ve looked at T-cell numbers, and almost every patient that’s had a course of bendamustine has T-cell counts, they’re 100 or less. And so, those are patients whom we routinely put on PCP prophylaxis, antiviral prophylaxis, and antifungal prophylaxis actually, and monitor CMV status on a monthly basis. That’s what’s now required by the FDA. So, if we’re going to look at idelalisib, it has to be with some caution, number 1, at least in lymphoma patients, and number 2, the other toxicities are something that people should become comfortable with managing, the colitis and the pneumonitis that tends to occur.

I think those are some of the second- and third-line agents. One thing that maybe we haven’t talked about much, that historically has been active, is radioimmunotherapy. There are plenty of data, and we’re still following patients 15, 16, 17 years out after 1 dose of Zevalin who are still in complete remission. So, I think it’s an agent that’s been forgotten about a little bit, but I think it shouldn’t be forgotten when we think about options for second- and third-line treatment for patients with follicular lymphoma.

Transcript Edited for Clarity
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