Adult Immune Thrombocytopenia Purpura - Episode 7
Ivy Altomare, MD: I absolutely agree with that. Let’s move on to one of the newer medical therapies, fostamatinib, which is an SYK [spleen tyrosine kinase] inhibitor. Can you explain what the SYK pathway is, why is it important in the pathogenesis, and how does this drug work?
Amit Mehta, MD: Yes, a great question. Fostamatinib just got FDA approved as a newer agent back in May of 2018. What’s interesting about this, and I happen to have worked in the laboratory with the SYK pathway a few years ago….
Ivy Altomare, MD: That’s exactly why I asked you.
Amit Mehta, MD: Exactly. So it’s near and dear to my heart. But so what’s interesting about it is that, as Dr Boccia eloquently explained at the beginning about the mechanism, about the macrophage-mediated phagocytosis destroying platelets, is that the mechanism has been postulated and understood for decades, basically. And as we’ve understood on a more cellular level what is really happening, intracellular signaling pathways and so forth, it’s been found that SYK is one of the key molecules intracellularly that gets activated, at least a cytoskeletal change of the macrophage, that causes phagocytosis of any antibody cell complex. In this case, an autoantibody binding to a platelet.
So the autoantibodies that are formed by whatever stimulus, whether it’s idiopathic or something following an infection, for example, autoantibodies form—the autoantibodies against platelet epitopes—they bind to platelets, then the platelet antibody complex will activate macrophages, most commonly in the spleen but it can be any macrophage in the reticuloendothelial system. And then when it binds by the Fc-gamma receptor, that’s a transmembrane protein on the macrophage cell surface, then the key lynchpin inside the macrophage cell is the SYK protein—S-Y-K—or spleen tyrosine kinase is the full name of it. And so that is the activated molecule that gets phosphorylated, and that causes downstream signaling to occur, which leads to that cytoskeletal change in the protein. So that was the concept behind saying that, well given that background, if we can somehow inhibit the macrophage phagocytosis step, perhaps we can abrogate the destruction that goes on in the peripheral blood stream. Because the autoantibodies may be present in the body, but if the macrophages are not phagocytosing the platelets, then perhaps we can effect a response. So that was the concept.
I’m glad you asked also because like any newer mechanism, I think it’s good for clinicians to understand.
Ivy Altomare, MD: Absolutely.
Amit Mehta, MD: I think that’s why the pathophysiology of the condition, whether you talk about destruction, production issues, is so crucial in ITP [immune thrombocytopenia], and that remains a big issue is that well, for this particular patient in front of you, what is the driving mechanism? And we don’t have an easy answer even though I think we’ll get to some clues soon. But that’s the biggest thing.
So fostamatinib is a molecule that is taken orally. The active metabolite of fostamatinib after it’s ingested is one that binds to the SYK molecule inside the macrophage cell, and that causes an inhibition of the downstream signaling and therefore the phagocytosis doesn’t occur. It’s abrogated by….
Ivy Altomare, MD: So it’s truly a targeted medicine.
Amit Mehta, MD: It’s a targeted therapy medicine. It’s a tyrosine kinase inhibitor, oral tyrosine kinase inhibitor therapy that’s specifically targeting the SYK molecule.
Ivy Altomare, MD: And you mentioned it’s oral, it’s once a day, twice a day?
Amit Mehta, MD: Correct. The dosing is twice a day. The FDA approved dosing is for 100 mg po by mouth twice a day. And it can be increased to 150 mg po bid twice a day if the clinician is not satisfied with the response at the 100 mg dose. But it’s 100 mg orally twice a day, and it can be taken with or without food.
Ivy Altomare, MD: Thank you for mentioning that. So, Dr Boccia, I believe you were involved in the randomized trials that led to the approval of this drug, FIT-1, and FIT-2 was in Europe I think.
Ralph V. Boccia, MD, FACP, LLC: Right FIT-2, and then FIT-3, which was the open label extension study. We did participate, and we accrued patients to it, and I would want to step back to both of your comments just to reiterate that I think it’s important for our clinicians out in the community to understand the mechanism of action so that they can realize that with different mechanisms of action you can switch therapies. Because, we’re going to get to talking about the TPO [thrombopoietin]-mimetic agents. So what I see all the time is someone who has tried romiplostim then goes to eltrombopag. Well you know if they’re both TPO-mimetic agents, the likelihood of response is very low. So now you have some completely different mechanism of action.
Ivy Altomare, MD: Works at the level of the macrophages. There's nothing that does that so far, except that it's IVIG [intravenous immunoglobulin].
