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TPO Receptor Agonists: Treatment Considerations

Panelists: Ivy Altomare, MD, Duke University Medical Center; Terry Gernsheimer, MD, Fred Hutchingson Cancer Research Center; Keith R McCrae, MD, The Cleveland Clinic
Published: Tuesday, Feb 13, 2018



Transcript: 

Ivy Altomare, MD: What’s the efficacy of these drugs, Dr. McCrae? Do you feel that there are any differences, other than the ease of use, or possible insurance issues, or maybe even financial issues? Are there any clinical differences in terms of efficacy between the 2 thrombopoietin mimetic agents?

Keith R. McCrae, MD: Well, they’re both TPO mimetics. They both act on the TPO receptor, but they’re not the same drug. I think an important thing to emphasize is that you can have patients who fail to respond well to one of these, but they respond very nicely to the other, even though they basically work through the same pathways.

Ivy Altomare, MD: And it can work both ways.

Keith R. McCrae, MD: It can go both ways. There are some class-specific toxicities that apply to both of these. Mostly, a little bit of reticulin in the bone marrow, which is not the same as collagen fibrosis. It’s mild reticular fibers that really, probably, don’t have much clinical significance and go away if the drug is stopped.

Of course, with eltrombopag develops some elevated transaminase levels, which are usually mildly elevated. Again, it doesn’t really have to be treated, but an occasional patient―a rare patient―can have marked elevations, so you do have to monitor that over time.

I agree with what Dr. Gernsheimer said. Romiplostim is a great drug, but I do think, regarding the management, that some people really do overreact to platelet counts. Some folks try to extend out the treatment from weekly to, let’s say, “Well, maybe I can get away with this every 2 weeks.” The platelets can really drop very quickly, and patients can get very thrombocytopenic.

I use both of them. Most of the patients I see prefer the oral medication. They don’t like to come into the hospital and pay for parking, and all of those kinds of things. I use romiplostim, sometimes, in hospitalized patients. You know, the recommended starting dose is quite low. But you can increase that 10-fold and still be within an approved range. I think you can really get more of a wallop at 10 ug/kg, if you need it. If you have somebody who is in the hospital and is really bleeding, I will start at quite a high dose, actually.

Ivy Altomare, MD: Yes. You know that the patient is getting it, and you know that there’s not a problem with absorption.

Keith R. McCrae, MD: Exactly, right.

Terry Gernsheimer, MD: I think you made a really good point that I want to elucidate on. The way both protocols were written, because we weren’t really sure what we were going to see, if the platelet count went over 400,000, the drug was to be held. What we quickly saw was―and this happens in about 10% of patients―if you stop either one of these drugs abruptly, patients can fall well below baseline. We had a couple of patients on study. There were protocol violations because I wasn’t willing to do it again. When they went up to 800,000, or something like that, the drug was held. Within days of missing a dose, they showed up in the emergency room bleeding.

Ivy Altomare, MD: Yes, we’ve seen it too.

Terry Gernsheimer, MD: Right. So, I think you have to be really careful. I can talk, off-label, about what I do when a patient’s platelet count gets really high. I don’t stop. I taper. I might decrease the dose by a third, or by half. If the count is really high, I might tell the patient to take an aspirin until the count comes down a little bit, which they just love. They’re like, “I’m allowed to take an aspirin?” It’s just so exciting. But I think people have to be really careful. They read that label. There is a warning at the top that got added because people started complaining, “Oh, I held the drug according to what the FDA said I was supposed to do. I got into trouble with it.” So, there is a warning at the top. The warning, for both of these drugs, if they are abruptly discontinued, is very low platelet counts and bleeding can occur.

Ivy Altomare, MD: Sure. Let’s say that you decide to actually stop therapy and not hold, as per dose adjustments. You’re actually stopping therapy. Would you taper the drug?

Terry Gernsheimer, MD: Always. Always taper. Usually, I begin to taper the drug anyway, if a patient is consistently over 100,000. I start backing down.

Ivy Altomare, MD: Why?

Terry Gernsheimer, MD: I’ve seen several patients like this. We’ve seen patients who go into remission. You don’t want to miss that remission.

Ivy Altomare, MD: Simply by the continued use of a thrombopoietin mimetic?

Terry Gernsheimer, MD: We don’t know why.

Ivy Altomare, MD: Do we have any data to further characterize the percentage of patients that will experience that?

Terry Gernsheimer, MD: There are some data that suggest that as many as one-third of patients will, if you continue this for 1 to 2 years, go into a spontaneous remission.

Ivy Altomare, MD: OK.

