VAYHIT1: A multicenter randomized, double-blind, Phase III trial evaluating ianalumab versus placebo in addition to first-line corticosteroids for patients with primary immune thrombocytopenia (ITP)

Cooper N et al. VAYHIT1: A multicenter, randomized, double-blind, phase III trial of ianalumab versus placebo in addition to first-line corticosteroids in patients with primary immune thrombocytopenia (ITP). EHA 2023;Abstract PB2636. 

Al-Samkari H et al. Primary results from VAYHIT2, a randomized, double-blind, phase 3 trial of ianalumab plus eltrombopag versus placebo plus eltrombopag in patients with primary immune thrombocytopenia (ITP) who failed first-line corticosteroid treatment. ASH 2025;Abstract LBA-2. 

DR LOVE: Welcome to “What Happened at ASH (the American Society of Hematology Meeting) in December 2025? Immune Thrombocytopenia.” Are we entering a new age of treatment of this entity, specifically the use of BTK inhibitors and BAFF-R antagonists (B-cell-activating factor receptor antagonists)? This is medical oncologist Dr Neil Love.

I met with Dr Hanny Al-Samkari from the Massachusetts General Hospital in Boston to discuss key papers presented at ASH. On the first issue of this series, Dr Al-Samkari provided the background for the VAYHIT2 paper he presented at a late-breaking abstract at the ASH meeting in December.

And I spoke with him more about the details of the rationale, design and outcomes from the VAYHIT2 trial.

DR LOVE: Both of the studies, VAYHIT2 and then this ongoing VAYHIT1, focus on this initial period. Maybe you can clarify a little bit. For example, VAYHIT1, is that all-comers ITP or high risk or just everybody?

DR AL-SAMKARI: Yeah. VAYHIT1 is anybody with primary ITP, so so long as you don’t have HIV-induced ITP or CLL-induced ITP you can enroll on the study. So it’s most patients with ITP, and it’s really, aside from that, mostly all comers. And so it’s, again, looking to answer the same questions as VAYHIT2 except in an even earlier line. Can we give people a nice duration off treatment, can we do it safely, and hopefully can we modify the course of their disease?

DR LOVE: So I’m curious also. What do you think the control arm of VAYHIT1 is going to show? In other words, and one question I have, is how many people get steroids and then have no problems?

DR AL-SAMKARI: Only about 20% of people typically get steroids and have no problems.

DR LOVE: Really?

DR AL-SAMKARI: Yeah.

DR LOVE: Really? Wow.

DR AL-SAMKARI: Yeah, of adults, right? 80% of patients who are — when they develop ITP as adults they progress to chronic disease. And so with clinical trials one of the things that we tend to see is that that number tends to be just a little bit better probably because every clinical trial excludes the patients that have really complicated other issues and so on and so forth. So we might see 30% or 25% or something like that do okay in the corticosteroid-only arm of VAYHIT1. That would be my guess.

But after they relapse then they’re going to be put on — they’re going to need to go on other ITP therapies, and so there will be treatment failures as per that trial’s primary endpoint.

DR LOVE: In terms of second-line therapy, what about the option of repeating corticosteroids? How do you factor that in? And what would you consider the typical VAYHIT2 patient? Is it somebody who’s had just 1 course of corticosteroids and relapses on the steroids? Do you have people on there who got steroids, responded, then were off treatment and then relapsed again?

DR AL-SAMKARI: For VAYHIT2 people have — people would have only received 1 course of — 1 treatment course of corticosteroids and either relapsed after those corticosteroids or they never responded in the first place. So that’s the population for VAYHIT2.

It’s actually you’re enrolling people that have just relapsed and often relapsed relatively quickly after steroids. It’s not an “easy” group of patients. It’s actually a group that they have some pretty significant disease, and their platelets counts are very low. But yeah, that’s the group.

In terms of can you use steroids in the second line, you can use steroids in any line, but we really recommend against it, right? The ITP guidelines from the American Society of Hematology, from International Consensus Report, really, really strongly push people no more than 6 weeks of corticosteroids up front and then switch to something else. Get the patient on a chronic controller medication, a thrombopoietin receptor agonist, a clinical trial. Give them rituximab. Give them something where they can be off of steroids because steroids are not disease modifying in this disease, and obviously we recognize all of the complications of long-term use of steroids.

