Transcript:
William G. Wierda, MD, PhD: Let’s move on to CD20 antibodies and have actually a little discussion on the various CD20 antibody choices and exactly how they could be used in the management of patients. Tom, could you begin by merely giving us a description or explanation concerning type 1 versus type 2, and mechanism of action of the CD20 antibodies, and exactly how you believe they may be most helpful in CLL?
Thomas J. Kipps, MD, PhD: The CD20 antibodies bind the healthy protein on the surface on the leukemia cell and they flag that cell for immune destruction along with antibody-dependent cytotoxicity. And they are rather efficient in doing this. The type 2, so-called antibody, such as obinutuzumab, have actually been engineered to be much more efficient in flagging the cells for that kind of immune destruction.
It’s translated in to having much more dramatic responses as witnessed by head-to-head clinical trials where patients were receiving chemoimmunotherapy along with rituximab versus chemoimmunotherapy along with obinutuzumab. That was the basis for the approval of obinutuzumab. Rituximab, obinutuzumab and ofatumumab, which have actually been proven to be rather efficient and actually can easily increase the survival of patients once offered with each other along with chemotherapy, have actually been rather helpful for the treatment of patients along with this disease.
I need to say a word concerning the infusion reactions and exactly what the basis of that might be. The infusion reactions appear to be a little bit much more pronounced along with obinutuzumab compared to along with rituximab or ofatumumab. However, in my opinion, we can easily regulate these. Sometimes the very first usage of them by a clinical group might result in infusion reactions, which appear much more dramatic. Yet I remember having patients come to me and tell me that they’re allergic to rituximab due to the fact that they had an infusion reaction along with rituximab. So, it’s not uncommon to get hold of an infusion reaction. This could be as a result of circulating levels of the CD20 healthy protein in the blood that are on exactly what we call micelles.
And that cross linking might actually affect release of cytokines that offer rise to the phenomenon we already know of as, infusion reaction. And this could be mitigated by giving it slowly and likewise combining that along with the usage of glucocorticoids, which are rather effective, particularly for the very first a couple of infusions of the antibody. And after you get hold of past that, it’s rather basic to tolerate. The therapeutic index has actually been rather higher along with these agents. They’ve been a genuine reward to our therapeutic regimens.
Richard F. Furman, MD: One interesting observation concerning the infusion reactions came from the idelalisib pivotal study, which was of path idelalisib plus rituximab versus placebo plus rituximab. In the arm of the patient that got idelalisib, which was administered two hours prior to the rituximab infusion, there was a decreased incidence of infusion reactions. So, it actually does suggest that this is cytokine-mediated and it is something that surely is controllable along with these novel agents as well.
William G. Wierda, MD, PhD: There’s a great deal of data that’s been generated along with CD20 antibodies in combination along with chemotherapy. There’s some newer data that’s coming out along with regard to combinations along with small molecule inhibitors. I know that there are likewise data in terms of route of administration and brand-new data along with regard to subcutaneous administration of CD20 antibody. I wonder if Dr. Ferrajoli can easily offer us some assistance in to that data and exactly what her thoughts are.
Alessandra Ferrajoli, MD: Yes. This approach has actually actually been pioneered in Europe. exactly what they’re doing is the very first infusion is a book intravenous infusion. And if there is no major reaction, after that the next infusion is moved to a subcutaneous administration. There are still some difficulties in terms of the volume, due to the fact that the volume is actually large for a subcutaneous administration. Yet it seemed to be a brand-new approach that is able to almost forever eliminate infusion reaction and of path bring us spine to, time is money, due to the fact that the administration is considerably shorter and the patient can easily leave the office fairly soon after the subcutaneous injection.
William G. Wierda, MD, PhD: And that’s along with which CD20 antibody?
Alessandra Ferrajoli, MD: Rituximab.
William G. Wierda, MD, PhD: Rituximab. So, most data are along 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 concerning the German randomized trial and efficacy difference in terms of obinutuzumab versus rituximab, and exactly what your thoughts are on that data?
Shuo Ma, MD, PhD: The German CLL-11 study compared chlorambucil alone versus the 2 antibody combinations, either chlorambucil plus rituximab or chlorambucil plus obinutuzumab. The 2 antibody combinations seemed to have actually prolonged the progression-free survival, and obinutuzumab even prolonged the overall survival. And once you’re comparing these two various antibody combinations, the obinutuzumab clearly prolonged the progression-free survival compared to the rituximab combination. This surely showed a superiority along with this novel type 2 anti-CD20 antibody compared to rituximab.