Terry Gernsheimer, MD: Why that happens, there are a lot of interesting questions about that. There is a lot of interesting data about what’s happening with transforming growth factor-beta, as well as what’s happening with regulatory T cells. I don’t think we really know. We do know, from data, that despite what we all learned in medical school, 85% of patients who come in as adults are chronic. That’s it. They’re going to have this forever. They’re never going to be cured, unless you do a splenectomy. There is published data suggesting that up to 40% of patients, if you wait long enough and just support the patient, will eventually, over the next 5 to 10 years, go into remission.

Ivy Altomare, MD: OK. We know that the TPO receptor agonists are effective. Where do you use them in therapy? Is it a particular type of patient, Dr. McCrae, that you like to use these drugs for? Is it a certain line? How do you fit them into practice?

Keith R. McCrae, MD: Any idiopathic thrombocytopenia purpura patient is a candidate for these drugs. I think, as Dr. Gernsheimer talked about, this early data using them very early in the course is quite interesting. It is definitely worth considering. It is certainly worth studying. Otherwise, it becomes a second-line therapy, along with rituximab and splenectomy. Those would really be the 3 things. There are, of course, other things that you might also consider for second-line therapy. They are less efficacious, but the 3 primary choices, in my mind, for second-line therapy are TPO agents, splenectomy, or rituximab.
And again, individualization of therapy is really important. For some people, when you talk with them about the different options, they might say, “Well, I’d like to try this intravenous drug and maybe not have to take something.” Other people would say, “You know what, I don’t want to do that. I just want to take a pill, or get a shot once a week.” So, it’s all good.

Ivy Altomare, MD: You give a trial of stopping a TPO mimetic to see if there has been a remission. Let’s say that there has not. What is the longest time that you’ve had a patient on a TPO mimetic? And really, what’s the data for long-term use, safety and efficacy?

Terry Gernsheimer, MD: When did we start the first trials? I’ve had patients on therapy since the first trial, so probably over 10 years.

Ivy Altomare, MD: Yes, 10 years.

Terry Gernsheimer, MD: I’ve got several patients who have been on therapy since the very first trial was done with romiplostim, and then with eltrombopag. For patients who were on for more than 10 years, they have been very happy. They haven’t had any issues. Some of them have been tapered off therapy, and they’re quite happy with it.

Ivy Altomare, MD: Is there any cumulative toxicity that you see, at all?

Terry Gernsheimer, MD: I have not seen any.

Ivy Altomare, MD: With either of the agents?

Terry Gernsheimer, MD: No, I really haven’t. They seem to be incredibly well tolerated.

Transcript Edited for Clarity 

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Transcript: 

Ivy Altomare, MD: What’s the efficacy of these drugs, Dr. McCrae? Do you feel that there are any differences, other than the ease of use, or possible insurance issues, or maybe even financial issues? Are there any clinical differences in terms of efficacy between the 2 thrombopoietin mimetic agents?

Keith R. McCrae, MD: Well, they’re both TPO mimetics. They both act on the TPO receptor, but they’re not the same drug. I think an important thing to emphasize is that you can have patients who fail to respond well to one of these, but they respond very nicely to the other, even though they basically work through the same pathways.

Ivy Altomare, MD: And it can work both ways.

Keith R. McCrae, MD: It can go both ways. There are some class-specific toxicities that apply to both of these. Mostly, a little bit of reticulin in the bone marrow, which is not the same as collagen fibrosis. It’s mild reticular fibers that really, probably, don’t have much clinical significance and go away if the drug is stopped.

Of course, with eltrombopag develops some elevated transaminase levels, which are usually mildly elevated. Again, it doesn’t really have to be treated, but an occasional patient―a rare patient―can have marked elevations, so you do have to monitor that over time.

I agree with what Dr. Gernsheimer said. Romiplostim is a great drug, but I do think, regarding the management, that some people really do overreact to platelet counts. Some folks try to extend out the treatment from weekly to, let’s say, “Well, maybe I can get away with this every 2 weeks.” The platelets can really drop very quickly, and patients can get very thrombocytopenic.

I use both of them. Most of the patients I see prefer the oral medication. They don’t like to come into the hospital and pay for parking, and all of those kinds of things. I use romiplostim, sometimes, in hospitalized patients. You know, the recommended starting dose is quite low. But you can increase that 10-fold and still be within an approved range. I think you can really get more of a wallop at 10 ug/kg, if you need it. If you have somebody who is in the hospital and is really bleeding, I will start at quite a high dose, actually.

Ivy Altomare, MD: Yes. You know that the patient is getting it, and you know that there’s not a problem with absorption.

Keith R. McCrae, MD: Exactly, right.

