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Chemoimmunotherapy 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: Monday, Feb 22, 2016


Transcript:

William G. Wierda, MD, PhD:
We're going to talk a little bit about the small molecule inhibitors in a second. But just stepping back again to the chemoimmunotherapy regimens, I wonder if Susan can comment on, since we're here at ASH 2015, if there are any particularly interesting and exciting chemoimmunotherapy combinations with the small molecule inhibitors that you're looking at the abstracts and are excited about.

Susan M. O’Brien, MD: Well, I think there are many. There's a whole bunch of them, and I think the key question that always comes up when we look at that data is, and most of it's in relapsed, to be fair, we get such good results with the small molecules, how much is the chemotherapy adding? Generally, the question is being asked in reverse. If you add ibrutinib or idelalisib, because we heard about the ibrutinib BR data at ASCO and we're hearing about the idelalisib BR data here at ASH, and the point that always comes up is, do you actually get more bang for your buck than if you had just gone to the single agent?

I think probably we can't completely answer that question when we look at these analyses, because the follow-ups are very limited and it's certainly possible that by starting with chemotherapy, you may get long responses. We know CRs increase over time with the small molecules. You may get to higher CRs or more MRD negativity. But when you just look, with very short follow up in particular, at the overall response rates, that question is coming up.

Again, most of these trials have not been done in the front-line setting where you get so much more benefit from chemotherapy than you ever get when you give it to a relapsed patient. So it might be that in the front-line setting it really may be different. Of course, then what confounds how you're going to use that is this whole discussion that we were talking about earlier about, do we just want to get away from chemotherapy and not even use it in the first place? So, I think what we do know is that you can give the small molecule inhibitors with chemotherapy. The real question is, where's that going to go? What's going to be the role for that? And I'm not very clear on that.

William G. Wierda, MD, PhD: I agree. I think there's a lot of interesting data and a lot of interesting trials that are ongoing now with these combinations. And the endpoint is really an issue here. I'd like to move on now. An FDA decision is expected this month for a new rapid-infusion formulation of bendamustine. A phase I trial that includes 81 patients showed that a 50 mL admixture of rapid infusion bendamustine could be delivered over 10 minutes and it was bioequivalent to Treanda given in a 500-mL admixture, which required 60 minutes to infuse. Tom, could you comment on what you think the community relevance of this is?

Thomas J. Kipps, MD, PhD: I think you have to certainly respect the patient. We call them patient because they keep waiting for treatment, and they have lives, too. And so anything that can shorten the time in the infusion chair can potentially help the patient. I must say that bendamustine is very commonly used here in the United States in combination with either rituximab or increasingly obinutuzumab.

I think that the use of the chemoimmunotherapy regimen with bendamustine could be improved by having a shorter infusion time. That seems obvious. And I must say, there's a lot of controversy about the benefit of BR versus FCR. I was convinced that FCR was a more effective regimen, and I think the jury is still out. The German CLL study group that did the comparison, it confuses me, because in the patients that receive BR, they were significantly older and they also had a significantly high proportion of patients with unmutated antibody genes for their CLL cells. And we know that if you treated those two patient populations with the same regimen, you would have a more adverse outcome in the group that received BR. And the outcome was very difficult.

Susan M. O’Brien, MD: Well, Tom, they looked within those mutated and in the unmutated.

Thomas J. Kipps, MD, PhD: I think it stratified that. But if you do, it's very difficult to parse this out. I think it still needs to be determined whether this is necessary, particularly with the advent of some of the new antibody regimens, and the advent and follow-up therapy to give to patients if they should not have as successful of a remission as we would hope. But I think it's confused the matter, for me at least.

Susan M. O’Brien, MD: Well I think what you're alluding to is, do we have better antibodies? And will using a not so myelosuppressive chemotherapy be more acceptable with a more effective antibody?

Thomas J. Kipps, MD, PhD: Correct.

Susan M. O’Brien, MD: So that question is open. It's clear, as you said, in the United States. People don't like to give FCR and they like to give bendamustine.

Thomas J. Kipps, MD, PhD: And this may make it easier. So if it makes it easier for the patient, go for it.

Susan M. O’Brien, MD: And we all know time is money.

William G. Wierda, MD, PhD: I indeed agree. We talked a little bit about CAT Scans and how in community practice and in patient management they may not be as critical. For clinical trial purposes, I think they are an important endpoint to objectively show responses. Dr. Ma, could you comment on bone marrows—bone marrow aspirate and bone marrow biopsies, and where those might be useful in our management and assessment of patients?

Shuo Ma, MD, PhD: In a clinical trial I think bone marrow biopsy is very important because really if you are calling a patient a complete response, you have to document that they have a complete response in the bone marrow. And the same thing goes for the MRD documentation. The MRD negativity in the bone marrow is the most reliable factor to predict a progression-free survival. And the MRD on the blood is much less reliable.

But in clinical practice, I think a lot of the physicians are not doing bone marrow biopsy. But I will say that in certain situations, especially if a patient pretreatment has significant cytopenia, then at that point, bone marrow biopsy is very important because it does help you to differentiate the cause of the cytopenia. Is it actually due to CLL infiltration and causing bone marrow failure due to endo production? Or is it due to some other immune phenomena? Because other immune cytopenia is not uncommon among CLL patients.

