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CD-20 Antibodies in Chronic Lymphocytic Leukemia

Panelists:Alessandra Ferrajoli, MD, The University of Texas MD Anderson Cancer Center; Richard R. Furman, MD, Weill Cornell Medical College; Thomas J. Kipps, MD, PhD, UC San Diego Moores Cancer Center; Shuo Ma, MD, PhD, Northwestern University Feinberg School of Medicine, Susan M. O’Brien, MD, UC Irvine Health; William G. Wierda, MD, PhD, University of Texas MD Anderson Cancer Center
Published: Tuesday, Mar 08, 2016


Transcript:

William G. Wierda, MD, PhD:
Let's move on to CD20 antibodies and have a little discussion on the various CD20 antibody options and how they may be used in the management of patients. Tom, could you start by just giving us a description or explanation about type 1 versus type 2, and mechanism of action of the CD20 antibodies, and how you think they might be most useful in CLL?

Thomas J. Kipps, MD, PhD: The CD20 antibodies bind the protein on the surface on the leukemia cell and they flag that cell for immune destruction with antibody-dependent cytotoxicity. And they are very effective in doing this. The type 2, so-called antibody, such as obinutuzumab, have been engineered to be even more efficient in flagging the cells for that type of immune destruction.

It's translated into having more dramatic responses as witnessed by head-to-head clinical trials where patients were receiving chemoimmunotherapy with rituximab versus chemoimmunotherapy with obinutuzumab. That was the basis for the approval of obinutuzumab. Rituximab, obinutuzumab and ofatumumab, which have been proven to be very effective and actually can improve the survival of patients when given together with chemotherapy, have been very useful for the treatment of patients with this disease.

I must say a word about the infusion reactions and what the basis of that may be. The infusion reactions appear to be a little bit more pronounced with obinutuzumab than with rituximab or ofatumumab. However, in my opinion, we can manage these. Sometimes the first use of them by a clinical group may result in infusion reactions, which appear more dramatic. But I remember having patients come to me and tell me that they're allergic to rituximab because they had an infusion reaction with rituximab. So, it's not uncommon to get an infusion reaction. This may be due to circulating levels of the CD20 protein in the blood that are on what we call micelles.

And that cross linking may actually affect release of cytokines that give rise to the phenomenon we know of as, infusion reaction. And this could be mitigated by giving it slowly and also combining that with the use of glucocorticoids, which are very effective, particularly for the first one or two infusions of the antibody. And after you get past that, it's very easy to tolerate. The therapeutic index has been quite high with these agents. They've been a real benefit to our therapeutic regimens.

Richard F. Furman, MD: One interesting observation regarding the infusion reactions came out of the idelalisib pivotal study, which was of course idelalisib plus rituximab versus placebo plus rituximab. In the arm of the patient who got idelalisib, which was administered two hours prior to the rituximab infusion, there was a decreased incidence of infusion reactions. So, it really does suggest that this is cytokine-mediated and it is something that certainly is controllable with these novel agents as well.

William G. Wierda, MD, PhD: There's a lot of data that's been generated with CD20 antibodies in combination with chemotherapy. There's some newer data that's coming out with regard to combinations with small molecule inhibitors. I understand that there are also data in terms of route of administration and new data with regard to subcutaneous administration of CD20 antibody. I wonder if Dr. Ferrajoli can give us some insight into that data and what her thoughts are.

Alessandra Ferrajoli, MD: Yes. This approach has actually been pioneered in Europe. What they're doing is the first infusion is a routine intravenous infusion. And if there is no severe reaction, then the next infusion is moved to a subcutaneous administration. There are still some difficulties in terms of the volume, because the volume is really large for a subcutaneous administration. But it seemed to be a new approach that is able to almost completely eliminate infusion reaction and of course bring us back to, time is money, because the administration is much shorter and the patient can leave the office fairly soon after the subcutaneous injection.

William G. Wierda, MD, PhD: And that's with which CD20 antibody?

Alessandra Ferrajoli, MD: Rituximab.

William G. Wierda, MD, PhD: Rituximab. So, most data are with rituximab. And rituximab is a type 1, and ofatumumab is a type 1 CD20 antibody. Obinutuzumab is a type 2. Dr. Ma, could you talk a little bit about the German randomized trial and efficacy difference in terms of obinutuzumab versus rituximab, and what your thoughts are on that data?