William G. Wierda, MD, PhD: So obinutuzumab is clearly much more efficient in that combination. Dr. O’Brien, exactly how do you decide which one to choose? Is it as a result of the data that’s available and the trials that have actually been done? Or do you swap out various CD20 antibodies due to the fact that you believe one is much more effective?
Susan M. O’Brien, MD: So far I haven’t, due to the fact that my believed is that chlorambucil is a weak chemotherapy backbone. And so, there’s no question from that randomized trial that along with chlorambucil, obinutuzumab is better. The progression-free survival difference is almost a year. It was actually substantially much better compared to chlorambucil and rituximab.
The genuine question you’re asking me is, in a chemoimmunotherapy program along with a much better backbone, so i.e., BR or FCR, Will certainly the antibody include as much? Here, chlorambucil is a low-hanging fruit due to the fact that it’s such a weak chemotherapy backbone that a much better antibody could make a substantial difference, which is exactly what we saw. Yet then, do I after that extrapolate from that and say, well I must offer everybody FC/obinutuzumab? I haven’t, due to the fact that I’d adore to see data.
My supposition is that it Will certainly be better, if you merely wanted me to guess. But, again, I don’t believe you can easily merely smoothly extrapolate from a chlorambucil-based program to a program along with a considerably much better chemotherapy backbone where arguably the antibody may not have actually as big of an impact. Yet if someone told me they were going to do that, I wouldn’t necessarily disagree along with them. I haven’t done it so far.
Thomas J. Kipps, MD, PhD: I agree along with Susan. It is complicated. There was a study called the GALTON study, for which institutions were allowed to decide on either bendamustine along with obinutuzumab or FC along with obinutuzumab. So, it wasn’t a randomized study. So, we don’t have actually a head-to-head comparison. Yet for whatever reason, the numbers of patients were small, the outcome along with FC/obinutuzumab was not comparable to along with the bendamustine or obinutuzumab.
Although, you can easily argue statistically that there could be lack of statistical significance as a result of the small study. Yet I believe it has to be studied particularly due to the fact that you can easily run in to troubles along with neutropenia along with the anti-CD20’s, and we’ve seen that along with obinutuzumab. If you combine it along with a much more efficient program that could be much more myelotoxic, it could force you to cut spine on the chemotherapy part, or delay therapy or avoid therapy, whereas you may not have actually to along with the drug rituximab. So, the studies should be done to be sure.
Transcript Edited for Clarity
Panelists:Allesandra 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 Online: Tuesday, March 8, 2016
Transcript:
William G. Wierda, MD, PhD: Let’s move on to CD20 antibodies and have actually a little discussion on the various CD20 antibody choices and exactly how they could be used in the management of patients. Tom, could you begin by merely giving us a description or explanation concerning type 1 versus type 2, and mechanism of action of the CD20 antibodies, and exactly how you believe they may be most helpful in CLL?
Thomas J. Kipps, MD, PhD: The CD20 antibodies bind the healthy protein on the surface on the leukemia cell and they flag that cell for immune destruction along with antibody-dependent cytotoxicity. And they are rather efficient in doing this. The type 2, so-called antibody, such as obinutuzumab, have actually been engineered to be much more efficient in flagging the cells for that kind of immune destruction.
It’s translated in to having much more dramatic responses as witnessed by head-to-head clinical trials where patients were receiving chemoimmunotherapy along with rituximab versus chemoimmunotherapy along with obinutuzumab. That was the basis for the approval of obinutuzumab. Rituximab, obinutuzumab and ofatumumab, which have actually been proven to be rather efficient and actually can easily increase the survival of patients once offered with each other along with chemotherapy, have actually been rather helpful for the treatment of patients along with this disease.
I need to say a word concerning the infusion reactions and exactly what the basis of that might be. The infusion reactions appear to be a little bit much more pronounced along with obinutuzumab compared to along with rituximab or ofatumumab. However, in my opinion, we can easily regulate these. Sometimes the very first usage of them by a clinical group might result in infusion reactions, which appear much more dramatic. Yet I remember having patients come to me and tell me that they’re allergic to rituximab due to the fact that they had an infusion reaction along with rituximab. So, it’s not uncommon to get hold of an infusion reaction. This could be as a result of circulating levels of the CD20 healthy protein in the blood that are on exactly what we call micelles.
And that cross linking might actually affect release of cytokines that offer rise to the phenomenon we already know of as, infusion reaction. And this could be mitigated by giving it slowly and likewise combining that along with the usage of glucocorticoids, which are rather effective, particularly for the very first a couple of infusions of the antibody. And after you get hold of past that, it’s rather basic to tolerate. The therapeutic index has actually been rather higher along with these agents. They’ve been a genuine reward to our therapeutic regimens.
