Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to “Practical Perspectives on the Current and Future Management of Immune Thrombocytopenia — What Happened at ASH 2025?” We have a great faculty today: Dr Hanny Al-Samkari from the Massachusetts General Hospital and Harvard Medical School in Boston, Massachusetts, Dr Cindy Neunert from the Columbia University Irving Medical Center in New York City and Professor Francesco Zaja from the University of Trieste and the Director of Unit of Hematology in Trieste, Italy.

Today we’re going to talk about ITP, a topic we haven’t been able to cover many times with CME programs, so I’m really excited, particularly in terms of what’s new in ITP, which I think, as you’re going to see, is very interesting, provocative and very, very relevant.

As always, we will be talking about the use of unapproved FDA regimens and agents, so check out the package insert for more information.

As we do with a lot of our webinars, we have a bunch of general medical oncologists who were nice enough to meet with me and present cases from their practices. You saw a bunch of cases last night with myeloma. Tonight we have a bunch of cases of ITP. Really looking forward to making rounds with the faculty.

Each one of the faculty’s going to be giving a talk. I’ll show you the agenda in a second. Some of it will include some basic issues in ITP just to kind of get us back up to speed but also to talk about what happened at ASH, and a lot happened at ASH this year. And we’ll hear about that and what’s ready for prime time, which seems like maybe some new things.

Here’s our agenda. We’re going to go back and forth between making rounds and hearing — looking at data, and if we have time at the end — we’re going to be going 90 minutes tonight because we want to take advantage of this opportunity, present as many cases as we can, so we’ll finish out with a bunch of additional cases.

Case: A woman in her early 30s with chronic relapsing immune thrombocytopenia (ITP) receives eltrombopag with ongoing stabilization of platelet counts — Neil Morganstein, MD

DR LOVE: But just to get you all warmed up a little bit before we kind of dive into the data in terms of some of the questions that I know our faculty hears every day from community-based general medical oncologists, we’re going to start out with Dr Morganstein from New Jersey who has a 33-year-old woman with chronic relapsing ITP, gets eltrombopag, has ongoing stabilization, and he has a bunch of questions.

DR MORGANSTEIN: 33-year-old woman diagnosed with ITP. She's had multiple relapses of chronic immune thrombocytopenia. So she'll go on steroids.

She's been on rituximab, and then she'd been on intermittent romiplostim, and then ultimately for ease of use and because her platelets kept dropping, she was placed on eltrombopag. She was initially placed on 50 mg. She did extremely well on it, and we were actually able to lower her dose to 25 mg. She's right now thrilled because her platelets, which were a chronic, constant issue with her, are now routinely and regularly greater than 50,000. She's been on medication now for over 3 years and has had no problems with any relapsing or recurrence or dropping of her platelets.

So question is, how do we sequence the TPO analogs. When do you use romiplostim versus eltrombopag? What about any of the other types of medications that are approved for this? And when do we use rituximab?

And what is our ultimate and optimal platelet count that we're looking at in these patients? 50,000? 40,000? Are we trying to get them on the lowest dose possible?

And last question, is there any long-term known bad side effects associated with these medications? She's 33 and may be on this medicine for decades.

DR LOVE: So Cindy, any thoughts about this case? And basic question, when do you think about a TPO agonist, and which one do you usually use? Or how do you decide which one?

DR NEUNERT: Yeah. So I think this is a great question that really gets at the heart of engaging patients in the process of shared decision-making. So with available agents out there we know that they’re all very similar in their efficacy profiles, and really the thing that varies between them is administration and potentially patient cost, as well as other things in terms of talking to patients about the different side effect profiles, particularly with a drug like eltrombopag, which can carry liver side effects and liver toxicity, as well as dietary restrictions. And so I think how to position one versus the other really comes down to what fits best with the patient preference.

I do think that it’s important to continuously revisit, though, and I think you had mentioned your patient had actually switched between TPO-RAs, and that switching is perfectly appropriate, either for efficacy or for patient preference, that once you select one it doesn’t mean you have to stay on that one indefinitely, and it’s something to always keep coming back to our patients about and make sure that we’re meeting their goals.

DR LOVE: Hanny, what about Dr Morganstein’s question about long-term issues that have been seen? Can you comment on that?

DR AL-SAMKARI: Absolutely. So this is a really important question, it comes up all the time, because as Dr Morganstein said, these patients may be on these drugs for years, decades, indefinitely, right? So initially there was some concern about thromboembolism with thrombopoietin receptor agonists, there was some concern about bone marrow fibrosis with these drugs, some concern about the possibility for leukemogenesis or leukemia transformation with use of these drugs for a long time. We can feel very, very comfortable for the latter 2, that our long-term safety data has really put those concerns to rest.

These drugs do not increase risk of any malignant transformations. They do cause increased reticulin fibrosis in the marrow, but that is eminently reversible when the drug is discontinued. They don’t cause collagen fibrosis in the marrow. That’s not reversible, so not something to be concerned about. I don’t follow with bone marrow biopsies over time or with even peripheral blood films over time. You will see sometimes patients will have some teardropping starting if they’re on drugs for — these drugs for a long time. It’s not clinically relevant.

In terms of thromboembolic risk, it’s one of the things that remains a theoretical concern. There are some longer-term studies that suggest that maybe it does — these agents increase thromboembolic risk, but for most patients they probably do not, and so by and large thrombopoietin receptor agonists have a pretty good long-term safety profile.

Case: A woman in her late 60s with a long history of ITP controlled by eltrombopag experiences acute exacerbations — Bhavana (Tina) Bhatnagar, DO

DR LOVE: So Francesco, I’d like you to listen to this next case and give me your comments. This is a patient of Dr Bhatnagar, a 68-year-old woman who has a long history of ITP, is on eltrombopag right now but having acute exacerbations. Here’s the case.

DR BHATNAGAR: 68-year-old female who was residing in a long-term care facility for 3 years because of various issues. But she also has a history of ITP dating back to the 1990s.

In the early 2020s her platelet count decreased to 35,00,0 and she was treated with steroids with good improvement in her platelet counts but over the next few years had recurrent bouts of worsening thrombocytopenia. And she was started on eltrombopag 50 mg daily, which was later escalated to 100 mg daily due to suboptimal improvement in her platelet counts. On the 100 mg dose her platelet counts have largely stayed between 50,000 to 120,000, though acute exacerbations still occur. And her most recent exacerbation happened probably about a month or 2 ago. And they ended up meeting with another oncologist who was covering for me while I was away and that oncologist wanted to consider her for rituximab.

And so my questions are, at what point do you consider treatment failure with eltrombopag? And also wanted to mention that this patient experiences significant gastrointestinal concerns, including nausea, and also has Stage IV CKD. What types of comorbidities do you consider when selecting eltrombopag for your patients? And can you comment on how patients are to be counseled with respect to their diet when they're on the medication?

And also, of course, commenting on whether or not there's a role for rituximab. I leaned away from rituximab because she is a long-term care resident and is immunocompromised and has had recurrent hospital stays. And I worry about just B-cell depletion in these patients and risk for opportunistic infections. But I'd be curious to know what the ITP experts think.

DR LOVE: So I was saying that we pattern our work off of rounds, and this is also a cognitive test if you can remember all the questions. In 90 seconds these people can ask 15 different questions, as you just saw. But let’s dive into a few of them. So first of all, any thoughts, Francesco, about this case and also her question about what you say to patients about dietary modifications on eltrombopag?

PROF ZAJA: Yeah. So this was a 68-year-old woman with initial response to eltrombopag and then acute exacerbation while she was receiving eltrombopag. So first of all, I would ask the patient if she has respected the dietary restrictions that are requested while a patient is receiving eltrombopag, because we know that bioavailability is an issue with eltrombopag, and the patient has to respect some dietary restrictions. So this would be the first issue that I ask to the patient.

But if everything was okay and so there is an acute exacerbation I don’t — I don’t know if the patient was — the dose of the eltrombopag was the highest or was only 50 gram — 50 mg or 25. If this was the case I would try to increase the dose of eltrombopag to 75 mg. And if it was the case, this situation to think about a switch to another TPO receptor agonist because we know that there is the possibility that patients that are not responsive to one TPO receptor agonist can respond to another one, so a switch from eltrombopag to romiplostim or even a switch from eltrombopag to avatrombopag. In nearly 50% of cases there is the possibility to have response after switch, even if the majority of the cases the response of those patients where the switch is because of intolerance more than relapsed or refractory to the treatment.

