Ivy Altomare, MD: Immune thrombocytopenia, without a known cause, is frequently encountered in clinical practice. In this OncLive® Peer Exchange panel discussion, my colleagues and I will discuss current thinking on the management of adult ITP [immune thrombocytopenic purpura], when to initiate therapy, and how to manage refractory disease. We’ll provide a practical perspective on current treatment options as well as look at future developments in the field.

I am Dr Ivy Altomare, an associate professor of medicine at Duke University School of Medicine and the assistant medical director of the Duke Cancer Network in Durham, North Carolina.

Today I am joined by Dr Ralph Boccia, a clinical associate professor of medicine at Georgetown University, the chief medical officer of the International Oncology Network [ION], and chairman of ION’s Medical Advisory Panel in Washington, D.C.;

Dr Terry Gernsheimer, the medical director of Transfusion Services at Seattle Cancer Care Alliance, and a professor in the Division of Hematology at the University of Washington School of Medicine in Seattle, Washington;

Dr Richard McDonough, a hematology and medical oncology specialist at Florida Medical Clinic in Tampa, Florida, and the immediate past president of the Florida Society of Clinical Oncology;

And Dr Amit Mehta, a hematologist/oncologist at Premier Hematology in Cary, North Carolina.

Thank you so much for joining us and let’s begin.

I would like to begin our panel on ITP with a definition of ITP. Terry, can you give us a definition and a little bit about the pathophysiology of this disease?

Terry B. Gernsheimer, MD: First of all, it’s not just a low platelet count, which would be below 150,000. We generally define it as being less than 100,000, in the absence of any other reason to have thrombocytopenia, unless of course the patient has been bleeding and has an associated anemia, for example. We don’t know the real root cause. We know perhaps some of the mechanisms by which the platelet count drops, but why people develop ITP is still a big question. And there definitely have to be multiple hits that are happening here.

Ivy Altomare, MD: Sure.

Terry B. Gernsheimer, MD: There is probably a genetic disposition to develop this, as well as perhaps some environmental factor that triggers this. We generally differentiate between primary and secondary ITP, seeing no other associated disorders. Secondary meaning that there is something else that either goes along with it or is driving it. Now, 1 of the questions that I think is becoming more and more relevant is whether any ITP is really primary, or whether all ITP is secondary. And there are many secondary causes, or at least associations with ITP.

The underlying viral illnesses that we sometimes see with immune thrombocytopenia such as CMV [cytomegalovirus], EBV [Epstein-Barr virus], hepatitis C, HIV, and all these, really should be looked for when we’re looking at a patient and trying to make the diagnosis. But I think also very prevalent in these patients are other autoimmune diseases like thyroid and also immune dysregulation and immune dysfunction such as in CVID [common variable immune deficiency]. And then I like to think of pregnancy perhaps in some cases actually being a cause of secondary ITP.

Ivy Altomare, MD: When you have a pregnant patient, very quickly, because we’re not going to talk about this again, but I think it’s an excellent point, and I think it’s an excellent clinical situation that we see that’s rare but concerning in practice. Very quickly, how do you treat your pregnant patients with ITP?

Terry B. Gernsheimer, MD: Obviously we need to avoid certain therapies that have never been used or are used extremely rarely because we’ve got 2 patients when we do this. The primary goal in these patients is pretty much to keep them safe, and looking at them more frequently and trying to keep the platelet counts a little higher as we get into the third trimester. Generally, we start with corticosteroids and/or IVIg [intravenous immunoglobulin therapy], frequently combining the 2. But as we need more secondary treatments, I think that becomes a lot more complicated and probably a different discussion.

Ivy Altomare, MD: Sure, thank you. I think that’s an excellent clinical scenario, and we need more education on that topic. Amit, talking about the pathogenesis of ITP, can you walk us through a little bit of what’s happening after antiplatelet antibodies are synthesized, there’s a loss of immune tolerance, and then the antibodies bind to the FC-gamma receptors in patients. What happens after that?

Amit Mehta, MD: As Terry alluded to, there’s a variety of mechanisms that might stimulate thrombocytopenia to occur in immune thrombocytopenia as a general syndrome, so to speak. The classical mechanism for autoantibody generation is triggered, then the autoantibodies wind up binding to platelet epitopes on the platelet cell surface, so glycoprotein, GP-IIb/IIIa, GP-Ib/IX, etcetera.