So, some patients who have thrombocytopenia, for example, if they have adequate amount of megakaryocytes and limited amount of CLL, then likely that's due to autoimmune mechanism rather than the bone marrow failure. So in that case, you can simply treat the autoimmune disease rather than treating the CLL. So, I think pretreatment bone marrow biopsy is really essential for patients with cytopenia.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity


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Transcript:

William G. Wierda, MD, PhD:
We're going to talk a little bit about the small molecule inhibitors in a second. But just stepping back again to the chemoimmunotherapy regimens, I wonder if Susan can comment on, since we're here at ASH 2015, if there are any particularly interesting and exciting chemoimmunotherapy combinations with the small molecule inhibitors that you're looking at the abstracts and are excited about.

Susan M. O’Brien, MD: Well, I think there are many. There's a whole bunch of them, and I think the key question that always comes up when we look at that data is, and most of it's in relapsed, to be fair, we get such good results with the small molecules, how much is the chemotherapy adding? Generally, the question is being asked in reverse. If you add ibrutinib or idelalisib, because we heard about the ibrutinib BR data at ASCO and we're hearing about the idelalisib BR data here at ASH, and the point that always comes up is, do you actually get more bang for your buck than if you had just gone to the single agent?

I think probably we can't completely answer that question when we look at these analyses, because the follow-ups are very limited and it's certainly possible that by starting with chemotherapy, you may get long responses. We know CRs increase over time with the small molecules. You may get to higher CRs or more MRD negativity. But when you just look, with very short follow up in particular, at the overall response rates, that question is coming up.

Again, most of these trials have not been done in the front-line setting where you get so much more benefit from chemotherapy than you ever get when you give it to a relapsed patient. So it might be that in the front-line setting it really may be different. Of course, then what confounds how you're going to use that is this whole discussion that we were talking about earlier about, do we just want to get away from chemotherapy and not even use it in the first place? So, I think what we do know is that you can give the small molecule inhibitors with chemotherapy. The real question is, where's that going to go? What's going to be the role for that? And I'm not very clear on that.

William G. Wierda, MD, PhD: I agree. I think there's a lot of interesting data and a lot of interesting trials that are ongoing now with these combinations. And the endpoint is really an issue here. I'd like to move on now. An FDA decision is expected this month for a new rapid-infusion formulation of bendamustine. A phase I trial that includes 81 patients showed that a 50 mL admixture of rapid infusion bendamustine could be delivered over 10 minutes and it was bioequivalent to Treanda given in a 500-mL admixture, which required 60 minutes to infuse. Tom, could you comment on what you think the community relevance of this is?

Thomas J. Kipps, MD, PhD: I think you have to certainly respect the patient. We call them patient because they keep waiting for treatment, and they have lives, too. And so anything that can shorten the time in the infusion chair can potentially help the patient. I must say that bendamustine is very commonly used here in the United States in combination with either rituximab or increasingly obinutuzumab.

I think that the use of the chemoimmunotherapy regimen with bendamustine could be improved by having a shorter infusion time. That seems obvious. And I must say, there's a lot of controversy about the benefit of BR versus FCR. I was convinced that FCR was a more effective regimen, and I think the jury is still out. The German CLL study group that did the comparison, it confuses me, because in the patients that receive BR, they were significantly older and they also had a significantly high proportion of patients with unmutated antibody genes for their CLL cells. And we know that if you treated those two patient populations with the same regimen, you would have a more adverse outcome in the group that received BR. And the outcome was very difficult.

Susan M. O’Brien, MD: Well, Tom, they looked within those mutated and in the unmutated.

Thomas J. Kipps, MD, PhD: I think it stratified that. But if you do, it's very difficult to parse this out. I think it still needs to be determined whether this is necessary, particularly with the advent of some of the new antibody regimens, and the advent and follow-up therapy to give to patients if they should not have as successful of a remission as we would hope. But I think it's confused the matter, for me at least.

Susan M. O’Brien, MD: Well I think what you're alluding to is, do we have better antibodies? And will using a not so myelosuppressive chemotherapy be more acceptable with a more effective antibody?

Thomas J. Kipps, MD, PhD: Correct.

Susan M. O’Brien, MD: So that question is open. It's clear, as you said, in the United States. People don't like to give FCR and they like to give bendamustine.

Thomas J. Kipps, MD, PhD: And this may make it easier. So if it makes it easier for the patient, go for it.

Susan M. O’Brien, MD: And we all know time is money.

William G. Wierda, MD, PhD: I indeed agree. We talked a little bit about CAT Scans and how in community practice and in patient management they may not be as critical. For clinical trial purposes, I think they are an important endpoint to objectively show responses. Dr. Ma, could you comment on bone marrows—bone marrow aspirate and bone marrow biopsies, and where those might be useful in our management and assessment of patients?

Shuo Ma, MD, PhD: In a clinical trial I think bone marrow biopsy is very important because really if you are calling a patient a complete response, you have to document that they have a complete response in the bone marrow. And the same thing goes for the MRD documentation. The MRD negativity in the bone marrow is the most reliable factor to predict a progression-free survival. And the MRD on the blood is much less reliable.

But in clinical practice, I think a lot of the physicians are not doing bone marrow biopsy. But I will say that in certain situations, especially if a patient pretreatment has significant cytopenia, then at that point, bone marrow biopsy is very important because it does help you to differentiate the cause of the cytopenia. Is it actually due to CLL infiltration and causing bone marrow failure due to endo production? Or is it due to some other immune phenomena? Because other immune cytopenia is not uncommon among CLL patients.

So, some patients who have thrombocytopenia, for example, if they have adequate amount of megakaryocytes and limited amount of CLL, then likely that's due to autoimmune mechanism rather than the bone marrow failure. So in that case, you can simply treat the autoimmune disease rather than treating the CLL. So, I think pretreatment bone marrow biopsy is really essential for patients with cytopenia.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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