If there is no response to the switch now we have to think about salvage therapy for this woman, which are the most used agents with robust evidence of activity in SYK inhibitors or now also in the US — at least in the US the BTK inhibitors or rituximab, or we can think about also splenectomy.

Because the patient’s 68 years old I would consider splenectomy only after having failure of other medical therapies, SYK inhibitors or BTK inhibitors or rituximab. Between rituximab and the SYK inhibitors or BTK inhibitors I would try before SYK inhibition or a BTK inhibitor because we know that the chance of response, at least in this woman at 68 years old, is higher with the use of fostamatinib or at least rilzabrutinib.

DR LOVE: So Cindy, going back actually to a question that Dr Morganstein asked that I don’t think we addressed, which is what’s the target platelet count in general with ITP. Also, we’re getting a lot of great questions in the chat room, Cindy. Dilip says any role for danazol? “I’m giving away my age,” he says. Also, Swati in the chat room wants to know are TPO agonists teratogenic. Can they be given to women who are pregnant?

DR NEUNERT: All very, very good questions. So I think with regards to the platelet count threshold this is really where ITP can be individualized. I think that you have to take into account what are the lifestyle goals for that patient. I certainly have different thresholds for different patients based on the activities they want to do or the things that they want to do in their lifestyle. I think it’s important to put it into the context of their previous bleeding history. Patients that we know have significant bleeding when the platelet count goes below a certain threshold we’re certainly less likely to let them do that and maintain a different threshold. Young women, I think, heavy menstrual bleeding can be very problematic, and the threshold at which that occurs is different for every woman.

So my goal is always really to try to get the platelet count that gives a patient back their quality of life that they’re looking for while at the same time minimizing any dose exposures or toxicities. And I think that really is a more individualized approach. I don’t have any one target for each patient that I consistently use. Somebody that’s about to go on a ski trip certainly has a different target than some of my other patients, so I think it can become rather individualized.

I think the main point is that a normal platelet count does not have to be the goal. There are certainly platelet thresholds that achieve good quality of life that are not normal platelet counts.

DR LOVE: So Hanny — go ahead. Sorry, sorry. Go ahead.

DR NEUNERT: No, no, no. That’s okay. I don’t know if you want to move on, but yeah.

DR LOVE: No. No. Keep going. Keep going.

DR NEUNERT: I was going to touch on the — just in the conversation about the TPO-RAs and the TPO-Ras in pregnancy —

DR LOVE: Right, right.

DR NEUNERT: And I think this is debated topic. I think there are — there are data out there of safe use in pregnancy. Has it gotten full clearance for use in pregnancy? No. Certainly if it is used probably after the early part of pregnancy is when it would be best to use. I think there’s data, particularly some data from the French group and some others, that they are felt to be safe in pregnancy but still are not considered a standard of care therapy during pregnancy, such as in azathioprine that’s been around for a very long time that we know has a good safety profile in pregnancy.

DR LOVE: Any comments on danazol?

DR NEUNERT: Yeah. I don’t use danazol. It’s certainly a historical therapy. We did not incorporate — it has not been incorporated into guidelines other than to mention that it is a potential therapy. I think it depends on what access to drugs are available in the place where a patient is needing therapy. But danazol, I think, is not as used in today’s landscape.

DR LOVE: So Hanny, I mentioned last night we did a program on myeloma with Sagar Lonial and Maria-Victoria Mateos. What a great time last night. You’ve got Noopur Raje there at your place, an incredible myeloma person, a lot of CAR T.

I bring this up because we’ve got an interesting case in the chat room. Here it is from Uzama. I have a patient with symptomatic myeloma, got a complete response following CAR T, developed severe ITP, platelets are 1, and 1 year after CAR T still in remission from the myeloma. ITP unresponsive to IVIG, Nplate, rituximab, responds to high-dose steroids but poorly tolerated. The academic medical center recommends daratumumab, and she had an immediate response to this. What’s the mechanism? Would you offer splenectomy? Any thoughts?

DR AL-SAMKARI: What a great case. So I’ve been in a very similar situation, and daratumumab has gotten patients of mine that I’ve been consulted on who’ve been in the hospital for 6 weeks, 8 weeks, tried everything, tried 2 TPO-RAs at the same time, all this stuff. Nothing works. The reality is, right, that all of those other therapies don’t touch the long-lived plasma cells that are secreting platelet autoantibodies and believed to be a significant perpetuator of the disease, and certainly anti-CD38 monoclonal antibodies like daratumumab absolutely can.

So daratumumab has been studied in ITP. There’s another anti-CD38 drug called mezagitamab that’s being developed specifically in ITP. The more and more — and I’ll get to this in my slides, but the more and more we progress in this disease the more and more ITP therapy is starting to look like key malignancy therapy: BTK inhibitors, anti-CD38 monoclonal antibodies. The mechanism with daratumumab in this case is getting rid of those pesky plasma cells that the other therapies aren’t touching, and that’s why it works.

DR LOVE: Great response there. I knew this was going to happen. The chat room’s totally exploding with cases. We could probably spend the next 90 minutes just on what’s in the chat room, but let’s try to keep on schedule here. But I do want to get back to a bunch of these cases.

Clinical Manifestations and Initial Management of ITP — Dr Neunert

DR LOVE: But Cindy, let’s talk a little bit about data here. You have kind of a review of ITP. Let’s talk about some newer data as well.

DR NEUNERT: Yeah. Thank you for the opportunity to speak today. I think this is going to be some great discussions, it sounds like, from our chat. So I’m just going to give an overview of clinical manifestations and the up-front kind of initial management approach.

So ITP, as many of you are aware, is an autoimmune disorder. It really is defined by isolated thrombocytopenia, less than 100,000 in the absence of other causes, and it remains a diagnosis of exclusion. It’s really based on your physical exam and review of the peripheral blood smear. Associated with an increased risk of bleeding, but this risk is different amongst every patient. No 2 patients with ITP will ever look the same. And ITP can be classified as either primary or secondary, so occurring in isolation or then occurring in the context of other autoimmunity or inborn errors of immunity or infections, as shown over here in the pie graph. But for the most part it’s primary ITP.

So as I mentioned, diagnosis of exclusion, platelet count less than 100,000 with no red or white cell abnormalities. There may be anemia if there is significant bleeding, and we need to pay attention to our red cell indices for any signs of marrow stress. When we look under the blood smear what we’re really looking for are these very large, healthy platelets, and in adults the only other testing that really is recommended by the American Society of Hematology Guidelines is hepatitis C and HIV testing. A bone marrow examination is not really needed on all patients at diagnosis but may be necessary in patients with atypical ITP or those with more advanced age or failure to respond to therapies.

So this shows the ASH Guidelines, the International Consensus Report and also data from what was sent on patients in the McMaster ITP Registry. And as you can see here, really the main thing that we want to look for is just that CBC and blood film. The other tests that are on here are mostly to identify other secondary causes, so sending a DAT to look for underlying Evans syndrome, which is autoimmune hemolytic anemia in the presence of ITP. Quantitative immunoglobulins I think are more and more getting incorporated into up-front diagnostic testing as we learn more about uncovering inborn errors of immunity in these patients as well.

This is a physical diagnosis. You’re looking for petechiae, which are rather specific to platelet disorders. When you see petechiae you want to think more about platelets and less about coagulopathies. And then we’re looking for an absence of other findings that would suggest there’s a more systemic process. Another thing I always like to stress, very important to look at the buccal mucosa. You can see down here in this one picture, where have some what we refer to as wet purpura or lesions in the mouth that are important to note when making treatment decisions as well.

So here’s out epidemiology. It’s really a bimodal disease occurring mostly in toddlers and then again in the elderly population. You can see the distribution of males and females is relatively stable, but again, the male predominance occurs mostly in toddlers and then those in an older age.

