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CLL: The Biologics of Ibrutinib Therapy

Insights From: Thomas J. Kipps, MD, PhD, UC San Diego Moores Cancer Center
Published: Wednesday, Aug 23, 2017



Transcript:

Thomas J. Kipps, MD, PhD: We really don’t quite understand what accounts for why patients with deletions in chromosome 11 fare better than, and at least as well as, patients who don’t have deletions in chromosome 11. So right now, we have observation, and there are several reasons that we have put forward as possible explanations for this. But we’re still investigating whether or not those reasons are actually accurate.

I think there’s some research activity that’s now ongoing to try and define, what is it about the deletions in chromosome 11 that make them less able to respond well to chemotherapy? We know practical experience is that patients with deletions in chromosome 11 tend to respond to a chemoimmunotherapy regimen or chemotherapy regimens; however, the duration of the response appears to be shorter than if they did not have deletions in chromosome 11. The exact reason for that is not clear, but it seems to indicate that when the leukemia cells have deletions in chromosome 11, they may have maybe less stability in their genome; they may be getting greater signaling through their receptor, such as the B-cell receptor; and they may be more prone to spinning off variants that could lead to resistance to therapy. But whatever it is, it seems to indicate that patients with deletion 11q may actually have a tendency to relapse faster after stopping chemotherapy.
With ibrutinib, we maintain therapy—we don’t stop therapy—so it may provide the ability to keep that clone from coming back, and that could also be contributing partly to my patients who are doing better. So, I think research still needs to be done to figure out the explanations here. And I think this will be very useful, because then we’ll be able to define what those features are that really govern success with treatment with ibrutinib versus other forms of treatment.

We were trying to evaluate what the relationship is between complete response, a partial response or stable disease, and clinical outcome. Complete response is defined by the IWCLL working group as when you have lymph nodes trickling down to normal size, the blood counts are normal, and you can’t detect leukemia cells in the blood or marrow unless you use very sensitive techniques.

So, the patient should have normal blood counts. They should have no anemia. They should not have a low platelet count. And if they achieve all of that, they have a complete response. This is a definition of good response to treatment, and with chemoimmunotherapy that’s what we want to achieve. Because, chemoimmunotherapy is given for only a short duration of time, up to 4 to 6 months of treatment. Then we stop treatment, at which time we assess for a complete response. And those patients who achieve a complete remission tend to do better than patients, of course, who do not achieve a complete response. A partial response is where they only have 50% reduction in the size of lymph nodes. Obviously, they still have residual disease after treatment.

Now with ibrutinib, we do maintain patients on continuous therapy. And so, it’s not the same when we compare the responses with chemoimmunotherapy, because it’s a little bit like apples and oranges. So, what we’re talking about is that patients don’t generally achieve a complete response in the first several months of treatment. Generally speaking, they have what’s called a partial response. Namely, you still can detect leukemia cells in the blood or in the marrow: It’s very easy to detect, even after 9 or 12 months of therapy. But the patients are responding well to treatment, the disease is being maintained, and they’re tolerating the drug well. It doesn’t seem like you have to worry about stopping therapy, because you’re not accumulating a lot of toxicity as you would with chemotherapy. If you administered chemotherapy on and on for months and months and years and years, chances are the patient wouldn’t tolerate that very well.

I think we have to now reassess what it means to be in complete remission versus partial remission, particularly with drugs that we can continue on and on. If the patients are tolerating the drug well and not having any side effects in therapy, then if they’re partial response, that partial response may maintain itself and may even over time turn into a complete response, maybe even after a year or 2 of therapy. And so, it’s like a moving target here. Since they’re continually on therapy, it’s probably safe to say that they’re going to continue to do well as they are doing on therapy at the time.

For that reason, we can’t really equate the 2. And as surrogate markers, which is what these are, these are markers that help to define overall survival—that’s the critical thing. And so, if you look at the RESONATE-2 study where we compared patients with chemotherapy versus patients treated with ibrutinib, we noted that we did not achieve a lot of complete responses, but patients on drug did well and actually had an improved survival over patients treated with chemotherapy, where we did have a few, although not many, complete responses with that regimen. I think that insofar as being able to equate a complete response with survival, that’s difficult for all types of therapy. I think we have to really look at the type of therapy to be able to make the leap of using that as a marker for survival.             