Richard F. Furman, MD: One interesting observation concerning the infusion reactions came from the idelalisib pivotal study, which was of path idelalisib plus rituximab versus placebo plus rituximab. In the arm of the patient that got idelalisib, which was administered two hours prior to the rituximab infusion, there was a decreased incidence of infusion reactions. So, it actually does suggest that this is cytokine-mediated and it is something that surely is controllable along with these novel agents as well.
William G. Wierda, MD, PhD: There’s a great deal of data that’s been generated along with CD20 antibodies in combination along with chemotherapy. There’s some newer data that’s coming out along with regard to combinations along with small molecule inhibitors. I know that there are likewise data in terms of route of administration and brand-new data along with regard to subcutaneous administration of CD20 antibody. I wonder if Dr. Ferrajoli can easily offer us some assistance in to that data and exactly what her thoughts are.
Alessandra Ferrajoli, MD: Yes. This approach has actually actually been pioneered in Europe. exactly what they’re doing is the very first infusion is a book intravenous infusion. And if there is no major reaction, after that the next infusion is moved to a subcutaneous administration. There are still some difficulties in terms of the volume, due to the fact that the volume is actually large for a subcutaneous administration. Yet it seemed to be a brand-new approach that is able to almost forever eliminate infusion reaction and of path bring us spine to, time is money, due to the fact that the administration is considerably shorter and the patient can easily leave the office fairly soon after the subcutaneous injection.
William G. Wierda, MD, PhD: And that’s along with which CD20 antibody?
Alessandra Ferrajoli, MD: Rituximab.
William G. Wierda, MD, PhD: Rituximab. So, most data are along 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 concerning the German randomized trial and efficacy difference in terms of obinutuzumab versus rituximab, and exactly what your thoughts are on that data?
Shuo Ma, MD, PhD: The German CLL-11 study compared chlorambucil alone versus the 2 antibody combinations, either chlorambucil plus rituximab or chlorambucil plus obinutuzumab. The 2 antibody combinations seemed to have actually prolonged the progression-free survival, and obinutuzumab even prolonged the overall survival. And once you’re comparing these two various antibody combinations, the obinutuzumab clearly prolonged the progression-free survival compared to the rituximab combination. This surely showed a superiority along with this novel type 2 anti-CD20 antibody compared to rituximab.
William G. Wierda, MD, PhD: So obinutuzumab is clearly much more efficient in that combination. Dr. O’Brien, exactly how do you decide which one to choose? Is it as a result of the data that’s available and the trials that have actually been done? Or do you swap out various CD20 antibodies due to the fact that you believe one is much more effective?
Susan M. O’Brien, MD: So far I haven’t, due to the fact that my believed is that chlorambucil is a weak chemotherapy backbone. And so, there’s no question from that randomized trial that along with chlorambucil, obinutuzumab is better. The progression-free survival difference is almost a year. It was actually substantially much better compared to chlorambucil and rituximab.
The genuine question you’re asking me is, in a chemoimmunotherapy program along with a much better backbone, so i.e., BR or FCR, Will certainly the antibody include as much? Here, chlorambucil is a low-hanging fruit due to the fact that it’s such a weak chemotherapy backbone that a much better antibody could make a substantial difference, which is exactly what we saw. Yet then, do I after that extrapolate from that and say, well I must offer everybody FC/obinutuzumab? I haven’t, due to the fact that I’d adore to see data.
My supposition is that it Will certainly be better, if you merely wanted me to guess. But, again, I don’t believe you can easily merely smoothly extrapolate from a chlorambucil-based program to a program along with a considerably much better chemotherapy backbone where arguably the antibody may not have actually as big of an impact. Yet if someone told me they were going to do that, I wouldn’t necessarily disagree along with them. I haven’t done it so far.
Thomas J. Kipps, MD, PhD: I agree along with Susan. It is complicated. There was a study called the GALTON study, for which institutions were allowed to decide on either bendamustine along with obinutuzumab or FC along with obinutuzumab. So, it wasn’t a randomized study. So, we don’t have actually a head-to-head comparison. Yet for whatever reason, the numbers of patients were small, the outcome along with FC/obinutuzumab was not comparable to along with the bendamustine or obinutuzumab.
Although, you can easily argue statistically that there could be lack of statistical significance as a result of the small study. Yet I believe it has to be studied particularly due to the fact that you can easily run in to troubles along with neutropenia along with the anti-CD20’s, and we’ve seen that along with obinutuzumab. If you combine it along with a much more efficient program that could be much more myelotoxic, it could force you to cut spine on the chemotherapy part, or delay therapy or avoid therapy, whereas you may not have actually to along with the drug rituximab. So, the studies should be done to be sure.
Transcript Edited for Clarity
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