As I mentioned, bleeding is highly variable among these patients. There’s lots of variation in our bleeding phenotype. The mucocutaneous bleeding is going to be our most common manifestation, and a lot of patients present just with those petechiae and bruises. And spontaneous intracranial hemorrhage, which is what people worry about the most, is rare, especially if the platelet count is over 20,000. And some things that might be kind of predisposing patients to intracranial hemorrhage include more advanced age, history of prior bleeding, antiplatelet and anticoagulant use. These have all been shown to be independent risk factors for bleeding in patients with ITP. There’s also this possible increased association with thrombotic events. Paradoxically, patients with ITP can also have thrombosis, and this is something that is often not found to have any other source.

So what the platelet count doesn’t tell us, though, I think is really important and the focus of what we’ve already talked about, which is how do we decide what works for each individual patient. And this is where we have to think about things like our treatment-related impact, which is the adverse effects of treatment, the cost of that treatment, the patient-related impact in terms of what is their bleeding severity, how’s their overall health-related quality of life. There’s definite knowledge that ITP can lead to fatigue in patients, and some early data on the impact on neurocognition. And again, all of these kind of factor into what is the patient’s daily goal and what does living with ITP look like both on and off therapy for that individual patient.

Health-related quality of life, we know, as I mentioned, is generally lower compared to the general population. It’s lower compared to — on multiple studies, both in Italian studies, US studies, and then also in patient web-based surveys. In fact, we also know that the physical component can be even compared to patients with hypertension, arthritis and/or cancer. So this really does have a big impact on our patients that we have to recognize and take into — into account when we’re trying to think about treatment goals, again, and where our patient is in their ITP journey.

Here’s some data on fatigue. This is from the ITP Natural History study. 89% of patients reported fatigue. 81% were bothered by their fatigue. From the iWISH study, which is a large study out of the UK group, it was the most frequent symptom, in 58%, and most severe in 73 at diagnosis. And then we even have data from children showing that in adolescence 62% had moderate to severe fatigue using a fatigue score.

This is likely multifactorial. I think it’s our job to rule out organic causes. Does this patient have concomitant thyroid disease, iron deficiency? Is there something else that’s driving the fatigue? I think there’s a psychological impact of ITP in terms of anxiety, depression, restrictions on activities and just that daily weight of living with that. And then I think we fully haven’t unteased the role that chronic inflammation may play and looking at any impact of cytokines or cytokine profiles, which also can vary greatly amongst patients with ITP.

This is just a quick slide on the cognitive impact, shown here. And if you just look at this bar here, the impaired bar, you can see that if you look across there’s definite impairment noted in patients with ITP across all domains; psychomotor, attention and memory. This is really early data that comes out of the rilzabrutinib clinical trials, but I think it is a growing place where people are starting to put some attention. And I think, again, the cause of this is really not clear to us yet.

So in terms of management, up front we have observation and education, which may be appropriate for certain adult patients with platelet counts that are above 30,000. We have corticosteroids, IVIG and anti-D, the last 2 really being reserved for a more prompt increase in the platelet count. And many of these are drugs in which you’re all familiar with the appropriate side effects.

So what about what do our guidelines say? If we come back to first-line treatment in adults, if you’re less than 30,000 it’s suggested to start corticosteroids rather than observation, but this does allow for a little bit of wiggle room in the individualized patient approach.

And there is a good practice statement that while patients are on corticosteroids it’s really important to pay attention to the potential side effects. This often gets overlooked, but patients on corticosteroids really can experience — the corticosteroids alone can impact their quality of life. We’ve heard from patients that many times they’re more concerned about their steroid side effects than they are about their platelet count and their bleeding, and that’s what they want to focus on at the visit.

We suggested either prednisone or dexamethasone. I think both of these are appropriate treatment strategies. Perhaps if a more rapid response is needed dexamethasone is appropriate based on a systematic review showing a slightly better response rate at 7 days.

And this is just showing that data right here with a slight increase in the dexamethasone group up front but relatively comparable outcomes at other timepoints.

So just a word of caution. We do have real-world data that suggests corticosteroids are the most common second- and third-line therapies in over 80% of patients. They are being used throughout the course of ITP. On a Spanish registry there were almost 60% of patients that received greater than 6 weeks of treatment with corticosteroids, and in an insurance review out of a Korean study 75% of patients still on at 3 months, 50% at 48 months. So truly we still need a little bit of word of caution to not just continue patients on corticosteroids indefinitely, particularly as new agents come out.

So we did carry forward recommendations on IVIG and anti-D, particularly if a more rapid response is needed or there’s a contraindication to corticosteroids.

And then augmented first-line therapy. This is a really kind of big topic right now. There is a revision underway of these guidelines really looking at this issue of can we augment up-front therapy with either rituximab or TPO-RAs or even MMF to see if we can get more patients into a lasting remission.

So lastly I’d just like to highlight an abstract from the American Society of Hematology Meeting that looked at immune thrombocytopenia in patients that were treated with immune checkpoint inhibitors.

So this was their study. They were looking to identify the incidence, risk factors and clinical characteristics and treatment outcomes associated with immune checkpoint inhibitor ITP, or ICI-ITP. And start to look for definitions, the diagnosis, treatment response and recurrent rates, and improve the recognition and management of this condition.

So what you can see here, these are the ICI-ITP treatment responses to glucocorticoids, IVIG and TPO-RAs, and actually at 60 days there was a pretty good response rate regardless of the treatment given that approximated 60%. And this does seem to be higher than what we would expect even from just standard non-ICI-associated ITP.

They also then did look at patients that were rechallenged. Of the patients that were rechallenged 30% developed recurrent ICI-ITP with the rechallenge. Many were transitioned from combination to just a single agent in an attempt to try to reduce the risk of overall recurrence. But recovery remained high even with recurrent rates of up to about 74% in this population.

Kind of the takeaways from the authors were that it has an incidence of about 0.25%. 75% of patients will achieve overall recovery. Most were commonly just treated with some degree of an up-front therapy without the need to move on to second-line therapies with either glucocorticoids, IVIG or TPO-RA, with minimal use of other immune modulators. And 30% were able to — many patients were rechallenged with only 30% developing a recurrence, and even that was a recoverable condition that did not lead to long-term ITP. The severity of this, though, was independently associated with a higher degree of associated death in the overall study population receiving the ICI.

So new data coming out. I know many of the audience here uses these immune checkpoint inhibitors, and so good information for us to have for recognition of this overall rare event.

DR LOVE: So it might be rare, 1 in 400, but actually we have a case of it coming up, but first a couple questions from the chat room. So Francesco, 2 comments came in at the same time. I’m guessing they might even be from different parts of the world. I don’t know. So Amjed says, “Do you treat all patients for H pylori?” and then at the same exact time, Danny says, “Does ITP associated with H pylori infection always resolve with eradication of the infection?” Any comments, Francesco?

PROF ZAJA: Yes. It’s part of our workup at diagnosis to evaluate the presence or not of Helicobacter pylori in patients with ITP. So if there is positivity what we do is to try to eradicate the Helicobacter pylori because at least in some areas of the world, as in Europe, as in Japan, this happens less in the US, there is the possibility that in eradicating Helicobacter pylori a significant proportion of patients have improvement in platelet count.

PROF ZAJA: The reason why in the US this doesn’t happen is probably because there may be different Helicobacter pylori in US than in Europe or in Japan.

DR LOVE: So Hanny, Dr Kumar from the Florida Cancer Specialists, who we work with a lot, has a patient with HIV and ITP who’s noncompliant with their HIV meds, finally taking it regularly. This is the real world.

DR AL-SAMKARI: Totally.

DR LOVE: Needs IVIG every 2 weeks since the platelet count drops to 2-4,000. She can remember to take avatrombopag, which she’s on. Any suggestion? He says I can’t give rituximab due to still high viral count.

DR AL-SAMKARI: Absolutely. So if she responds to a thrombopoietin receptor agonist that would be, I think, the best path to achieving a reasonable platelet count. Obviously, right, the best thing to do would be treating the underlying HIV as an HIV-associated ITP almost always, very, very frequently will respond to treatment of the underlying HIV. If it doesn’t, thrombopoietin receptor agonist is the way to go. Avatrombopag would be the one I would choose. I would not use rituximab. I agree.