Shuo Ma, MD, PhD: The German CLL-11 study compared chlorambucil alone versus the two antibody combinations, either chlorambucil plus rituximab or chlorambucil plus obinutuzumab. Both antibody combinations seemed to have prolonged the progression-free survival, and obinutuzumab even prolonged the overall survival. And when you're comparing these two different antibody combinations, the obinutuzumab clearly prolonged the progression-free survival compared to the rituximab combination. This definitely showed a superiority with this novel type 2 anti-CD20 antibody compared to rituximab.

William G. Wierda, MD, PhD: So obinutuzumab is clearly more effective in that combination. Dr. O'Brien, how do you decide which one to choose? Is it because of the data that's available and the trials that have been done? Or do you swap out different CD20 antibodies because you think one is more effective?

Susan M. O’Brien, MD: So far I haven't, because my thought is that chlorambucil is a weak chemotherapy backbone. And so, there's no question from that randomized trial that with chlorambucil, obinutuzumab is better. The progression-free survival difference is almost a year. It was really substantially better than chlorambucil and rituximab.

The real question you're asking me is, in a chemoimmunotherapy regimen with a better backbone, so i.e., BR or FCR, will the antibody add as much? Here, chlorambucil is a low-hanging fruit because it's such a weak chemotherapy backbone that a better antibody could make a substantial difference, which is what we saw. But then, do I then extrapolate from that and say, well I should give everybody FC/obinutuzumab? I haven't, because I’d like to see data.

My supposition is that it will be better, if you just wanted me to guess. But, again, I don't think you can just smoothly extrapolate from a chlorambucil-based regimen to a regimen with a much better chemotherapy backbone where arguably the antibody might not have as big of an impact. But if somebody told me they were going to do that, I wouldn't necessarily disagree with them. I haven't done it so far.

Thomas J. Kipps, MD, PhD: I agree with Susan. It is complicated. There was a study called the GALTON study, for which institutions were allowed to pick either bendamustine with obinutuzumab or FC with obinutuzumab. So, it wasn't a randomized study. So, we don't have a head-to-head comparison. But for whatever reason, the numbers of patients were small, the outcome with FC/obinutuzumab was not as good as with the bendamustine or obinutuzumab.

Although, you can argue statistically that there may be lack of statistical significance because of the small study. But I think it needs to be studied particularly because you can run into problems with neutropenia with the anti-CD20's, and we've seen that with obinutuzumab. If you combine it with a more effective regimen that could be more myelotoxic, it could force you to cut back on the chemotherapy part, or delay therapy or stop therapy, whereas you might not have to with the drug rituximab. So, the studies need to be done to be sure.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity


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Transcript:

William G. Wierda, MD, PhD:
Let's move on to CD20 antibodies and have a little discussion on the various CD20 antibody options and how they may be used in the management of patients. Tom, could you start by just giving us a description or explanation about type 1 versus type 2, and mechanism of action of the CD20 antibodies, and how you think they might be most useful in CLL?

Thomas J. Kipps, MD, PhD: The CD20 antibodies bind the protein on the surface on the leukemia cell and they flag that cell for immune destruction with antibody-dependent cytotoxicity. And they are very effective in doing this. The type 2, so-called antibody, such as obinutuzumab, have been engineered to be even more efficient in flagging the cells for that type of immune destruction.

It's translated into having more dramatic responses as witnessed by head-to-head clinical trials where patients were receiving chemoimmunotherapy with rituximab versus chemoimmunotherapy with obinutuzumab. That was the basis for the approval of obinutuzumab. Rituximab, obinutuzumab and ofatumumab, which have been proven to be very effective and actually can improve the survival of patients when given together with chemotherapy, have been very useful for the treatment of patients with this disease.

I must say a word about the infusion reactions and what the basis of that may be. The infusion reactions appear to be a little bit more pronounced with obinutuzumab than with rituximab or ofatumumab. However, in my opinion, we can manage these. Sometimes the first use of them by a clinical group may result in infusion reactions, which appear more dramatic. But I remember having patients come to me and tell me that they're allergic to rituximab because they had an infusion reaction with rituximab. So, it's not uncommon to get an infusion reaction. This may be due to circulating levels of the CD20 protein in the blood that are on what we call micelles.

And that cross linking may actually affect release of cytokines that give rise to the phenomenon we know of as, infusion reaction. And this could be mitigated by giving it slowly and also combining that with the use of glucocorticoids, which are very effective, particularly for the first one or two infusions of the antibody. And after you get past that, it's very easy to tolerate. The therapeutic index has been quite high with these agents. They've been a real benefit to our therapeutic regimens.