Terry Gernsheimer, MD: I think you made a really good point that I want to elucidate on. The way both protocols were written, because we weren’t really sure what we were going to see, if the platelet count went over 400,000, the drug was to be held. What we quickly saw was―and this happens in about 10% of patients―if you stop either one of these drugs abruptly, patients can fall well below baseline. We had a couple of patients on study. There were protocol violations because I wasn’t willing to do it again. When they went up to 800,000, or something like that, the drug was held. Within days of missing a dose, they showed up in the emergency room bleeding.

Ivy Altomare, MD: Yes, we’ve seen it too.

Terry Gernsheimer, MD: Right. So, I think you have to be really careful. I can talk, off-label, about what I do when a patient’s platelet count gets really high. I don’t stop. I taper. I might decrease the dose by a third, or by half. If the count is really high, I might tell the patient to take an aspirin until the count comes down a little bit, which they just love. They’re like, “I’m allowed to take an aspirin?” It’s just so exciting. But I think people have to be really careful. They read that label. There is a warning at the top that got added because people started complaining, “Oh, I held the drug according to what the FDA said I was supposed to do. I got into trouble with it.” So, there is a warning at the top. The warning, for both of these drugs, if they are abruptly discontinued, is very low platelet counts and bleeding can occur.

Ivy Altomare, MD: Sure. Let’s say that you decide to actually stop therapy and not hold, as per dose adjustments. You’re actually stopping therapy. Would you taper the drug?

Terry Gernsheimer, MD: Always. Always taper. Usually, I begin to taper the drug anyway, if a patient is consistently over 100,000. I start backing down.

Ivy Altomare, MD: Why?

Terry Gernsheimer, MD: I’ve seen several patients like this. We’ve seen patients who go into remission. You don’t want to miss that remission.

Ivy Altomare, MD: Simply by the continued use of a thrombopoietin mimetic?

Terry Gernsheimer, MD: We don’t know why.

Ivy Altomare, MD: Do we have any data to further characterize the percentage of patients that will experience that?

Terry Gernsheimer, MD: There are some data that suggest that as many as one-third of patients will, if you continue this for 1 to 2 years, go into a spontaneous remission.

Ivy Altomare, MD: OK.

Terry Gernsheimer, MD: Why that happens, there are a lot of interesting questions about that. There is a lot of interesting data about what’s happening with transforming growth factor-beta, as well as what’s happening with regulatory T cells. I don’t think we really know. We do know, from data, that despite what we all learned in medical school, 85% of patients who come in as adults are chronic. That’s it. They’re going to have this forever. They’re never going to be cured, unless you do a splenectomy. There is published data suggesting that up to 40% of patients, if you wait long enough and just support the patient, will eventually, over the next 5 to 10 years, go into remission.

Ivy Altomare, MD: OK. We know that the TPO receptor agonists are effective. Where do you use them in therapy? Is it a particular type of patient, Dr. McCrae, that you like to use these drugs for? Is it a certain line? How do you fit them into practice?

Keith R. McCrae, MD: Any idiopathic thrombocytopenia purpura patient is a candidate for these drugs. I think, as Dr. Gernsheimer talked about, this early data using them very early in the course is quite interesting. It is definitely worth considering. It is certainly worth studying. Otherwise, it becomes a second-line therapy, along with rituximab and splenectomy. Those would really be the 3 things. There are, of course, other things that you might also consider for second-line therapy. They are less efficacious, but the 3 primary choices, in my mind, for second-line therapy are TPO agents, splenectomy, or rituximab.
And again, individualization of therapy is really important. For some people, when you talk with them about the different options, they might say, “Well, I’d like to try this intravenous drug and maybe not have to take something.” Other people would say, “You know what, I don’t want to do that. I just want to take a pill, or get a shot once a week.” So, it’s all good.

Ivy Altomare, MD: You give a trial of stopping a TPO mimetic to see if there has been a remission. Let’s say that there has not. What is the longest time that you’ve had a patient on a TPO mimetic? And really, what’s the data for long-term use, safety and efficacy?

Terry Gernsheimer, MD: When did we start the first trials? I’ve had patients on therapy since the first trial, so probably over 10 years.

Ivy Altomare, MD: Yes, 10 years.

Terry Gernsheimer, MD: I’ve got several patients who have been on therapy since the very first trial was done with romiplostim, and then with eltrombopag. For patients who were on for more than 10 years, they have been very happy. They haven’t had any issues. Some of them have been tapered off therapy, and they’re quite happy with it.

Ivy Altomare, MD: Is there any cumulative toxicity that you see, at all?

Terry Gernsheimer, MD: I have not seen any.

Ivy Altomare, MD: With either of the agents?

Terry Gernsheimer, MD: No, I really haven’t. They seem to be incredibly well tolerated.

Transcript Edited for Clarity 
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