Case: A woman in her early 80s with metastatic adenocarcinoma of the lung who responded to carboplatin/pemetrexed/pembrolizumab presents with ITP after 14 months of maintenance pembrolizumab — Susmitha Apuri, MD

DR LOVE: So Cindy, you were talking about ITP with IOs, and here it is. 81-year-old woman, a patient of Dr Apuri, another doc from the Florida Cancer Specialists. 81-year-old woman, metastatic adenocarcinoma of the lung, responds to chemo and IO, so carboplatin/pemetrexed/pembrolizumab, a very common induction, and then usually followed by pembrolizumab maintenance. 14 months into pembrolizumab maintenance she presents with ITP. Here’s the case.

DR APURI: I did treat her with steroids. There was a very brief response. The platelets went up to 40,000. But as soon as I tapered off the steroids, they would come back to under 10,000. So during this time the immunotherapy was held. The bone marrow biopsy did show a normocellular marrow with trilineage hematopoiesis and the megakaryocytes are preserved. And there was really no evidence of hemolysis or PNH in the peripheral blood.

So I did initiate her on eltrombopag. I think only out of the thought process that I want her to complete her maintenance immunotherapy.

She did very well on the eltrombopag, and I changed the treatment to 3 times a week. Her platelets were consistently above 50K and she completed the immunotherapy. And I discontinued the eltrombopag because I said, let's see what happens. She's done very well. And she's not really symptomatic with thrombocytopenia anymore. So she's been off the eltrombopag now for over 6 months, and her platelets are consistently above 100K.

So my question to the experts is how often do you see immunotherapy-induced thrombocytopenia? This was my first case and I have given my fair share of immunotherapy to our patients.

How would you treat this patient? Would you leave them on the eltrombopag and taper it down slowly? Because her current platelet count after 6 months is now trending in the 80s and 90s. So there has been a drop over time, but really not a significant enough drop for me to reinitiate any therapy. And in these individuals who develop the thrombocytopenia how often do you see a recurrence?

DR LOVE: And I should say, Cindy, too, that like a number of patients with lung cancer, this patient had a complete response. I mean, we see 5-year cures in metastatic non-small cell nowadays, and this is a situation — that’s why she was so determined to try to get her back on IO. Any thoughts, Cindy, about this case? Is it kind of typical?

DR NEUNERT: Yeah. I mean, I think to answer the question of how often does this happen we have at least a little bit of data now from the abstract that this is a rare event and that the majority of patients seem to be able to be supported the way this patient was. With glucocorticoids, IVIG and/or a TPO-RA many were able to be rechallenged without significant complications in their ITP. I think the fact that she’s now off and living at 80-90,000, as long as she’s not having any bleeding or symptoms like that, I would let her sit here. It does seem like these are more short-lived courses of ITP compared to ITP outside of this setting.

And also there was a kind of question we did about how do we stop the TPO-RAs, and I think that for most of us the clinical platelet count — the platelet count kind of lets us slowly wean patients off these TPO-RAs. We do know that there is a risk of an abrupt discontinuation leading to significant thrombocytopenia and bleeding, so following the platelet count and letting the platelet count guide us in kind of coming off is my approach in terms of how to come off the TPO-RAs.

But for this patient I think everything that was done actually mirrors what’s been done in the study that we presented and got the patient through their therapy that was necessary.

DR LOVE: So actually, Cindy, with your background in pediatrics you may be interested in this case from Amjad who has a 17-year-old diagnosed with ITP when 12, treated initially and then with IVIG with normalization of the platelets. Every 6-8 months the counts drop precipitously to below 10. She presents — actually, I’m not sure of the gender, presents with petechiae, bruises, nosebleeds, has had IVIG and remains responsive, on 1 occasion presented late when the count was recovering spontaneously and then maintained the count for another 8 months. Oh, it is a man. I’ve only seen him twice since he transferred to adult, so I guess he got transferred from pediatrics, and have refrained from giving anything except IVIG.

Any thoughts, first of all, Cindy, about this transition that occurs between the pediatrician and the medical oncologist? Any thoughts about this case, a patient who started at age 12 and is now 17?

DR NEUNERT: Yeah. I think this is really an important time for patients with ITP, particularly the adolescents as they go on to adults. And I think also we have — we know that there’s different treatment philosophies that even exist between pediatrics and adults, and so I think wherever possible to really have a good handoff and conversation about the patient. And we try to start pretty early educating our patients about their condition, making sure that we’re identifying a provider for them as they transition to adults. So I think as many other conditions in pediatrics, this is — transition of care is always something that we’re highly focused on, and we even have readiness surveys to let us know where our patient is in that transition.

I think with regards to this patient it’s really interesting. We think of patients once they kind of normalize, they’ve been off therapy for a while, we don’t think of this as an event, at least in children, that can come and go. But we do know that certain triggers can bring about exacerbations. I think if you’re getting long-lasting effects from IVIG that that would be okay to use intermittently. I think what we try to discourage are the patients that are getting IVIG every 2, 3 weeks to maintain the platelet count, and it’s just a terrible rollercoaster of an IVIG response, and then they crash back down, and then you give it. And those are the patients that I think really we should start to think about okay, what can I give them to maintain a good platelet count. It sounds like this patient comes up quite nicely in between for several months so may not need a maintenance therapy of sorts.

And then the other thing I would ask myself about this patient is is there something else going on that may not be an ITP but either an ITP associated with something else or some other form of a thrombocytopenia that just we should be looking for.

Incorporation of Thrombopoietin Receptor Agonists and Other Second-Line Therapies into ITP Management — Prof Zaja

DR LOVE: Francesco, we asked you to talk a little bit about TPO-RAs and other second-line therapies.

PROF ZAJA: Thank you for the opportunity to share with you some concepts and news on the second-line treatments of immune thrombocytopenia (ITP).

We know that although corticosteroids are initially effective in most patients the effect of the therapy is maintained in the long-term only in a minority, nearly 20-40%, so that the majority of patients eventually will lose the response and need second-line therapy.

At the same time, prolonged treatment with corticosteroids should not be pursued due to a series of metabolic and other well-known side effects that can arise even with the use of low dose.

For patients who fail or relapse after corticosteroids tapering and withdrawal different second-line therapies are available nowadays: splenectomy, TPO receptor agonists, rituximab, fostamatinib, and most recently also the BTK inhibitor rilzabrutinib, that is not included in this slide, are considered treatments with robust evidence of activity.

Splenectomy and rituximab are short-term treatments. Other TPO receptor agonists and fostamatinib are considered long-term treatments and a response to these agents, even if not always are treatment dependent.

As we can see from this slide, which comes from an Italian multicenter retrospective analysis, splenectomy remains a valued therapeutic opportunity to cure nearly two thirds of ITP patients, even if it can be associated with long-term complications, in particular sepsis and thrombosis. Also, for this reason, together with the availability of therapeutic alternatives, splenectomy is used less and less.

And the guidelines agree to consider splenectomy a therapeutic option for the chronic phase of ITP, which means 12 months or more from diagnosis. For this reason there is no rush to do splenectomy, at least after having failed treatment with TPO receptor agonist and rituximab, depending on patient age and comorbidities.

Regarding the selection of patients to undergo splenectomy, better probability of cure has been described in patients with previous response to immunoglobulin, younger age, primary ITP, elective splenic platelet sequestration. And as far as the pre- and post-intervention indications, it is recommended to achieve a platelet count of 50,000 or more before procedure, to vaccinate patients against pneumococcus, meningococcus, Haemophilus influenzae, education of the patient regarding infection risk, monitoring prophylaxis for thrombosis, in particular splanchnic thrombosis, in the perioperative period.

As far as second — medical second-line therapies, the use of rituximab, an anti-B-cell monoclonal antibody, allows an initial response rate in 60% of patients with nearly 45 complete response with a generally good safety profile.

However, most of the patients eventually relapse or worsen platelet count, so that 20-40% maintains the response in the long term, according to different patient selection. Several studies highlighted a better, longer-term outcome when rituximab is used in the early — in the early course of the disease and in young women, although this data has not been properly verified in prospective studies.