And a variety of them have been described in the literature, only a few of which can actually be tested for by commercial laboratory assays, and that even not very reliably. But once the platelet antibody complex forms and that gets recognized by the macrophage system, primarily for immune thrombocytopenia by splenic macrophages, although other macrophages can also potentially do it. So the key is, as you were just alluding to as well is that the FC-gamma receptor is the binding point on the macrophage cell surface with the platelet antibody complex. Then what happens downstream from there has been more understood really in the past 20 years approximately; before that we knew superficially what was happening from macrophage induced mechanism but not really intracellularly as far as signaling what was causing the actual situation to totally go through from start to finish.

Once the platelet antibody complex binds to the macrophage by the FC-gamma receptor, intracellular signaling gets triggered via the Syk molecule, the S-y-k is the spelling, and that’s the key linchpin for what happens downstream within the macrophage cytoplasm and causes a cytoskeletal change in the macrophage, leading to a phagocytosis event. The macrophage phagocytosis of a platelet antibody complex, and therefore degradation and clearance of platelet, happens because of the Syk molecule stimulation by the binding to the macrophage cell surface. That understanding from the science side has only been worked out relatively recently in the past couple of decades and also has led to developments for therapeutic indications as we’ll talk about later on.

Ivy Altomare, MD: Absolutely. And thank you for that work that you do because I know that you were key in analyzing and characterizing this pathway.

Amit Mehta, MD: Yes, thank you. We worked on it in the laboratory now several years ago, so it’s always interesting when things come to market many years later. But yes, I think it’s important because just like Terry was mentioning, there are so many different possible stimuli to lead to immune thrombocytopenia, and maybe there is no true idiopathic type of case. There may be a mechanism, but we just don’t quite understand it fully yet based on our current understanding. But that being said, that’s the key mechanism for what happens with platelet clearance by the macrophage system. A variety of other mechanisms also come into play in immune thrombocytopenia as a general syndrome. But that’s the way the Syk pathway functions as far as we understand.

Ivy Altomare, MD: Excellent. Thank you so much. Actually, Ralph, I want to ask you, can you speak a little bit about the mechanism of decreased platelet production that happens in patients with ITP?

Ralph V. Boccia, MD: We really believe that at a physiologic level, we’re taught of course in medical school and training, what not, that this is a platelet destructive process. But to the question you’re asking, the point is that it’s not only platelet destruction, but it’s decreased production. And I think, Terry, you were instrumental looking at measuring thrombopoietin [TPO] levels a number of years ago in patients who were thrombocytopenic for a variety of different reasons, including aplastic anemia and ITP, and actually showing that there was, if anything, a low level of thrombopoietin often measured, in the laboratory at least, in those patients with ITP compared to, for instance, patients who had aplastic anemia.

And we believe that that has to do with the fact that once bound to the platelets, that destructive process that occurs in the spleen takes the circulating thrombopoietin out of the circulation, therefore the levels will fall. And so not only have we got the destructive process, but we no longer have the stimulant, the thrombopoietin to increase macrophage proliferation differentiation, all the things that it needs to do.

Terry B. Gernsheimer, MD: If I can add to that, I think one of the very interesting things that we realized was that these same antibodies are binding to that same target that is present on macrophages. So glycoprotein IIb/IIIa is right on the megakaryocyte. And in fact, if you give anti-IIb/IIIa with any kind of fluorescent, you will see the entire bone marrow just light up.

Ivy Altomare, MD: No kidding.

Terry B. Gernsheimer, MD: Yes, because the megakaryocytes are carrying that target and it leads to apoptosis. So not only do we have TPO levels that are not as high as one would expect, but we also have these megakaryocytes just dying.

Ivy Altomare, MD: From the antibody.

Terry B. Gernsheimer, MD: Yes.

Ralph V. Boccia, MD: I think that’s an important point, and I think we used to call them anti-megakaryocyte antibodies, but they’re really the same antibody. It just so happens, as we know, the megakaryocyte degenerates into platelets those same epitopes naturally that were there before. So why didn’t we think about that earlier? And I think that’s why we see the so-called paraptosis in megakaryocytes as opposed to apoptosis.

Transcript Edited for Clarity