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Managing Toxicities from CML Treatment

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 08, 2016


Transcript:

Jorge Cortes, MD:
Let me ask you, Javier. One of the biggest concerns that we have recently is the issue of the cardiovascular adverse events that we’re starting to recognize more in the setting of the tyrosine kinase inhibitor (TKI) therapy. Some drugs may have a little bit more than others, but we’re seeing it with many of them. So, that brings [up] a question of how do you follow a patient for these side effects, again focusing on these arterial thrombotic, events and do you do it by yourself? Do you engage one of your cardiologist colleagues or somebody else in assessing this?

Javier Pinilla-Ibarz, MD, PhD: So, there is no doubt that after long follow-up of the second-generation TKI trials, we start to recognize these long-term side effects, and definitely, maybe, the cardiovascular ones are the ones that concern us the most. Everyone has their own setting. I think we’re talking a lot about the role of cardio-oncologists. Cardio-oncologists are not really available in many, many places. However, as every specialty, it seems like they are coming to work [in large cancer centers] because there is not only CML, there is breast cancer, there are many other VEGF inhibitors being used that really have an important impact on cardiovascular health.

So I think we’re going to see these specialists coming more and more, and I think we need to start to really work with them. For now, I don’t think that we have much we can offer in terms of what we’re going to do. Of course, prophylaxis is the thing that we recommend, but there is no doubt that the incorporation of these specialists in the future may assess how to better control the risk and there’s no doubt they are more up-to-date in any other areas that we are not really so specialized [in]. I think it’s going to have an important role in the future treatment of these long-term patients on TKI.

Jorge Cortes, MD: Let me add a different perspective. Part of the problem we see with some of these patients that have developed these arterial thrombotic events is that these are patients who have risk factors. They have hypertension, and hypercholesterolemia, and diabetes, and all these things. And perhaps, and I think it was shown in some of these studies, like the PACE study with ponatinib, we were not very good at controlling their blood pressure and we were not very good at controlling their cholesterol and all these things. So, perhaps we don’t even need a cardio-oncologist, we just need a cardiologist, somebody who’s a little bit more dedicated or more knowledgeable about managing these common issues and that if you address them better, perhaps we can decrease the risk. We’re probably not going to eliminate it, but perhaps we’re going to improve it. Do you agree?

Javier Pinilla-Ibarz, MD, PhD: I fully agree. I talk about the potential role of cardio-oncology because, once again, a cardio-oncologist is someone you’re going to find in a tertiary institution, in large cancer center. In real life, they are not going to be there. So, I think, one: our role is to try to educate the local cardiologist that most of our patients after 65, 70 may have to really let them be aware of these side effects. And again, the first time I meet a patient or a patient who’s already in a TKI who has potential long-term cardiovascular effect, I will really, really emphasize, ‘Okay, give me the number of your cardiologist’ or ‘Let me talk to them’ or ‘You are really educated enough, let them know that you’re on a drug that can increase your cardiovascular profile.’

Jorge Cortes, MD: Okay. Somewhat related to this, Kevin. Because these events are arterial-thrombotic and we’re worried about heart attacks, and strokes, and whatever, do you see a role for using prophylactic aspirin or statins on patients that are going to start with ponatinib, nilotinib, maybe dasatinib?

Kevin Kelly, MD, PhD: Yeah, certainly I think this is going to be a major issue, particularly as we move forward, and these patients stay on these medications longer and longer. I think the incidence of cardiovascular side effects is up to nearly 9% with some of the second-generation TKIs, so it’s quite significant. So, what I do, each patient I have I just address the cardiovascular risk factors—smoking, hypertension, and family history.

If they do have any cardiovascular risk factors, I do a risk-benefit ratio analysis in terms of starting aspirin, and I have started some patients on aspirin who are on TKIs. I do check a lipid profile once a year. I just do it myself because I can’t guarantee that it’s going to be done otherwise, and if it’s high, I’ll start the statin because I feel responsible because I prescribed a TKI in the first place. I don’t want the patient to get a cardiovascular side effect.

Jorge Cortes, MD: All right. So, David, just to wrap up a little bit about this issue of toxicity: can you give us two or three pearls, your wisdom on what should the physician treating a patient with CML with a TKI, what are the important things that we need to remember about managing adverse events in general? Of course, importantly, arterial-thrombotic, but, in general, adverse events?

David Snyder, MD, FACP: Right. Well, I think the most important ones are the cardiovascular-type of toxicities, pulmonary, as well as we know. I think it’s important for the community-based physicians to be aware of these risks. I would go beyond that. I think it’s incumbent upon us to educate our nonhematology colleagues in the community—the cardiologists, the pulmonologists who may be the first ones to see some of these patients with these complications—to increase the level of awareness at that point.