In recent years the use of TPO receptor agonists, romiplostim, eltrombopag, avatrombopag, as second-line therapy has become increasingly widespread. Treatment with TPO receptor agonist is benefit in 70-80% of patients in the short term and in nearly 60% in the long term. It should be noticed that during TPO receptor agonist treatment it has been reported a risk of developing a thrombotic complication in nearly 6% of patients, particularly in the elderly or in those with associated vascular risk factors, as antiphospholipid antibodies or other cardiovascular risks.

The suspension of treatment, as expected, is associated with a return of the platelet count to baseline level. However, already initial registration studies show that a small proportion of patients maintain the response despite drug withdrawal, and on this basis the concept of sustained response of treatment has been proposed.

This slide summarizes the results of 4 prospective studies aimed to study the sustained response of treatment effect either with romiplostim or eltrombopag. These studies confirmed the possibility to achieve a sustained response of treatment effect in early 30% of patients, a proportion that can raise up to 50% if the platelet count required to start tapering was 100,000 or more.

On this ground, various efforts have been made to try to identify the best candidates to whom to propose tapering and withdrawal. This slide summarizes the results of a consensus paper and were considered appropriate from the authors of that paper to propose patients undergoing TPO receptor agonist treatment tapering and withdrawal. Characteristics related to patients as age, comorbidities, antiplatelet or anticoagulant treatments. Characteristics related to the disease as ITP duration, primary versus secondary ITP, previous severe bleeding, platelet count. And the characteristics that were related with treatment were quality of response to treatment, the duration of treatment with TPO agonist, the dose of the TPO and the platelet stability.

Another important aspect that resulted from the previous studies with TPO receptor agonists is that a significant proportion of patients not responsive to one TPO receptor agonist or with significant fluctuation in the platelet count during treatment or patients who complained of side effects could improve the effects of the treatment switching from one TPO to the other one. And for this reason, it is important to test at least 2 different TPO receptor agonists to be sure that the patient is not responding to this class of agent.

Let’s now change the class of drug and move on illustrating the results observed with fostamatinib, an agent that inhibits the SYK pathway. SYK kinase is expressed predominantly in immune system cells, and its inhibition in patients with ITP appears important to interfere with the process that regulates the phagocytosis of immune complex platelet antibody on macrophages and with the production of autoantibodies by B cells.

This slide summarizes the characteristics of the patients that were included in the FIT-1/FIT-2 studies, 2 parallel prospective studies that compared fostamatinib with placebo in immune thrombocytopenia patients. As you can see, the characteristics of the patients included into the studies are representative of patients with an old history of disease. In fact, the median time from diagnosis to treatment is nearly 8 years and numerous previous lines of treatment. The median number of previously therapy was 3.

The results of the FIT studies show fostamatinib to be superior if compared with placebo. And keeping in mind the characteristics of the patients, the results of the … appeared to be of interest. The overall response rate is 43%, and the stable response rate, a primary endpoint of the study. In fact, the proportion of patients who achieve a platelet count of 50,000 or more on at least 4 of the 6 visits occurring every 2 weeks during weeks 14-24 resulted in 80% versus 2% in the placebo arm.

A subanalysis of the FIT studies conducted in patients who received fostamatinib in an early phase of disease showed much higher response rates, closer to those observed with TPO receptor agonists.

The positive effective of fostamatinib has been confirmed also in the real-life setting. This slide summarizes data from 3 real-life studies: 2 Spanish, 1 Italian. And with the major limitation of comparing different studies this experience underlined the favorable impact of fostamatinib in real life, where the response rate appeared to be nearly 70%. The response was durable in nearly half of the patients with an overall good safety profile.

And of interest, either in the registration trial and in the real-life studies, the rate of thrombotic events was found to be extremely low, less than 1%, possibly secondary to glycoprotein-6 and CLEC-2 inhibition, which is SYK dependent. For this reason, fostamatinib appeared to be a valued alternative to TPO receptor agonists, particularly in patients considered at risk of thrombosis.

Taking into consideration the results observed with these second-line treatments with robust evidence of activity, what I generally propose to my patients is treatment with TPO receptor agonist as first second-line of therapy with the aim to pursue sustained response of treatment effect in selective responsive patients and with the possibility to switch from one to another TPO receptor agonist in case of no response, platelet fluctuation, intolerance.

Fostamatinib or rituximab are generally proposed as third-line therapy after failing treatment with TPO receptor agonist with the exception of patients with high thrombotic risk, where these agents may represent an alternative to TPO receptor agonists.

For young females or for those patients who wish to undergo short treatment, rituximab can be considered an alternative to TPO receptor agonists. Splenectomy is generally proposed in chronic phase after having failed previous 2-3 lines of medical therapy.

I’m going to finish my presentation showing you the preliminary results of 2 abstracts recently presented at the American Society of Hematology Meeting that highlight a new major trend, that is the combination of different agents even in the initial phase of the disease.

The first abstract, presented by Professor Waleed Ghanima from Norway, refers to the PROLONG study, a Phase II, multicenter, international, randomized, placebo-controlled study aimed to compare the addition of dexamethasone to rituximab versus rituximab single agent and the role of maintenance therapy with rituximab as second-line therapy in ITP patients who received only corticosteroids front line.

As you can see from the slide, during Phase I of the study patients are randomized to receive 2 flat doses of rituximab single agent, 1 gram on day 1 and 15, versus the same therapy plus 2 cycles of dexamethasone 20 mg for 4 days on days 1 and 15. Responsive patients … in the Phase II of the study, where there is a double-blind randomization between placebo and rituximab 500 mg on week 0 and 24.

The results of the study shows an improvement in the combination arm, with 61 versus 38.5% response rate at month 6 without safety concern. Similarly, patients allocated to the rituximab maintenance arm had an improvement in the time to loss of response even if the statistical significance was not reached, likely due to the limited study power.

The second abstract, presented by Professor Maria-Eva Mingot from Spain, refers to the RODEX study, a multicenter, international, randomized, open-label study of romiplostim, starting dose 3 mcg/kg, administered for up to 12 months plus dexamethasone 40 mg daily for 4 days for 1 single course versus dexamethasone 40 mg daily for 4 days for up to 3 cycles as first-line therapy in patients with ITP. The primary endpoint of the study was the achievement of sustained response of treatment at month 6. The study design included a gradual dose reduction of romiplostim until discontinuation in responsive patients.

The interim analysis of the study showed higher sustained response of treatment at month 6, the primary endpoint, for the patients who received the combination of rituximab plus dexamethasone versus dexamethasone single agent, 61% versus 41%, which is 53% versus 30% if the platelet count for response evaluation was increased from 30,000 to 50,000. The authors underlined that the response occurred with a median maximum dose of romiplostim of 3 mcg/kg a week. The addition of romiplostim allowed to spare corticosteroid dose. In fact, the overall safety profiles were similar between regimens.

In conclusion, some take-home messages. New therapeutic opportunities to treat ITP patients are available. In fact, new agents will be available in the next futures. These new agents have different mechanisms of action, and therefore it will be more and more important to better understand the individual pathophysiology of the disease and at the same time the characteristics of the patients in order to better individualize treatment. Combinations appear possible new strategies, also in the early phases in selected patients.

And thank you for your attention.

DR LOVE: Thank you very much, Francesco. So we’re about to get into how things are about to change, and I think they maybe are going to be changing real soon now. We’re about to get into that, but first a couple more questions from the chat room. Hanny, Dilip, he was the same person who asked about the danazol, maybe a more mature oncologist, he says, “Splenectomy, I think, has been unfairly maligned in adults. It produces more sustained remissions with platelet counts over 100,000. Any challenges to this statement?” And here’s a case from Danny in addition to that, Hanny. “Any recommendations for a 65-year-old woman with ITP who suffered an MI with a platelet count of 14,000, had stents placed, and cardiology wants to put the patient on DAPT if feasible?”

DR AL-SAMKARI: Yeah, yeah. Alright, so first we’ll talk about splenectomy, and I will challenge your question about unfair malignment. I think that by and large I like spleens. I want to keep spleens in bodies as much as I can, alright? And so there is a place for splenectomy in ITP, I think that is true. However, I do think that for most patients we can get them under control with medical therapies.

