Transcript:
Jorge Cortes, MD: If you can easily simply summarize briefly the issue of changing therapy. Now, you have actually a patient that’s relapsed or is refractory to therapy. Once exactly do we have actually to actually think of a modification in therapy of the TKIs?
Javier Pinilla-Ibarz, MD, PhD: I believe we’re going to discuss [that there are] two different main reasons why we modification TKI therapy: tolerance and lack of response. In terms of the lack of response, I think, once again, we have to actually go to our NCCN and ELN guidelines, which have actually subtle differences, and again use some common sense, toreally grab a sense at the time of the milestone exactly how this patient is doing. However, if the milestone is not actually obtained at three months and certainly at 6 months—and this period, in my opinion, is a gray area where you can easily actually move a lot more to the three or a lot more to the 6 where to start with—the a patient ought to be considered to actually modification to various other TKI.
It is rather simple to think, in my opinion, that if a patient started along with imatinib, I might hope to achieve a much better response if it’s not actually obtained at three to 6 months. However, in a second-generation TKI, in general, we could be a lot more conservative due to the fact that we might not have actually so numerous options. We constantly say that, ‘Well, I might not be so aggressive to switch therapy. I will certainly wait a little longer to see exactly how points go.’ These are the early points that we think of Once changing therapies. However, sometimes we see patients that have actually not been assessed at the rather start and they come to our practices, and, of course, we apply subsequent milestones; the classical lack of finish cytogenetic response, for example at a year, in my opinion, is a rather good argument to switch therapy immediately.
Lastly, in terms of major molecular response, despite the fact that I agree along with David, I adore to do that, I could be a lot more conservative regarding switching therapies upon lack of MMR. And of course, patient to patient will certainly be something that I have actually to actually consider.
Jorge Cortes, MD: David, simply to round up this a little bit more: Javier stated the issue that it can easily be as a result of resistance or as a result of intolerance. exactly how frequently do you believe we actually see true intolerance? I’ve been recently actually concerned that are switching for edge events that are manageable, very compared to for true intolerance. can easily you tell us your impression regarding exactly how frequently is true intolerance seen versus resistance, of course?
David Snyder, MD, FACP: No question for resistance. You have to make a change, and there are choices. Intolerance, as we’ve said: it’s rather common for patients to have actually low-grade, grade-1, grade-2 toxicities along with any kind of of the TKIs. As we said, fortunately, for most of those toxicities, along with time and support, those symptoms abate and patients can easily go on on. So, I’m fairly slow to make modifications based on intolerance and it’s very rare in my method that I have actually to do that. I do have actually a patient or a few that have actually [intolerance]; it’s grade 2, however it’s certainly interfering along with quality of life on a everyday basis along with one TKI. And I say to them, ‘Okay, you’ve gotten a good response, we’re where we hope to be, however your quality of life I believe could be improved.’ There’s rather little cross intolerance from one to another. But, as you said, Harry, it doesn’t mean that you wouldn’t grab some various other toxicity.
You have actually to maintain that in mind, and maybe that one would certainly be worse compared to exactly what the patient has actually now. however I believe due to the fact that we do have actually options, you have actually to remember exactly what the comorbidities are, particularly patients’ risk for cardio complications. however I believe there’s choices to move to a different drug devoid of feeling that you’re going to compromise the manage of the disease; hopefully, you’re going to improve their quality of life. And, of course, after a trial, you could end up going spine to the original drug due to the fact that they might actually feel worse on the second one compared to on first.
Jorge Cortes, MD: Harry, if I can easily ask you: so we changed from a initial treatment to a second treatment. Now, you’re in your second treatment. It starts becoming a little bit trickier. exactly how long do you offer that second treatment prior to you identify that it’s working or not working? Once do I know Once I have to go to yet another TKI or Once do I know that I have 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 actually been earned based on all the data which would certainly include ABL mutational analysis. We know it appears, at least, that nilotinib may be a much better choice in patients along with a codon 317 or a codon 299 mutation. Dasatinib could be a much better choice for patients along with P-loop mutations, and, of course, patients along with a T315I mutation, that is the labeled indication for ponatinib. So, let’s say your decision to switch was informed by all the data available to you. I believe there’s growing evidence from a number of institutions that outcome does relate to a rather early response at three and 6 months. You don’t have actually to wait actually long. If patients are achieving cytogenetic or even molecular responses early on, after that you can easily rest assured that they’re going to do better.
The question is exactly what ought to be the strategy for patients that don’t achieve those early responses. And section of it depends on whether you believe the patient is a candidate for allogeneic stem cell transplant. If it’s a younger patient, no comorbidities, a family of 10, numerous sibling donors, it could be a much less complicated decision to send them to transplant. And we have actually learned, unlike in our interferon days where we were all of warned, if you offer interferon a lot more compared to a year or two, the outcome of transplant is much worse. We haven’t seen that in patients that have actually been treated along with TKIs except if they’ve progressed in to accelerated phase. If they’re still in chronic phase regardless of the mutation that’s there, their outcome is simply as good regardless of Once they are transplanted. So the trick is not letting them progress.