I think most hematologists are probably not going to be comfortable being primarily responsible for reducing risk and managing these problems, even though that would be ideal. But I think we need to partner with our colleagues out there, and so they need to be educated about the importance of working with a hematologist for these kind of patients. In terms of mitigating risk, I think there’s speculation, so far; not a lot of data about the value of aspirin or statins. It kind of makes sense, but I think it would be good to generate data showing the value. We assume that people who have these other traditional risk factors, that they should be optimally controlled. But we don’t know yet that that’s going to be sufficient to eliminate these risks.

Javier Pinilla-Ibarz, MD, PhD: Absolutely. And, as a matter of fact, as you know, we don’t really know from cardiology literature, but every time in any of these large, enormous multi-center trials that are done for cardiovascular risk prevention are really, really large. Unfortunately, I don’t think that we’re going to be able to really see these in our small community settings. So, we’ll have to take a little faith and say, ‘Well, we’ll do this because we believe it’s going to really help.’ However, we always say, ‘Oh, we love to really have data.’ I think it’s going to be really challenging to have data in our center.

Jorge Cortes, MD: I think in this topic, in terms of the antithrombotic, I think the major deficiency we have is we still don’t understand the mechanism, and obviously we need to do those studies because once we understand the mechanism, we’ll be perhaps better equipped to find ways to prevent it and manage it. In general, for adverse events, I think something that Harry mentioned earlier is very important. We need to stay connected with our patients. I mean, it’s not just about the PCR. It’s about staying very close to the patients, answering their questions, and managing their adverse events, whatever they be, and making sure that they let us know when they have issues so that we can address them appropriately.

Harry Erba, MD, PhD: And to get back to that. Something that you said very quickly before, David, was about [how] many of the toxicities are transient, and that’s the case. We all see patients who are started on a TKI. Maybe it’s bosutinib and they develop diarrhea, but it tends to get better, or rashes or aches and pains with imatinib and nilotinib and dasatinib, they tend to get better. And what we need to be very cognizant of is, you just started a patient on a drug that you told them that they’re going to have to be on for the rest of their life, and what they hear is, ‘I’m going to feel like this for the rest of my life.’ So, what I would say as well, in terms of monitoring, is that at the beginning when you start therapy, I do toxicity assessments on my patients at a week, at a month, at two months, three months, and then I go to every three-month visits if they’re stable because you need to help them through and manage those toxicities early on.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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Transcript:

Jorge Cortes, MD:
Let me ask you, Javier. One of the biggest concerns that we have recently is the issue of the cardiovascular adverse events that we’re starting to recognize more in the setting of the tyrosine kinase inhibitor (TKI) therapy. Some drugs may have a little bit more than others, but we’re seeing it with many of them. So, that brings [up] a question of how do you follow a patient for these side effects, again focusing on these arterial thrombotic, events and do you do it by yourself? Do you engage one of your cardiologist colleagues or somebody else in assessing this?

Javier Pinilla-Ibarz, MD, PhD: So, there is no doubt that after long follow-up of the second-generation TKI trials, we start to recognize these long-term side effects, and definitely, maybe, the cardiovascular ones are the ones that concern us the most. Everyone has their own setting. I think we’re talking a lot about the role of cardio-oncologists. Cardio-oncologists are not really available in many, many places. However, as every specialty, it seems like they are coming to work [in large cancer centers] because there is not only CML, there is breast cancer, there are many other VEGF inhibitors being used that really have an important impact on cardiovascular health.

So I think we’re going to see these specialists coming more and more, and I think we need to start to really work with them. For now, I don’t think that we have much we can offer in terms of what we’re going to do. Of course, prophylaxis is the thing that we recommend, but there is no doubt that the incorporation of these specialists in the future may assess how to better control the risk and there’s no doubt they are more up-to-date in any other areas that we are not really so specialized [in]. I think it’s going to have an important role in the future treatment of these long-term patients on TKI.

Jorge Cortes, MD: Let me add a different perspective. Part of the problem we see with some of these patients that have developed these arterial thrombotic events is that these are patients who have risk factors. They have hypertension, and hypercholesterolemia, and diabetes, and all these things. And perhaps, and I think it was shown in some of these studies, like the PACE study with ponatinib, we were not very good at controlling their blood pressure and we were not very good at controlling their cholesterol and all these things. So, perhaps we don’t even need a cardio-oncologist, we just need a cardiologist, somebody who’s a little bit more dedicated or more knowledgeable about managing these common issues and that if you address them better, perhaps we can decrease the risk. We’re probably not going to eliminate it, but perhaps we’re going to improve it. Do you agree?