And one of the things that we recognize about splenectomy is thanks to some nice new data from the French group there actually — if you refer a patient for splenectomy after they’ve failed 1 TPO-RA and rituximab, that’s it, just 2 second-line therapy options, their chances of success are actually less than 50%, right? So that’s not so great, right? And most of the — most of the studies that showed that two thirds cure, right, that was done after patients had failed first-line therapy with steroids and/or IVIG a number of years ago.

So is there a place for it? Yes. Is it something that is really — in my opinion and in my practice, it’s really a salvage option because we know these patients are at increased risk of thrombosis because of their ITP, even without splenectomy. We know these patients are at an increased risk of infection and of having serious complications from infection. So I don’t want to make that any worse if I don’t have to, so I think that that’s my take on that.

In terms of the patient with an MI, right, we have some pretty good data that if your platelet count’s above 20,000 you can generally feel — and the person’s not bleeding, you can generally feel comfortable using single-agent antiplatelet therapy. For double-agent antiplatelet therapy, for dual-agent antiplatelet therapy, if it’s really felt to be absolutely necessary, then you have to treat that patient.

And we have multiple options, right, including options that aren’t necessarily thrombogenic or don’t necessarily have a theoretical risk for thrombosis, right, our tyrosine kinase inhibitors. Rilzabrutinib is an option. Fostamatinib is an option. Fostamatinib, as Francesco pointed out, has some evidence that it may be antithrombotic. And so I would treat that patient to get them to a platelet count at least above 30-40,000, ideally about 50,000, and I would say once they’ve achieved that okay, proceed with the medically indicated dual antiplatelet therapy.

Case: A woman in her late 60s with stress cardiomyopathy and corticosteroid-refractory ITP receives rituximab followed by eltrombopag — Eric Fox, DO

DR LOVE: So we’re going to do 1 more case, and then we’ll get into some new things. You heard Hanny mention rilzabrutinib. Have you heard about ianalumab, and Hanny’s been trying to teach me how to pronounce that correctly, but you’re going to know how to pronounce it — you’ll know how to pronounce it real soon. You’re going to know a lot about it real soon, but first 1 more quick case. Cindy, maybe you can respond to this. This is a 69-year-old woman who’s a patient of Dr Fox, has stress cardiomyopathy and corticosteroid-refractory ITP, gets rituximab and now on eltrombopag. Here are his questions.

DR FOX: She got eltrombopag. She had done really well with her TPO agonist, and her platelets normalized.

And she came to the office and told me basically she self-discontinued the drug. She took herself off the drug, she didn’t let me know, and her platelet count had basically normalized at 150 or 200,000, and they had been stable a month off therapy.

Are there any patterns, anything to do with cardiac comorbidities, exposure with viral illnesses or other events that can predict who these patients are that are going to need lifelong therapy and who is short, time-limited therapy?

How do they get them off if that’s an option? Is it just one of those things that you don’t know until you have to follow their labs closely and check?

What about the role of a rheumatologic evaluation? I mean we sometimes test ANAs for patients like this. Do they have all their patients get a formal rheumatology consult? Where does your lab workup begin and end in the rheumatologic workup for patients with ITP?

DR LOVE: So Cindy, any comments? This woman actually, it turns out, got chest pain issues about to board a flight earlier this year, got taken to the hospital, had cardiac cath, stress cardiomyopathy, and then 3 months later had easy bruising, found to have a platelet count of 12, and you heard the rest of the story. Any thoughts, Cindy?

DR NEUNERT: Yeah. We already talked a little bit about how do we take these patients off, right? The gradual taper is the preferred, and we’ve had some discussions about this. I think we don’t know. We don’t have the biology correlates yet to tell us even why some patients get a sustained response off therapy or go into remission, and certainly not at diagnosis the predictive ability to say you are or are not going to go into some degree of remission at some point.

I think these are the biology correlates that we’re hoping come out of the studies that Hanny’s about to present that might give us some clues as to which patients, which drugs, which responses and who can benefit best from these. But these are all really good questions that we don’t have great answers to yet. Rheumatology-wise —

DR LOVE: Alright —

DR NEUNERT: — I start with an ANA and then only if that’s positive do I add in all the other rheumatology workup.

DR LOVE: Great.

Current and Future Role of Novel Therapies in ITP — Dr Al-Samkari

DR LOVE: So Hanny, I noticed that there was 1 question they didn’t ask you when you did that big presentation at ASH with the LBA about ianalumab, and maybe you can explain where it got its name, incidentally, but — which I always find interesting. But what they didn’t ask you is what does this mean to clinical practice and what are we going to do about it, but that’s the question we’re going to ask here today, but first we’ll take a look at the data.

DR AL-SAMKARI: Yes, absolutely.

DR LOVE: Anything you want to say about how it got its name, incidentally?

DR AL-SAMKARI: Yeah. So this is — it’s spelled like I-A-N-alumab, but it’s actually pronounced “yanalumab,” named after the god Janus, or Janus, the same god that gave its name to the Janus kinase, right? So this god had 2 heads, and the drug got its name because it has 2 distinct mechanisms, 1 as a very, very potent B-cell deplete, more so than rituximab, and is glycoengineered to be a very, very potent B-cell depleter. But then also it blocks the BAFF receptor pathway, the BCL-activating factor receptor pathway, which is really critical in maturation, survival, differentiation of B-cells, including the autoreactive B-cells that cause so much trouble. So that’s why it’s got this name. Obviously, not the easiest to pronounce, but just pretend like it’s Y-A-N-alumab instead of I-A-N-alumab, yanalumab. Alright.

DR LOVE: I like it because the Y is like 2 things.

DR AL-SAMKARI: It’s an antibody. It’s Y, exactly.

DR LOVE: Alright. Go for it. Let’s talk about the data.

DR AL-SAMKARI: Absolutely. So again, Neil, thank you for the invitation. Always a pleasure. So let’s talk about new therapies in ITP that are here and that are coming, alright?

So ITP, it’s been really fascinating to watch a disease like myeloma go from melphalan and prednisone to all of these incredible targeted therapies that have really changed the game, and we’re hopeful now that we’re making that same transition in ITP. We’ve had thrombopoietin receptor agonists for a long time, which totally changed the game, and now we’re going through another kind of potential revolution in ITP with therapies that are very targeted to specific aspects of the disease.

I’m going to start with BTK inhibitor, right? So we use BTK inhibitors all day every day in lymphoid malignancies, and now BTK inhibitors are being developed for autoimmune hematologic conditions, ITP, warm autoimmune hemolytic anemia, and also being developed in other areas of autoimmunity. And so BTK inhibition has many effects, but very, very important effects in treating ITP in that these drugs block B-cell maturation, they prevent phagocytosis, they have a number of effects that we would expect to be helpful in autoimmune hematology.

And we remember, right, that ibrutinib and acalabrutinib, some of these earlier-generation BTK inhibitors, they affect more than just BTK on the kinome, including other kinases like Tec, right, and that causes impairment of platelet function. It can cause bleeding, and so people initially were — in the early days of this people would say gosh, a BTK inhibitor in ITP? A patient with a platelet count of 10? That’s not safe. We can’t to that, right? I wouldn’t recommend using a drug like ibrutinib in that circumstance to treat ITP, but a drug like rilzabrutinib, formerly known at PRN1008, right, is much more selective on the kinome and does not cause problems with platelet aggregation like ibrutinib and some of the earlier-generation drugs do.

And so we see here, right, what happens with — this is light transmission platelet aggregometry. These are various different agonists to platelets. We see ibrutinib causes a lot of impairments in healthy volunteers who have normal platelet counts, right, receiving them, and platelet aggregation. And rilzabrutinib in both healthy volunteers and patients with ITP do not have that same impairment in platelet aggregation.

So with that rilzabrutinib was evaluated initially in an early Phase I/II study that was positive and very promising, and now the Phase III LUNA3 study, which was presented as a plenary at ASH last year, right, this was a study that was intended to show safety and efficacy in a pivotal trial of rilzabrutinib and actually has both an adult arm that has been reported out and has resulted in FDA approval of rilzabrutinib for ITP in adults, but also a pediatric arm that is still ongoing.

