Adult Immune Thrombocytopenia Purpura - Episode 9

Adult Immune Thrombocytopenic Purpura: TPO Receptor Agonists

Transcript: Ivy Altomare, MD: Let’s talk about TPO [thrombopoietin] receptor agonists. For over 10 years now, the TPO receptor agonists have been available for clinical use. Terry, do you want to talk about the mechanism of action of that class of drugs? What’s available? I think there are 3 now approved in the United States.

Terry B. Gernsheimer, MD: As Ralph mentioned, we learned somewhere actually probably more than 20 years ago that platelet production is decreased in ITP [immune thrombocytopenic purpura], which came as a big surprise to many of us. And it was looked hard and long for how we can stimulate the megakaryocyte to make more platelets. And the first 1 out of the gate was romiplostim. It binds at the exact same spot that TPO binds on the megakaryocyte. Given subcutaneously once weekly. Eltrombopag, which came out not long afterward, is preferred by a lot of patients because it’s an oral drug, which has a lot of food problems. You can’t take it with most foods. But what’s nice about it is it’s a once-a-day oral drug. It binds differently. It binds in the intramembrane portion of the receptor. And that may have other reasons why it’s useful. It also actually chelates iron, which may for some patients be a problem. For other patients it may be quite good.

The most recently approved drug is avatrombopag. And a lot of us are very excited about this because it doesn’t have any food interactions. Eltrombopag can be very difficult for some patients to take. I have patients who wake up literally in the middle of the night to take it because they cannot not eat for 4 hours before they go to bed, and they need to have their coffee with milk in the morning. So avatrombopag has actually become a very welcome addition to this, and that also binds at the intramembrane portion of the receptor.

Ivy Altomare, MD: So it does not need to be taken on an empty stomach, no drug-drug interactions. How is the efficacy looking in comparison to the other agents?

Terry B. Gernsheimer, MD: They all look the same. They’re all very efficacious. Although in the clinical trials they were very strict on how we called a response, because you had to have a response for the last 4 weeks. I think it was the last 6 weeks of the 24 weeks. And so if somebody got a cold—boom, they no longer were a responder. It probably works about 90% of the time. They’re very good drugs. They may act rapidly. Eltrombopag and avatrombopag probably act a little bit more rapidly because you reach the effective dose much more quickly. Whereas with romiplostim you’re gradually increasing the dose.

It’s interesting. You would think that everybody would want a pill.

Ivy Altomare, MD: Yes.

Terry B. Gernsheimer, MD: But it’s interesting that some patients actually prefer to come into the clinic and get just a once-weekly injection.

Ivy Altomare, MD: I find that as well, absolutely. Plus, they also like to see what their platelet count is. Well, everybody is different. Rick, what about you? When you’re going to a TPO receptor agonist, how do you choose between these agents?

Richard F. McDonough, MD: The factors that you’ve been talking about—does the patient want to be on an oral medication? Do they want to come in for the shot? And you mentioned about their eagerness to know their platelet counts, and they’re like a hawk on exactly what their platelet count is, and up and down, even if it’s in like the 120s, you know: “It’s 128, it was 123 last week.” And that’s going to factor into the decision making on that.

And then also how far are the coming from? Are they going to be able to tolerate that therapy? But as you stated, Terry, they’re all efficacious. They all have benefits. You have to look at the concern there too as far as adverse effects. The interactions with food, thrombosis, being concerned as we talked earlier on about pathophysiology of the disease is probably a factor, but certainly there are patients who have had issues with thrombosis.

Ivy Altomare, MD: Have you had a patient with a clot?

Richard F. McDonough, MD: I’ve had 1 patient with a clot.

Ivy Altomare, MD: I have too.

Richard F. McDonough, MD: And that was on 1 of the orals. But that’s a real concern, particularly if your patient has other conditions, cardiac and otherwise, that you’re concerned about, or cerebrovascular disease.

Terry B. Gernsheimer, MD: In terms of thrombosis with those drugs, 1 of the interesting things that we found is that the venous thrombosis that we’ve seen in some of these patients when it occurred was not associated with a very high platelet count. Whereas the arterial thrombosis appears to be more likely to be associated with a higher platelet account, which I think is very interesting.

Ivy Altomare, MD: Yes, that’s noteworthy. Ralph, you talked about the current version of the ASH [American Society of Hematology] guidelines mentioning TPO receptor agonists as a preferred earlier line of therapy. And I think that that must have been influenced by the phase II data that we have for TPO receptor agonists, that when used early, can lead to a degree of disease remission and a treatment-free interval for some patients, from Adrian Newland, MD’s, publication from 2016. Would either of you like to comment on those data? Do those data affect your practice?

Terry B. Gernsheimer, MD: It was interesting. When we were doing the clinical trials, there were patients whose count suddenly went up, up above 100,000, and the way that the protocol was written, you then decreased the dose and their counts would drop back down and then, boom, it went back up again.

Ivy Altomare, MD: In clinical trials with Nplate or Promacta?

Terry B. Gernsheimer, MD: Well, actually with both. But the Newland data were on romiplostim, and that’s where we saw it first. And occasionally a patient, you will keep adjusting the dose down and suddenly they’re off, and I’ve seen this in multiple patients.

Adrian’s data suggested that a third of patients will go into a remission, off all drugs, which is absolutely remarkable. And whether we’re inducing immune tolerance, or we were just waiting for a spontaneous remission to occur, some of these patients that I have, have relapsed later, several years later. I have 1 woman who came to me just recently, 6 years off drug, and suddenly relapsed. So you have to keep watching these people and they have to be cautioned that it doesn’t mean this is over, but you should be always looking for that remission.

I know Adrian suggests, and other people suggest, that at least once a year look for that remission, drop your dose down just a little bit and see whether they actually are going to tolerate a reduction in dose.

Ivy Altomare, MD: And that’s how the study was designed, it was a taper at 12 months.

Terry B. Gernsheimer, MD: Right, exactly.

Ivy Altomare, MD: Forced, or it could have been sooner, but it was forced at 12 months. Yes, I do, I think the ability to achieve a remission with any medication, how can it be bad for ITP patients?

Terry B. Gernsheimer, MD: Yes. But this whole idea, this concept of immune tolerance I think is absolutely fascinating. Because some of these patients really had had ITP for decades.

Ivy Altomare, MD: Exactly.

Terry B. Gernsheimer, MD: And suddenly, boom, they went into remission.

Richard F. McDonough, MD: We’ve all had patients who are refractory, who have blown through multiple lines of therapy, and maybe they’re on a TPO last. And so you really wonder, is that an effect of the TPO, or is that their prior splenectomy? Or is it other natural history or just events that are going to occur with the ebb and flow of the disease?

Ivy Altomare, MD: That’s why it’s so difficult to devise a 1-size-fits-all treatment strategy. Because this disease does different things in different people.

Ralph V. Boccia, MD: Very heterogeneous.

Transcript Edited for Clarity