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Switching Therapy in Chronic Myeloid Leukemia

Panelists:Jorge E. Cortes, MD, University of Texas MD Anderson Cancer Center; Harry P. Erba, MD, PhD, University of Alabama; Kevin Kelly, MD, PhD, University of Southern California; Javier Pinilla-Ibarz, MD, PhD, Moffitt Cancer Center; David S. Snyder, MD, FACP, City of Hope
Published: Tuesday, Mar 15, 2016


Transcript:

Jorge Cortes, MD:
If you can just summarize briefly the issue of changing therapy. Now, you have a patient that’s relapsed or is refractory to therapy. When exactly do we have to really consider a change in therapy of the TKIs?

Javier Pinilla-Ibarz, MD, PhD: I think we’re going to discuss [that there are] two different main reasons why we change TKI therapy: tolerance and lack of response. In terms of the lack of response, I think, once again, we need to really go to our NCCN and ELN guidelines, which have subtle differences, and again use some common sense, toreally get a sense at the time of the milestone how this patient is doing. However, if the milestone is not really achieved at three months and definitely at six months—and this period, in my opinion, is a gray area where you can really move more to the three or more to the six where to start with—the a patient should be considered to really change to other TKI.

It is very easy to think, in my opinion, that if a patient started with imatinib, I may want to achieve a better response if it’s not really achieved at three to six months. However, in a second-generation TKI, in general, we may be more conservative because we may not have so many options. We always say that, ‘Well, I may not be so aggressive to switch therapy. I will wait a little longer to see how things go.’ These are the early things that we consider when changing therapies. However, sometimes we see patients that have not been assessed at the very beginning and they come to our practices, and, of course, we apply subsequent milestones; the classical lack of complete cytogenetic response, for example at a year, in my opinion, is a very good argument to switch therapy immediately.

Lastly, in terms of major molecular response, although I agree with David, I like to do that, I may be more conservative about switching therapies upon lack of MMR. And of course, patient to patient will be something that I have to really consider.

Jorge Cortes, MD: David, just to round up this a little bit more: Javier mentioned the issue that it can be because of resistance or because of intolerance. How often do you think we really see true intolerance? I’ve been recently really concerned that are switching for adverse events that are manageable, rather than for true intolerance. Can you tell us your impression about how often is true intolerance seen versus resistance, of course?

David Snyder, MD, FACP: No question for resistance. You need to make a change, and there are choices. Intolerance, as we’ve said: it’s very common for patients to have low-grade, grade-1, grade-2 toxicities with any of the TKIs. As we said, fortunately, for most of those toxicities, with time and support, those symptoms abate and patients can continue on. So, I’m fairly slow to make changes based on intolerance and it’s pretty rare in my practice that I have to do that. I do have a patient or a few who have [intolerance]; it’s grade 2, but it’s definitely interfering with quality of life on a daily basis with one TKI. And I say to them, ‘Okay, you’ve gotten a good response, we’re where we want to be, but your quality of life I think could be improved.’ There’s very little cross intolerance from one to another. But, as you said, Harry, it doesn’t mean that you wouldn’t get some other toxicity.

You have to keep that in mind, and maybe that one would be worse than what the patient has now. But I think since we do have options, you have to keep in mind what the comorbidities are, particularly patients’ risk for cardiovascular complications. But I think there’s options to move to a different drug without feeling that you’re going to compromise the control of the disease; hopefully, you’re going to improve their quality of life. And, of course, after a trial, you might end up going back to the original drug because they may actually feel worse on the second one than on first.

Jorge Cortes, MD: Harry, if I can ask you: so we changed from a first treatment to a second treatment. Now, you’re in your second treatment. It starts becoming a little bit trickier. How long do you give that second treatment before you determine that it’s working or not working? When do I know when I need to go to another TKI or when do I know that I need to go to a transplant, for example, after I’ve gone to,, my second line of therapy?

Harry Erba, MD, PhD: Let’s assume that the switch has been made based on all of the data which would include ABL mutational analysis. We know it appears, at least, that nilotinib might be a better choice in patients with a codon 317 or a codon 299 mutation. Dasatinib may be a better choice for patients with P-loop mutations, and, of course, patients with a T315I mutation, that is the labeled indication for ponatinib. So, let’s say your decision to switch was informed by all of the data available to you. I think there’s growing evidence from a number of institutions that outcome does relate to a very early response at three and six months. You don’t have to wait really long. If patients are achieving cytogenetic or even molecular responses early on, then you can rest assured that they’re going to do better.

The question is what should be the plan for patients who don’t achieve those early responses. And part of it depends on whether you think the patient is a candidate for allogeneic stem cell transplant. If it’s a younger patient, no comorbidities, a family of 10, lots of sibling donors, it may be a much easier decision to send them to transplant. And we have learned, unlike in our interferon days where we were all warned, if you give interferon more than a year or two, the outcome of transplant is much worse. We haven’t seen that in patients who have been treated with TKIs except if they’ve progressed into accelerated phase. If they’re still in chronic phase regardless of the mutation that’s there, their outcome is just as good regardless of when they are transplanted. So the trick is not letting them progress.