And we can see the results from rilzabrutinib showed that patients receiving rilzabrutinib as opposed to placebo, and again, these were heavily pretreated patients, what we would — some people would call relapsed/refractory-type ITP patients. Very, very difficult to treat patients on the whole. They did much better on rilzabrutinib than the people that were randomized to placebo. Rates of durable response to rilzabrutinib were 23% versus 0% on placebo. Overall response in rilzabrutinib was 65% versus 33% on placebo. Much better improvements. And the time to platelet count response was as expected much quicker.

This is a BTK inhibitor. These types of mechanisms may not — you may not expect them to work quickly, but they actually in many patients do work quite quickly. Within about a week you can start seeing improvements in that platelet count. When you look at the amount of rescue therapy in this Phase III pivotal trial it’s much less in people receiving rilzabrutinib as opposed to placebo.

And really dramatic improvements in ITP. Consider, right, everything that Cindy told us about fatigue in ITP, how big of a problem this is and how it’s multifactorial. And one of the things that seems to contribute to it is inflammation. And so it’s theorized that the anti-inflammatory impact of rilzabrutinib may be the reason why patients have such significant improvements in their fatigue. And so rilzabrutinib, in my practice, right, not only do I reach for it after people have failed thrombopoietin receptor agonists, for example, but perhaps earlier on, people that have a really dramatic fatigue component of their ITP, this may be a good choice and something to think about.

And this study, by the way, showed higher response rates when rilzabrutinib was used earlier in the course, earlier lines, as with almost every ITP therapy. So don’t compare 20-something percent response with a drug trial in 2025 with a 60 or 70% response with a drug trial in 2009, right? These are different populations.

In terms of safety, rilzabrutinib was quite safe in this study overall. About a third of patients get GI side effects. That’s the take home, alright? So some heartburn, some diarrhea, typically Grade 1, rarely Grade 2, usually temporary, lasting for a month, 2 months before the person kind of gets used to it. Generally speaking tolerable. Overall a better side effect profile, I would say, than fostamatinib, which causes quite a bit of hypertension and more diarrhea. And so it’s something that is obviously a tyrosine kinase inhibitor, and we aren’t all that used to using TKIs in ITP, but a pretty good side effect profile overall. More side effects than typical TPO-RA, but then again, right, potential for improvement in fatigue that we may not see with TPO-RA.

So moving on to ianalumab, this is the drug that I had mentioned earlier, how it got its name. This is an antibody that’s directed against the B-cell activating factor receptor, BAFF-R, alright? And this is a very potent B-cell depleter. It’s glycoengineered to be a very potent B-cell depleter, more so than a CD20 antibody. And then on top of that it has a very important impact on reducing the maturation, the differentiation, and ultimately the transition to long-lived plasma cell of the autoreactive B-cells that cause so much trouble in ITP.

This was evaluated in actually 3 studies, 2 of which have completed, 1 is still ongoing, looking at this drug in first-line ITP in the VAYHIT1 study as a pivotal Phase III study, looking at the drug in second-line ITP in the VAYHIT2 study. And this is the one I had the pleasure of presenting as a late-breaking abstract. This was in combination with eltrombopag in the second line. And then VAYHIT3 looked at ianalumab in later lines.

And so VAYHIT2 as a pivotal Phase III study enrolled about 152 patients with ITP in the second line. These are patients who had just failed corticosteroids, not received any other lines of therapy, so truly a virgin second-line population so to speak. And it looked at combining ianalumab with eltrombopag, either a higher-dose ianalumab or a lower-dose ianalumab or placebo with eltrombopag. So remember, this is not — the placebo arm here is an active comparator arm. It’s standard of care.

And these patients were treated for 6 months, 4 infusions of study drug plus eltrombopag for the first 4 months, and then after that eltrombopag taper, right, a required taper to get patients off and see how they did off of treatment. And then patients were followed for safety and efficacy over a long follow up period.

The primary endpoint in the study was time to treatment failure, which is new for most ITP studies. This has really never been used in a drug — in a new drug ITP study and previously was used in studies of repurposed drugs, like mycophenolate in the FLIGHT trial. But this endpoint really looks at what we care about clinically, keeping the patient’s platelet count above 30,000, they’re not bleeding, they don’t need rescue, they’re not dying, and in this case they’re able to taper off of their TPO-RA.

And this study demonstrated that ianalumab was — gave both a statistically significant and a clinically significant improvement in time-to-treatment failure, whether you were low-dose ianalumab, higher-dose ianalumab, still a significant improvement over the eltrombopag-only arm.

And the higher the dose of ianalumab the better the overall platelet response, right? Not a surprise with combination therapy.

And this drug also improved fatigue, potentially through an anti-inflammatory-type mechanism, and it did so in dose-dependent fashion, right? The highest dose of ianalumab had the greatest improvement in fatigue.

Patients receiving ianalumab had less bleeding than patients receiving only eltrombopag, so people receiving both ianalumab and eltrombopag had less bleeding.

And overall the drug did this with a pretty good side effect profile. The thing that we worry about with B-cell depletion primarily, infusion reactions is one, and that was really not a significant issue in this. Infusion reactions were mild and actually not altogether different in frequency between the low-dose ianalumab arm and the placebo arm and only slightly higher in the high-dose ianalumab arm. And infections were of the same incidence and severity in the ianalumab arms as the placebo arm. This drug caused a little bit of neutropenia, but it lasts for a few days to maybe a couple weeks. So really not something we expect to be clinically relevant.

So one question we get is what about IgG levels. This drug only reduced IgG levels by about 10-15%, so really not that much. We’re not causing hypogammaglobulinemia in very many patients. Only 1 patient had it in this study, and that was after they were actually started on other ITP therapies.

VAYHIT3 is the third study in the ianalumab program. And this, again, was really focused on more relapsed/refractory patients, patients that had received many other prior lines of therapy. And this was a single-arm Phase II study, and it showed about a 44 response — 44% response rate in this heavily pretreated population. And in terms of patients who had a stable response, about a quarter of the patients did. And that’s pretty typical, right, in patients that have received a median of 5 or 6 or 7 prior therapies.

Patients receiving ianalumab in this study, right, had a reduction in bleeding events compared to previous — before they were treated with the ianalumab.

And just to briefly mention the VAYHIT1 study. This is very similar to VAYHIT2. It’s still ongoing, and this is looking at adding ianalumab to corticosteroids in the first line, and again seeing what happens. And one question that VAYHIT1 and VAYHIT2 will both help us answer is can we, in addition to giving people a nice duration off treatment with little additional side effect burden, can we defang the ITP. Can we actually with a potent drug very early on in the disease course, before these patients develop oligoclonal T-cell clones and a very complex autoimmune phenotype? Can we do something about that early on by giving them a very potent drug? We don’t know the answer to that yet, but we will know because these patients are being followed for multiple years.

Lastly, I’ll just mention 2 other drugs, efgartigimod, which is a neonatal Fc receptor antagonist. This is a type of drug that is already approved for multiple indications in neurology, including generalized myasthenia gravis. And what this drug does, it reduces the half-life of circulating IgG by blocking the neonatal Fc receptor, which is very important in IgG recycling, physiologic IgG recycling. And so this reduces your levels of IgG by about 60-70% within about a week, and that is good for getting rid of a large chunk of the platelet autoantibodies that cause trouble in ITP.

This study, the ADVANCED IV study, which was presented a couple years ago, showed again that weekly infusions, this is an IV infusion, of efgartigimod did affect significant improvements in patients’ platelet counts relative to placebo. And it was really due to this significant drop in IgG levels, not so low that we’re really, really, really worried about infection but low enough that we’re getting enough of those platelet autoantibodies out of the system and improving things for these patients.

Finally, anti-CD38 drugs, which I mentioned before in response to one of the questions, are coming on strong in ITP, right? So we use these drugs all the time in plasma cell neoplasms and now mezagitamab, in addition to daratumumab, daratumumab evaluated in investigator-initiated study, mezagitamab being evaluated in a full pharma development program in ITP, showing rapid and sustained improvements in patients’ platelet counts. Very good response rates, in the 70-80% range, in heavily pretreated patients, again because you’re getting at those pesky plasma cells that other treatments aren’t touching. Certainly a bigger gun, right? We do think about sometimes the more significant immune impact of using a CD38 drug, but undeniably effective.