Javier Pinilla-Ibarz, MD, PhD: I fully agree. I talk about the potential role of cardio-oncology because, once again, a cardio-oncologist is someone you’re going to find in a tertiary institution, in large cancer center. In real life, they are not going to be there. So, I think, one: our role is to try to educate the local cardiologist that most of our patients after 65, 70 may have to really let them be aware of these side effects. And again, the first time I meet a patient or a patient who’s already in a TKI who has potential long-term cardiovascular effect, I will really, really emphasize, ‘Okay, give me the number of your cardiologist’ or ‘Let me talk to them’ or ‘You are really educated enough, let them know that you’re on a drug that can increase your cardiovascular profile.’

Jorge Cortes, MD: Okay. Somewhat related to this, Kevin. Because these events are arterial-thrombotic and we’re worried about heart attacks, and strokes, and whatever, do you see a role for using prophylactic aspirin or statins on patients that are going to start with ponatinib, nilotinib, maybe dasatinib?

Kevin Kelly, MD, PhD: Yeah, certainly I think this is going to be a major issue, particularly as we move forward, and these patients stay on these medications longer and longer. I think the incidence of cardiovascular side effects is up to nearly 9% with some of the second-generation TKIs, so it’s quite significant. So, what I do, each patient I have I just address the cardiovascular risk factors—smoking, hypertension, and family history.

If they do have any cardiovascular risk factors, I do a risk-benefit ratio analysis in terms of starting aspirin, and I have started some patients on aspirin who are on TKIs. I do check a lipid profile once a year. I just do it myself because I can’t guarantee that it’s going to be done otherwise, and if it’s high, I’ll start the statin because I feel responsible because I prescribed a TKI in the first place. I don’t want the patient to get a cardiovascular side effect.

Jorge Cortes, MD: All right. So, David, just to wrap up a little bit about this issue of toxicity: can you give us two or three pearls, your wisdom on what should the physician treating a patient with CML with a TKI, what are the important things that we need to remember about managing adverse events in general? Of course, importantly, arterial-thrombotic, but, in general, adverse events?

David Snyder, MD, FACP: Right. Well, I think the most important ones are the cardiovascular-type of toxicities, pulmonary, as well as we know. I think it’s important for the community-based physicians to be aware of these risks. I would go beyond that. I think it’s incumbent upon us to educate our nonhematology colleagues in the community—the cardiologists, the pulmonologists who may be the first ones to see some of these patients with these complications—to increase the level of awareness at that point.

I think most hematologists are probably not going to be comfortable being primarily responsible for reducing risk and managing these problems, even though that would be ideal. But I think we need to partner with our colleagues out there, and so they need to be educated about the importance of working with a hematologist for these kind of patients. In terms of mitigating risk, I think there’s speculation, so far; not a lot of data about the value of aspirin or statins. It kind of makes sense, but I think it would be good to generate data showing the value. We assume that people who have these other traditional risk factors, that they should be optimally controlled. But we don’t know yet that that’s going to be sufficient to eliminate these risks.

Javier Pinilla-Ibarz, MD, PhD: Absolutely. And, as a matter of fact, as you know, we don’t really know from cardiology literature, but every time in any of these large, enormous multi-center trials that are done for cardiovascular risk prevention are really, really large. Unfortunately, I don’t think that we’re going to be able to really see these in our small community settings. So, we’ll have to take a little faith and say, ‘Well, we’ll do this because we believe it’s going to really help.’ However, we always say, ‘Oh, we love to really have data.’ I think it’s going to be really challenging to have data in our center.

Jorge Cortes, MD: I think in this topic, in terms of the antithrombotic, I think the major deficiency we have is we still don’t understand the mechanism, and obviously we need to do those studies because once we understand the mechanism, we’ll be perhaps better equipped to find ways to prevent it and manage it. In general, for adverse events, I think something that Harry mentioned earlier is very important. We need to stay connected with our patients. I mean, it’s not just about the PCR. It’s about staying very close to the patients, answering their questions, and managing their adverse events, whatever they be, and making sure that they let us know when they have issues so that we can address them appropriately.

Harry Erba, MD, PhD: And to get back to that. Something that you said very quickly before, David, was about [how] many of the toxicities are transient, and that’s the case. We all see patients who are started on a TKI. Maybe it’s bosutinib and they develop diarrhea, but it tends to get better, or rashes or aches and pains with imatinib and nilotinib and dasatinib, they tend to get better. And what we need to be very cognizant of is, you just started a patient on a drug that you told them that they’re going to have to be on for the rest of their life, and what they hear is, ‘I’m going to feel like this for the rest of my life.’ So, what I would say as well, in terms of monitoring, is that at the beginning when you start therapy, I do toxicity assessments on my patients at a week, at a month, at two months, three months, and then I go to every three-month visits if they’re stable because you need to help them through and manage those toxicities early on.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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