I think the more difficult issue is the patient who may not be the best candidate, however you define it, for transplant—age, comorbidities, donor, whatever it is. In fact, Jorge, you and I share a patient who’s 70 years old, has been on all five TKIs, has had true toxicities managed by an expert and couldn’t tolerate any of them. The patient is now on bosutinib and she has persistent disease at the cytogenetic level, complete hematologic remission, feels great, and she’s 70 years old. So, if she was 17 years old, I might feel a lot more strongly about a stem cell transplant. But, in her situation, she’s choosing quality of life right now.

The other thing, I think the last point I’ll make here that we have to consider, is that I know we’re very invested in these cytogenetic and molecular remissions. But a curious observation from the START trials with dasatinib and ENACT trials with nilotinib is that only about 45%, 50% of patients achieved these great remissions. But if you look at the survival curves, they’re much better than we would have expected. In fact, Jorge, you published on this from your MD Anderson experience; that patients who had a hematologic remission with an ABL TKI seemed to be doing better. And so the conversation I have with that 70-year-old is, this isn’t optimal. When we have a clinical trial of a novel therapy that might add to the effects of an ABL TKI or some different approach, let’s consider that. But, at this point, we’re making the decision to continue with what we would consider suboptimal therapy. What we don’t know finally is, if I took that patient to an allogeneic transplant at the age of 70 with a reduced intensity conditioning regimen and unrelated donor, would her outcome be better than just continuing with what I’m doing? We don’t know.

Jorge Cortes, MD: Exactly. I think that that’s a very important point. I think we always have to keep in mind that our assessment of response and how quickly we need to trigger a change depends on what we know about that level of response and what it means for the patient. But also what alternatives do you have for that patient that realistically offer a better chance. I have a patient that’s treated with imatinib and after a year, maybe six months, he’s falling behind and he’s a young patient. I may want to pull the trigger a little bit sooner. If I have a patient with T359 and it’s a little bit slow to respond to ponatinib, what realistically do we have that’s going to give a better probability?

So, I mean you need to put these things, all these recommendations, and Javier and others have emphasized this point. The recommendations, they give you some general guidelines, but we always have to individualize these to our patient, to what exactly is happening, and we still have to be doctors, not just following a recipe. It’s not like if I pull one of these recipe books from my wife and I do the same thing that she does; it’s not going to be the same thing. You have to put a little bit of your touch, and it’s not going to be the same.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Jorge Cortes, MD:
If you can just summarize briefly the issue of changing therapy. Now, you have a patient that’s relapsed or is refractory to therapy. When exactly do we have to really consider a change in therapy of the TKIs?

Javier Pinilla-Ibarz, MD, PhD: I think we’re going to discuss [that there are] two different main reasons why we change TKI therapy: tolerance and lack of response. In terms of the lack of response, I think, once again, we need to really go to our NCCN and ELN guidelines, which have subtle differences, and again use some common sense, toreally get a sense at the time of the milestone how this patient is doing. However, if the milestone is not really achieved at three months and definitely at six months—and this period, in my opinion, is a gray area where you can really move more to the three or more to the six where to start with—the a patient should be considered to really change to other TKI.

It is very easy to think, in my opinion, that if a patient started with imatinib, I may want to achieve a better response if it’s not really achieved at three to six months. However, in a second-generation TKI, in general, we may be more conservative because we may not have so many options. We always say that, ‘Well, I may not be so aggressive to switch therapy. I will wait a little longer to see how things go.’ These are the early things that we consider when changing therapies. However, sometimes we see patients that have not been assessed at the very beginning and they come to our practices, and, of course, we apply subsequent milestones; the classical lack of complete cytogenetic response, for example at a year, in my opinion, is a very good argument to switch therapy immediately.

Lastly, in terms of major molecular response, although I agree with David, I like to do that, I may be more conservative about switching therapies upon lack of MMR. And of course, patient to patient will be something that I have to really consider.

Jorge Cortes, MD: David, just to round up this a little bit more: Javier mentioned the issue that it can be because of resistance or because of intolerance. How often do you think we really see true intolerance? I’ve been recently really concerned that are switching for adverse events that are manageable, rather than for true intolerance. Can you tell us your impression about how often is true intolerance seen versus resistance, of course?