And dose-dependent improvements in people’s bleeding, where the people in this Phase II study of mezagitamab that got the highest dose had no bleeding events at all. And you can see that as the dose lowered there were more bleeding events, and the placebo arm had the highest rate of bleeding events.

DR LOVE: So I’m a simple person, I just have a basic question, which is where does rilzabrutinib fit in? It was approved in the United States here in September.

DR AL-SAMKARI: Yeah. Yeah.

DR LOVE: And particularly where ianalumab fits in. Before we get to that just Swati in the chat room had the same question I did about the rilza, Hanny, which is — I was looking. I didn’t see any cardiac issues on your adverse events thing. Do you see AFib or ventricular arrhythmias?

DR AL-SAMKARI: No. No. We don’t see AFib, don’t see —

DR LOVE: Okay, well that’s a good thing.

DR AL-SAMKARI: Yeah.

DR LOVE: And then another — go ahead. Go ahead.

DR AL-SAMKARI: Go ahead, please. Sorry, sorry.

Rilzabrutinib, it’s really quite targeted, right? So you don’t have — they have not seen atrial fibrillation, other — those arrhythmias that we see with the early-generation BTK inhibitors.

And where does it fit in? I mean, right, it’s approved for people who have ITP that have failed other therapies. So there’s no law saying that a patient has to fail 1 or 2 or 3 TPO-RAs and rituximab before they get rilzabrutinib, right? It goes back to I think the shared decision-making piece, right? Discuss with patients the various options. In second, third line about 70% of people respond to rilzabrutinib, as was demonstrated in the subanalysis of LUNA3.

So I think that it’s a very promising drug and one that we certainly can reach for in later lines, but we also can think about it particularly in those patients that have a lot of fatigue, or those patients that have a significant thrombocytosis history, why not maybe potentially thinking about using it a little bit earlier for those folks?

DR LOVE: So I want to get Cindy and Francesco’s take on this, too, but just to come back to you, Hanny. Again, we had a bunch of questions after your talk on the role of vaccines, other tumors, CLL, et cetera, we can talk about, but what I want to know is based on the data you presented would you like to be able to have ianalumab available? And in what situations would you use it?

DR AL-SAMKARI: I definitely would like to have it available, right, as an additional option. I think I would — until we have more data, I’m a pretty data-driven guy, so I’d like to use it primarily in situations that we know it works, and we know it’s safe, so second-line patients and beyond the second line, from both VAYHIT2 and VAYHIT3. I think that it has high value there.

I think if I was hospitalized with ITP tomorrow, and you said you could get this drug and have a nice duration off treatment without major concern in terms of adverse events, which we didn’t really see in VAYHIT2, and it might be disease modifying, we don’t know yet, but it might be, I think I probably would be somebody who would say yeah. I’ll take the combination. I’ll take the TPO-RA plus the ianalumab.

But, right, there’s still more data to come, and I think it’s important, right, to see what that long-term shows. Are we getting true disease modification? If so, that’s a game changer. I mean, to me it’s why not use it. But if you’re not, then it becomes more of a question of shared decision-making and why would we choose this versus other things. Certain priorities of patients will drive that.

DR LOVE: So we just got back from the San Antonio Breast Cancer Symposium, where we had 4 posters, and most of them were surveys of investigators asking what do they do in their practice. So I’m really anxious to do the survey and ask 20 investigators what they think about these new data. And also, Cindy, theoretically, I mean, putting aside reimbursement issues, FDA, et cetera, what would come first, rilzabrutinib or ianalumab?

DR NEUNERT: Yeah. I don’t know. I think this is part of where we’re going to get some real-world data, as I’ve said. As you’re saying, these surveys and things, but I think to see where they’re getting used. I mean, I think to Hanny’s point, right, the benefit of a ianalumab is the potential to get a response that is lasting that does not require ongoing therapy. And I think for a lot of patients that will become an important goal. And when we talk to patients that is already an important goal. I like Hanny’s approach of saying what would I do if I was a patient with ITP tomorrow.

For a lot of people the impact on quality of life comes not just from the disease itself but from the medication that they’re on or the number of visits to the physician and all these other things. Time lost from work. So I think to have an option in this new era that can potentially provide the patients that highly desire that time off of ongoing medicine is really a game changer.

And then I do think as we start to position all of these sustained response off treatment for drugs like rilzabrutinib that require ongoing therapy, that is to me another piece of data that we really need to see. Because if you could show that after a couple months of rilzabrutinib you have very impressive sustained response off treatment that’s also a game changer, right? So these are the pieces of the puzzle that we still need the data to guide us on to really know where to go next.

DR LOVE: Yeah, and of course in CLL the issue of time-limited therapy is a big issue. Now the BTK’s coming in with venetoclax in that respect.

So Francesco, what are your thoughts? Again, putting aside the ability to access, cost, just purely based on medical science, what do you see right now as an appropriate role? Would you like to be able to use ianalumab? Would you like to be able to use rilzabrutinib?

PROF ZAJA: Yes. What is clear is the paradigm of the treatment of ITP is more and more changing. In the past treatment — the goal of treatment was to prevent bleeding. Now with these new agents, with new targeted agents, fostamatinib, rilzabrutinib ianalumab … we can change the course of the disease. And by this way, I believe that it’s important to use these agents early in the phase of the disease, not in a late phase. And I believe that these new agents might really change — maybe are game changers and may change the course of the disease.

DR LOVE: So again, Hanny, what about the use of this therapy, ianalumab, outside of ITP? I saw trials on CLL. What’s the thinking there?

DR AL-SAMKARI: Yeah, so outside of ITP. So ianalumab is also being evaluated in autoimmune hemolytic anemia, warm autoimmune hemolytic anemia and the V-A-Y-H-I-A study. That’s also a pivotal Phase III. So it’s a big program in autoimmune cytopenias. But in addition, right, in other autoimmune diseases. Sjogren’s syndrome already demonstrated efficacy. It's being evaluated in lupus. So there’s a number of different areas, including, again, potentially B-cell malignancies, as well, that this mechanism may be quite efficacious.

Ianalumab is not rituximab, but it is in some ways maybe a more — a more advanced kind of therapeutic in that regard. Only time will tell if that’s true, but I think the potential is there.

DR LOVE: So we have a bunch of other cases. We’re going to actually present them in a separate piece that we’re going to send out along with this, but I want to use the remaining few seconds to go back to you, Hanny, and talk a little bit more about how ianalumab actually works. To me the diagrams are diagrams. I like people to just explain stuff to me. Can you take another shot at explaining how this drug works?

DR AL-SAMKARI: Absolutely. So when you give an infusion of ianalumab very shortly after the patient’s B-cell count drops to zero, okay? So you completely deplete their B-cells. The drug is still hanging around and preventing the potential maturation of additional B-cells over time, right? so when people get multiple infusions of this, and the VAYHIT3 additional data that was presented at ASH actually showed now deep and prolonged that B-cell depletion is without, again, really dramatically impacting the IgG levels, which obviously makes us feel a little bit more comfortable with causing such deep and profound B-cell depletion. But that’s essentially how it works. It’s that 2-headed mechanism of the B-cell depletion and then prevention of things coming back.

And so that’s the — that’s what we understand now. One of the things that the long-term safety data will tell us is when exactly does the return of B-cells happen, and when it happens are those B-cells going to be different than the complement we saw before? Is there going to be somewhat of an immune reset particularly useful in people with autoimmune problems or not? And we still have to find that out.

DR LOVE: So it was a pretty interesting ASH for a lot of reasons. Last night on the myeloma program we were talking about this new viral vector off-the-shelf in vivo CAR-T therapy. Tonight we’re talking about this fascinating new molecule as well. It’s really an exciting time to be in oncology.

Thanks so much to Cindy, Hanny and Francesco for working with us tonight. Audience, thank you for attending.

Be safe, stay well, and have a great night.

Thanks so much, Cindy. Thanks, Hanny. Thanks so much, Francesco.