Richard F. Furman, MD: One interesting observation regarding the infusion reactions came out of the idelalisib pivotal study, which was of course idelalisib plus rituximab versus placebo plus rituximab. In the arm of the patient who got idelalisib, which was administered two hours prior to the rituximab infusion, there was a decreased incidence of infusion reactions. So, it really does suggest that this is cytokine-mediated and it is something that certainly is controllable with these novel agents as well.

William G. Wierda, MD, PhD: There's a lot of data that's been generated with CD20 antibodies in combination with chemotherapy. There's some newer data that's coming out with regard to combinations with small molecule inhibitors. I understand that there are also data in terms of route of administration and new data with regard to subcutaneous administration of CD20 antibody. I wonder if Dr. Ferrajoli can give us some insight into that data and what her thoughts are.

Alessandra Ferrajoli, MD: Yes. This approach has actually been pioneered in Europe. What they're doing is the first infusion is a routine intravenous infusion. And if there is no severe reaction, then the next infusion is moved to a subcutaneous administration. There are still some difficulties in terms of the volume, because the volume is really large for a subcutaneous administration. But it seemed to be a new approach that is able to almost completely eliminate infusion reaction and of course bring us back to, time is money, because the administration is much shorter and the patient can leave the office fairly soon after the subcutaneous injection.

William G. Wierda, MD, PhD: And that's with which CD20 antibody?

Alessandra Ferrajoli, MD: Rituximab.

William G. Wierda, MD, PhD: Rituximab. So, most data are with rituximab. And rituximab is a type 1, and ofatumumab is a type 1 CD20 antibody. Obinutuzumab is a type 2. Dr. Ma, could you talk a little bit about the German randomized trial and efficacy difference in terms of obinutuzumab versus rituximab, and what your thoughts are on that data?

Shuo Ma, MD, PhD: The German CLL-11 study compared chlorambucil alone versus the two antibody combinations, either chlorambucil plus rituximab or chlorambucil plus obinutuzumab. Both antibody combinations seemed to have prolonged the progression-free survival, and obinutuzumab even prolonged the overall survival. And when you're comparing these two different antibody combinations, the obinutuzumab clearly prolonged the progression-free survival compared to the rituximab combination. This definitely showed a superiority with this novel type 2 anti-CD20 antibody compared to rituximab.

William G. Wierda, MD, PhD: So obinutuzumab is clearly more effective in that combination. Dr. O'Brien, how do you decide which one to choose? Is it because of the data that's available and the trials that have been done? Or do you swap out different CD20 antibodies because you think one is more effective?

Susan M. O’Brien, MD: So far I haven't, because my thought is that chlorambucil is a weak chemotherapy backbone. And so, there's no question from that randomized trial that with chlorambucil, obinutuzumab is better. The progression-free survival difference is almost a year. It was really substantially better than chlorambucil and rituximab.

The real question you're asking me is, in a chemoimmunotherapy regimen with a better backbone, so i.e., BR or FCR, will the antibody add as much? Here, chlorambucil is a low-hanging fruit because it's such a weak chemotherapy backbone that a better antibody could make a substantial difference, which is what we saw. But then, do I then extrapolate from that and say, well I should give everybody FC/obinutuzumab? I haven't, because I’d like to see data.

My supposition is that it will be better, if you just wanted me to guess. But, again, I don't think you can just smoothly extrapolate from a chlorambucil-based regimen to a regimen with a much better chemotherapy backbone where arguably the antibody might not have as big of an impact. But if somebody told me they were going to do that, I wouldn't necessarily disagree with them. I haven't done it so far.

Thomas J. Kipps, MD, PhD: I agree with Susan. It is complicated. There was a study called the GALTON study, for which institutions were allowed to pick either bendamustine with obinutuzumab or FC with obinutuzumab. So, it wasn't a randomized study. So, we don't have a head-to-head comparison. But for whatever reason, the numbers of patients were small, the outcome with FC/obinutuzumab was not as good as with the bendamustine or obinutuzumab.

Although, you can argue statistically that there may be lack of statistical significance because of the small study. But I think it needs to be studied particularly because you can run into problems with neutropenia with the anti-CD20's, and we've seen that with obinutuzumab. If you combine it with a more effective regimen that could be more myelotoxic, it could force you to cut back on the chemotherapy part, or delay therapy or stop therapy, whereas you might not have to with the drug rituximab. So, the studies need to be done to be sure.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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