I believe the a lot more difficult issue is the patient that might not be the most effective candidate, But 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 actually been on all of 5 TKIs, has actually had true toxicities managed by an expert and couldn’t tolerate any kind of of them. The patient is now on bosutinib and she has actually persistent illness at the cytogenetic level, finish hematologic remission, feels great, and she’s 70 years old. So, if she was 17 years old, I could feel a lot a lot more strongly regarding a stem cell transplant. But, in her situation, she’s going with quality of life right now.
The various other thing, I believe the last point I’ll make here that we have actually to consider, is that I know we’re rather invested in these cytogenetic and molecular remissions. however a curious observation from the START trials along with dasatinib and ENACT trials along with nilotinib is that only regarding 45%, 50% of patients obtained these excellent remissions. however if you consider the survival curves, they’re much much better compared to we would certainly have actually expected. In fact, Jorge, you published on this from your MD Anderson experience; that patients that had a hematologic remission along with an ABL TKI seemed to be doing better. And so the conversation I have actually along with that 70-year-old is, this isn’t optimal. Once we have actually a clinical trial of a novel therapy that could include to the effects of an ABL TKI or some different approach, let’s think of that. But, at this point, we’re making the decision to go on along with exactly what we would certainly think of suboptimal therapy. exactly what we don’t know finally is, if I took that patient to an allogeneic transplant at the age of 70 along with a reasonable intensity conditioning regimen and unrelated donor, would certainly her outcome be much better compared to simply continuing along with exactly what I’m doing? We don’t know.
Jorge Cortes, MD: Exactly. I believe that that’s a rather vital point. I believe we constantly have actually to remember that our assessment of response and exactly how swiftly we have to induce a modification depends on exactly what we know regarding that degree of response and exactly what it means for the patient. however likewise exactly what replacements do you have actually for that patient that realistically offer a much better chance. I have actually a patient that’s treated along with imatinib and after a year, maybe 6 months, he’s falling behind and he’s a young patient. I might hope to pull the induce a little bit sooner. If I have actually a patient along with T359 and it’s a little bit slow to respond to ponatinib, exactly what realistically do we have actually that’s going to offer a much better probability?
So, I mean you have to put these things, all of these recommendations, and Javier and others have actually emphasized this point. The recommendations, they offer you some general guidelines, however we constantly have actually to individualize these to our patient, to exactly what exactly is happening, and we still have actually to be doctors, not simply complying with a recipe. It’s not adore if I pull one of these recipe manuals from my wife and I do the same thing that she does; it’s not going to be the same thing. You have actually to put a little bit of your touch, and it’s not going to be the same.
Transcript Edited for Clarity
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 Online: Tuesday, March 15, 2016
Transcript:
Jorge Cortes, MD: If you can easily simply summarize briefly the issue of changing therapy. Now, you have actually a patient that’s relapsed or is refractory to therapy. Once exactly do we have actually to actually think of a modification in therapy of the TKIs?
Javier Pinilla-Ibarz, MD, PhD: I believe we’re going to discuss [that there are] two different main reasons why we modification TKI therapy: tolerance and lack of response. In terms of the lack of response, I think, once again, we have to actually go to our NCCN and ELN guidelines, which have actually subtle differences, and again use some common sense, toreally grab a sense at the time of the milestone exactly how this patient is doing. However, if the milestone is not actually obtained at three months and certainly at 6 months—and this period, in my opinion, is a gray area where you can easily actually move a lot more to the three or a lot more to the 6 where to start with—the a patient ought to be considered to actually modification to various other TKI.
It is rather simple to think, in my opinion, that if a patient started along with imatinib, I might hope to achieve a much better response if it’s not actually obtained at three to 6 months. However, in a second-generation TKI, in general, we could be a lot more conservative due to the fact that we might not have actually so numerous options. We constantly say that, ‘Well, I might not be so aggressive to switch therapy. I will certainly wait a little longer to see exactly how points go.’ These are the early points that we think of Once changing therapies. However, sometimes we see patients that have actually not been assessed at the rather start and they come to our practices, and, of course, we apply subsequent milestones; the classical lack of finish cytogenetic response, for example at a year, in my opinion, is a rather good argument to switch therapy immediately.
Lastly, in terms of major molecular response, despite the fact that I agree along with David, I adore to do that, I could be a lot more conservative regarding switching therapies upon lack of MMR. And of course, patient to patient will certainly be something that I have actually to actually consider.
Jorge Cortes, MD: David, simply to round up this a little bit more: Javier stated the issue that it can easily be as a result of resistance or as a result of intolerance. exactly how frequently do you believe we actually see true intolerance? I’ve been recently actually concerned that are switching for edge events that are manageable, very compared to for true intolerance. can easily you tell us your impression regarding exactly how frequently is true intolerance seen versus resistance, of course?