David Snyder, MD, FACP: No question for resistance. You need to make a change, and there are choices. Intolerance, as we’ve said: it’s very common for patients to have low-grade, grade-1, grade-2 toxicities with any of the TKIs. As we said, fortunately, for most of those toxicities, with time and support, those symptoms abate and patients can continue on. So, I’m fairly slow to make changes based on intolerance and it’s pretty rare in my practice that I have to do that. I do have a patient or a few who have [intolerance]; it’s grade 2, but it’s definitely interfering with quality of life on a daily basis with one TKI. And I say to them, ‘Okay, you’ve gotten a good response, we’re where we want to be, but your quality of life I think could be improved.’ There’s very little cross intolerance from one to another. But, as you said, Harry, it doesn’t mean that you wouldn’t get some other toxicity.

You have to keep that in mind, and maybe that one would be worse than what the patient has now. But I think since we do have options, you have to keep in mind what the comorbidities are, particularly patients’ risk for cardiovascular complications. But I think there’s options to move to a different drug without feeling that you’re going to compromise the control of the disease; hopefully, you’re going to improve their quality of life. And, of course, after a trial, you might end up going back to the original drug because they may actually feel worse on the second one than on first.

Jorge Cortes, MD: Harry, if I can ask you: so we changed from a first treatment to a second treatment. Now, you’re in your second treatment. It starts becoming a little bit trickier. How long do you give that second treatment before you determine that it’s working or not working? When do I know when I need to go to another TKI or when do I know that I need to go to a transplant, for example, after I’ve gone to,, my second line of therapy?

Harry Erba, MD, PhD: Let’s assume that the switch has been made based on all of the data which would include ABL mutational analysis. We know it appears, at least, that nilotinib might be a better choice in patients with a codon 317 or a codon 299 mutation. Dasatinib may be a better choice for patients with P-loop mutations, and, of course, patients with a T315I mutation, that is the labeled indication for ponatinib. So, let’s say your decision to switch was informed by all of the data available to you. I think there’s growing evidence from a number of institutions that outcome does relate to a very early response at three and six months. You don’t have to wait really long. If patients are achieving cytogenetic or even molecular responses early on, then you can rest assured that they’re going to do better.

The question is what should be the plan for patients who don’t achieve those early responses. And part of it depends on whether you think the patient is a candidate for allogeneic stem cell transplant. If it’s a younger patient, no comorbidities, a family of 10, lots of sibling donors, it may be a much easier decision to send them to transplant. And we have learned, unlike in our interferon days where we were all warned, if you give interferon more than a year or two, the outcome of transplant is much worse. We haven’t seen that in patients who have been treated with TKIs except if they’ve progressed into accelerated phase. If they’re still in chronic phase regardless of the mutation that’s there, their outcome is just as good regardless of when they are transplanted. So the trick is not letting them progress.

I think the more difficult issue is the patient who may not be the best candidate, however you define it, for transplant—age, comorbidities, donor, whatever it is. In fact, Jorge, you and I share a patient who’s 70 years old, has been on all five TKIs, has had true toxicities managed by an expert and couldn’t tolerate any of them. The patient is now on bosutinib and she has persistent disease at the cytogenetic level, complete hematologic remission, feels great, and she’s 70 years old. So, if she was 17 years old, I might feel a lot more strongly about a stem cell transplant. But, in her situation, she’s choosing quality of life right now.

The other thing, I think the last point I’ll make here that we have to consider, is that I know we’re very invested in these cytogenetic and molecular remissions. But a curious observation from the START trials with dasatinib and ENACT trials with nilotinib is that only about 45%, 50% of patients achieved these great remissions. But if you look at the survival curves, they’re much better than we would have expected. In fact, Jorge, you published on this from your MD Anderson experience; that patients who had a hematologic remission with an ABL TKI seemed to be doing better. And so the conversation I have with that 70-year-old is, this isn’t optimal. When we have a clinical trial of a novel therapy that might add to the effects of an ABL TKI or some different approach, let’s consider that. But, at this point, we’re making the decision to continue with what we would consider suboptimal therapy. What we don’t know finally is, if I took that patient to an allogeneic transplant at the age of 70 with a reduced intensity conditioning regimen and unrelated donor, would her outcome be better than just continuing with what I’m doing? We don’t know.

Jorge Cortes, MD: Exactly. I think that that’s a very important point. I think we always have to keep in mind that our assessment of response and how quickly we need to trigger a change depends on what we know about that level of response and what it means for the patient. But also what alternatives do you have for that patient that realistically offer a better chance. I have a patient that’s treated with imatinib and after a year, maybe six months, he’s falling behind and he’s a young patient. I may want to pull the trigger a little bit sooner. If I have a patient with T359 and it’s a little bit slow to respond to ponatinib, what realistically do we have that’s going to give a better probability?

So, I mean you need to put these things, all these recommendations, and Javier and others have emphasized this point. The recommendations, they give you some general guidelines, but we always have to individualize these to our patient, to what exactly is happening, and we still have to be doctors, not just following a recipe. It’s not like if I pull one of these recipe books from my wife and I do the same thing that she does; it’s not going to be the same thing. You have to put a little bit of your touch, and it’s not going to be the same.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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