Transcript Edited for Clarity  
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Transcript:

Thomas J. Kipps, MD, PhD: We really don’t quite understand what accounts for why patients with deletions in chromosome 11 fare better than, and at least as well as, patients who don’t have deletions in chromosome 11. So right now, we have observation, and there are several reasons that we have put forward as possible explanations for this. But we’re still investigating whether or not those reasons are actually accurate.

I think there’s some research activity that’s now ongoing to try and define, what is it about the deletions in chromosome 11 that make them less able to respond well to chemotherapy? We know practical experience is that patients with deletions in chromosome 11 tend to respond to a chemoimmunotherapy regimen or chemotherapy regimens; however, the duration of the response appears to be shorter than if they did not have deletions in chromosome 11. The exact reason for that is not clear, but it seems to indicate that when the leukemia cells have deletions in chromosome 11, they may have maybe less stability in their genome; they may be getting greater signaling through their receptor, such as the B-cell receptor; and they may be more prone to spinning off variants that could lead to resistance to therapy. But whatever it is, it seems to indicate that patients with deletion 11q may actually have a tendency to relapse faster after stopping chemotherapy.
With ibrutinib, we maintain therapy—we don’t stop therapy—so it may provide the ability to keep that clone from coming back, and that could also be contributing partly to my patients who are doing better. So, I think research still needs to be done to figure out the explanations here. And I think this will be very useful, because then we’ll be able to define what those features are that really govern success with treatment with ibrutinib versus other forms of treatment.

We were trying to evaluate what the relationship is between complete response, a partial response or stable disease, and clinical outcome. Complete response is defined by the IWCLL working group as when you have lymph nodes trickling down to normal size, the blood counts are normal, and you can’t detect leukemia cells in the blood or marrow unless you use very sensitive techniques.

So, the patient should have normal blood counts. They should have no anemia. They should not have a low platelet count. And if they achieve all of that, they have a complete response. This is a definition of good response to treatment, and with chemoimmunotherapy that’s what we want to achieve. Because, chemoimmunotherapy is given for only a short duration of time, up to 4 to 6 months of treatment. Then we stop treatment, at which time we assess for a complete response. And those patients who achieve a complete remission tend to do better than patients, of course, who do not achieve a complete response. A partial response is where they only have 50% reduction in the size of lymph nodes. Obviously, they still have residual disease after treatment.

Now with ibrutinib, we do maintain patients on continuous therapy. And so, it’s not the same when we compare the responses with chemoimmunotherapy, because it’s a little bit like apples and oranges. So, what we’re talking about is that patients don’t generally achieve a complete response in the first several months of treatment. Generally speaking, they have what’s called a partial response. Namely, you still can detect leukemia cells in the blood or in the marrow: It’s very easy to detect, even after 9 or 12 months of therapy. But the patients are responding well to treatment, the disease is being maintained, and they’re tolerating the drug well. It doesn’t seem like you have to worry about stopping therapy, because you’re not accumulating a lot of toxicity as you would with chemotherapy. If you administered chemotherapy on and on for months and months and years and years, chances are the patient wouldn’t tolerate that very well.

I think we have to now reassess what it means to be in complete remission versus partial remission, particularly with drugs that we can continue on and on. If the patients are tolerating the drug well and not having any side effects in therapy, then if they’re partial response, that partial response may maintain itself and may even over time turn into a complete response, maybe even after a year or 2 of therapy. And so, it’s like a moving target here. Since they’re continually on therapy, it’s probably safe to say that they’re going to continue to do well as they are doing on therapy at the time.

For that reason, we can’t really equate the 2. And as surrogate markers, which is what these are, these are markers that help to define overall survival—that’s the critical thing. And so, if you look at the RESONATE-2 study where we compared patients with chemotherapy versus patients treated with ibrutinib, we noted that we did not achieve a lot of complete responses, but patients on drug did well and actually had an improved survival over patients treated with chemotherapy, where we did have a few, although not many, complete responses with that regimen. I think that insofar as being able to equate a complete response with survival, that’s difficult for all types of therapy. I think we have to really look at the type of therapy to be able to make the leap of using that as a marker for survival.             

Transcript Edited for Clarity  
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