David Snyder, MD, FACP: No question for resistance. You have to make a change, and there are choices. Intolerance, as we’ve said: it’s rather common for patients to have actually low-grade, grade-1, grade-2 toxicities along with any kind of of the TKIs. As we said, fortunately, for most of those toxicities, along with time and support, those symptoms abate and patients can easily go on on. So, I’m fairly slow to make modifications based on intolerance and it’s very rare in my method that I have actually to do that. I do have actually a patient or a few that have actually [intolerance]; it’s grade 2, however it’s certainly interfering along with quality of life on a everyday basis along with one TKI. And I say to them, ‘Okay, you’ve gotten a good response, we’re where we hope to be, however your quality of life I believe could be improved.’ There’s rather little cross intolerance from one to another. But, as you said, Harry, it doesn’t mean that you wouldn’t grab some various other toxicity.
You have actually to maintain that in mind, and maybe that one would certainly be worse compared to exactly what the patient has actually now. however I believe due to the fact that we do have actually options, you have actually to remember exactly what the comorbidities are, particularly patients’ risk for cardio complications. however I believe there’s choices to move to a different drug devoid of feeling that you’re going to compromise the manage of the disease; hopefully, you’re going to improve their quality of life. And, of course, after a trial, you could end up going spine to the original drug due to the fact that they might actually feel worse on the second one compared to on first.
Jorge Cortes, MD: Harry, if I can easily ask you: so we changed from a initial treatment to a second treatment. Now, you’re in your second treatment. It starts becoming a little bit trickier. exactly how long do you offer that second treatment prior to you identify that it’s working or not working? Once do I know Once I have to go to yet another TKI or Once do I know that I have 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 actually been earned based on all the data which would certainly include ABL mutational analysis. We know it appears, at least, that nilotinib may be a much better choice in patients along with a codon 317 or a codon 299 mutation. Dasatinib could be a much better choice for patients along with P-loop mutations, and, of course, patients along with a T315I mutation, that is the labeled indication for ponatinib. So, let’s say your decision to switch was informed by all the data available to you. I believe there’s growing evidence from a number of institutions that outcome does relate to a rather early response at three and 6 months. You don’t have actually to wait actually long. If patients are achieving cytogenetic or even molecular responses early on, after that you can easily rest assured that they’re going to do better.
The question is exactly what ought to be the strategy for patients that don’t achieve those early responses. And section of it depends on whether you believe the patient is a candidate for allogeneic stem cell transplant. If it’s a younger patient, no comorbidities, a family of 10, numerous sibling donors, it could be a much less complicated decision to send them to transplant. And we have actually learned, unlike in our interferon days where we were all of warned, if you offer interferon a lot more compared to a year or two, the outcome of transplant is much worse. We haven’t seen that in patients that have actually been treated along with TKIs except if they’ve progressed in to accelerated phase. If they’re still in chronic phase regardless of the mutation that’s there, their outcome is simply as good regardless of Once they are transplanted. So the trick is not letting them progress.
I believe the a lot more difficult issue is the patient that might not be the most effective candidate, But 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 actually been on all of 5 TKIs, has actually had true toxicities managed by an expert and couldn’t tolerate any kind of of them. The patient is now on bosutinib and she has actually persistent illness at the cytogenetic level, finish hematologic remission, feels great, and she’s 70 years old. So, if she was 17 years old, I could feel a lot a lot more strongly regarding a stem cell transplant. But, in her situation, she’s going with quality of life right now.
The various other thing, I believe the last point I’ll make here that we have actually to consider, is that I know we’re rather invested in these cytogenetic and molecular remissions. however a curious observation from the START trials along with dasatinib and ENACT trials along with nilotinib is that only regarding 45%, 50% of patients obtained these excellent remissions. however if you consider the survival curves, they’re much much better compared to we would certainly have actually expected. In fact, Jorge, you published on this from your MD Anderson experience; that patients that had a hematologic remission along with an ABL TKI seemed to be doing better. And so the conversation I have actually along with that 70-year-old is, this isn’t optimal. Once we have actually a clinical trial of a novel therapy that could include to the effects of an ABL TKI or some different approach, let’s think of that. But, at this point, we’re making the decision to go on along with exactly what we would certainly think of suboptimal therapy. exactly what we don’t know finally is, if I took that patient to an allogeneic transplant at the age of 70 along with a reasonable intensity conditioning regimen and unrelated donor, would certainly her outcome be much better compared to simply continuing along with exactly what I’m doing? We don’t know.
Jorge Cortes, MD: Exactly. I believe that that’s a rather vital point. I believe we constantly have actually to remember that our assessment of response and exactly how swiftly we have to induce a modification depends on exactly what we know regarding that degree of response and exactly what it means for the patient. however likewise exactly what replacements do you have actually for that patient that realistically offer a much better chance. I have actually a patient that’s treated along with imatinib and after a year, maybe 6 months, he’s falling behind and he’s a young patient. I might hope to pull the induce a little bit sooner. If I have actually a patient along with T359 and it’s a little bit slow to respond to ponatinib, exactly what realistically do we have actually that’s going to offer a much better probability?
So, I mean you have to put these things, all of these recommendations, and Javier and others have actually emphasized this point. The recommendations, they offer you some general guidelines, however we constantly have actually to individualize these to our patient, to exactly what exactly is happening, and we still have actually to be doctors, not simply complying with a recipe. It’s not adore if I pull one of these recipe manuals from my wife and I do the same thing that she does; it’s not going to be the same thing. You have actually 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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