Ralph V. Boccia, MD, FACP, LLC: Yes, exactly, except … I guess that’s the best way to say it. Yes, it does. I was going to make another comment, but I think I’ll hold out for later. Anyway, so we accrued patients to it. This is a very effective drug. It is twice a day. It is interesting that in the clinical trial though, 80% of the patients required the higher dose. So, although the approved dose is 100 mg twice a day, most patients are going to require, after 4 weeks of less than 50,000 platelets, are going to require that higher dose. Actually, in the phase I trials, the dose went up to 175 but it was intolerant. It was actually a more effective dose than the 150 is. So there is some evidence for some dose response there. The 2 major adverse effects that you have to deal with, and if you know this you can preempt these things and get patients through it, is diarrhea, which is most common. About a quarter of patients will get diarrhea from it, so just have Imodium onboard and ready to go.
Ivy Altomare, MD: Well, oncologists should know how to treat diarrhea, right?
Amit Mehta, MD: Exactly. Well, I think that is a reassuring thing, as I think you’ll elaborate on, that these kind of adverse effects are in the wheelhouse, so to speak, of most practicing hematologist- oncologists.
Ralph V. Boccia, MD, FACP, LLC: And the diarrhea, if you manage it for the first several weeks, usually subsides. So it is a more transient effect than anything else, at least the grade 3s that people could get, and grade 4s are very uncommon. And then the other is hypertension. And about a quarter of patients, 20% of patients maybe will get hypertensive. So it’s a little bit like the antiangiogenics, you’ve got to be ready to deal with that. If you’re on an antihypertensive, you may have to adjust it. If you’re not on an antihypertensive, you may need to start it. But actually, when they went back and looked at, in all 3 of the FIT trials, the median rise in blood pressure was only about 5 mm, but you had that 15% of patients where it does go up to a level where you have to make some dose adjustments. Those are the 2 main things that we saw in the trial. Those are the 2 main things that you need to deal with and be prepared for.
Ivy Altomare, MD: Are there any predictors at all that can lead us to choose?
Ralph V. Boccia, MD, FACP, LLC: Yes. In the trial, we did regular autoantibody testing, and about 60% or 65% of the patients had autoantibodies and the others did not. And the difference in responses were fairly striking. So, if you look at the FIT-1 and FIT-2 trial data and you remember that these are in patients that had a median of 4 prior lines of therapy, so this was fifth-line therapy, and the median number of years since diagnosis was 8.5. So this is a population that’s very different than the population we studied for either romiplostim or eltrombopag much further down.
Ivy Altomare, MD: Yes, much more refractory.
Ralph V. Boccia, MD, FACP, LLC: Much more refractory, exactly.
Ivy Altomare, MD: Yes, which makes sense because before the TPO receptor agonist, there really wasn’t anything.
Ralph V. Boccia, MD, FACP, LLC: Exactly. In the trials, about 20% to 25% of the patients will have what they call a sustained response, and that sustained response, it was a 24-month trial and patients were seen every 2 weeks, so in the last half or last 12 weeks were seen. And you had to have a platelet count above 50,000 on at least 4 of the 6 visits. And that was called a sustained response. There was also overall response, which was anybody that got a platelet count above 50,000 starting from the beginning; so 20%, 25%. If you look now at the population of patients that had autoantibodies, it was 36% sustained responses compared to 9% in those who did not. So it may be a different pathophysiology in that group of patients. It may be more T-cell mediated in those who don’t produce the autoantibodies, and it’s a T-cell process that’s operating and more autoantibody-related than the other. So that may be a clue for both pathophysiology and potentially selecting the right agent for the patient.
Ivy Altomare, MD: Yes, it doesn’t seem like 100% correlation, but at least it’s something.
Ralph V. Boccia, MD, FACP, LLC: It’s something there.
Ivy Altomare, MD: And also that this correlative work is being done to help identify either clinical predictors or molecular biomarkers because it would be nice to not arbitrarily select a therapy but really have a targeted treatment and know when to select that. So, I’m glad that work’s being done.
Ralph V. Boccia, MD, FACP, LLC: Good stuff.
Ivy Altomare, MD: Yes.
Amit Mehta, MD: I think also to add to that briefly, is that in practice what winds up happening is that this might help us choose treatments. I still think that we might need even more robust data to say that reliably, like based on TPO levels or based on autoantibody presence, because some of those assays can vary so much, depending on what’s available in practice.
Ivy Altomare, MD: Sure. And he even said that there were patients that responded to the drug that did not have these circulating antibodies.
Amit Mehta, MD: It is tricky insofar as is it either a yes/no type of thing or more likely or less likely. So it becomes trickier, but I think it’s very helpful that at least it’s being looked at, these correlative studies. At least we have some indication that, OK, this patient, maybe it’s a T-cell pathway that’s the real key driving thing for that patient.
Transcript Edited for Clarity