DR LOVE: So one final question about VAYHIT2 and — I was not surprised that when you did the presentation afterwards nobody asked this question because they never do, which is would you yourself like to be able to use this agent right now in your practice. If it were available would you use it? Would you use it pretty much in everybody who could get into the trial, which sounds like a lot of people?

DR AL-SAMKARI: I would like to have this agent in my practice, yes, absolutely. If I had it I would definitely use it. I would use it in patients like those enrolled in the VAYHIT2 study. And also, right, I would use it in patients that have had multiple prior therapies, like in VAYHIT3, because that was also a positive study, and the drug clearly works for them too.

And so if I think about it to myself, if I had ITP, and I was hospitalized tomorrow, second-line ITP after — if I failed corticosteroids, I would want ianalumab in addition to a thrombopoietin receptor agonist. I’d want to give myself that opportunity to have a good duration off treatment and also disease modification.

One question that I was asked, that people ask a lot is how is this different than rituximab, right? Rituximab is not disease modifying in ITP. Rituximab does not have any impact on B-cell maturation. Rituximab is not as good of a B-cell depleter as ianalumab is. And rituximab actually increases levels of the B-cell activating factor, or BAFF, that this drug blocks the receptor for, right? If you give people a CD20 monoclonal antibody you actually increase the levels of the cytokine that would normally cause differentiation and growth of more B cells, including autoreactive B cells.

So we don’t — that’s not good, right? So this is definitely a very different drug than is rituximab and has more potential both up front and in improvement of disease in the shorter term and potentially in the long term with disease modification.

DR LOVE: It’s always challenging to do indirect comparisons, but when you look just at short-term clinical outcomes, rituximab versus ianalumab, do they look similar? Does ianalumab look better?

DR AL-SAMKARI: Ianalumab looks better, right? So ianalumab, it has — there’s never been a study that has compared rituximab plus eltrombopag with ianalumab plus eltrombopag. All the rituximab studies are in combination with steroids. So it’s a little bit different — it’s different. It’s different. In different populations. So you’re right about the caveat, but even in spite of that, right, and in controlling for those differences, I would argue that ianalumab has produced better results, not just as it pertains to platelet counts and bleeding and side effects, but also as it pertains to fatigue and the constitutional symptoms of ITP, quality-of-life-type considerations.

DR LOVE: So we’re always doing surveys of investigators. We just had 4 posters at the San Antonio Breast Cancer meeting. We go to 20 investigators and say whatever. What do you do in this situation? If I go to 20 investigators in ITP are they going to say pretty much the same thing you said do you think? You’ve probably already been talking to your colleagues.

DR AL-SAMKARI: I think that probably 60% of them would say something similar to me and 40% would probably say something a little bit different.

DR LOVE: 60?

DR AL-SAMKARI: Yeah. That’s what I would say.

DR LOVE: Really? Interesting.

DR AL-SAMKARI: Yeah. Just feeling the pulse.

DR LOVE: Yeah. Well, we do this over time, too, and sometimes you see an early pickup and then you see over time people — or sometimes people present stuff and everybody changes right away. So I hope we get a chance to see what people think about this. It’d be really interesting.

Secondary analysis results from VAYHIT3, a Phase II study of ianalumab for patients with primary ITP previously treated with at least 2 lines of therapy

Choi P et al. Secondary analysis results from VAYHIT3, a phase 2 study of ianalumab in patients with primary immune thrombocytopenia previously treated with at least two lines of therapy. ASH 2025;Abstract 844. 

DR LOVE: You were mentioning the VAYHIT3 study, which is, I think, really relevant to patients in practice right now. Do you want to talk about that?

DR AL-SAMKARI: Absolutely. VAYHIT3 was a Phase II study that looked at ianalumab in patients that had received many prior treatments using ianalumab as a single-agent treatment. Patients who were on stable doses of corticosteroids or thrombopoietin receptor agonist could continue those at a stable dose throughout the study, but the intervention was just ianalumab. And no placebo arm. It was a single-arm study.

And so the patients on the study were heavily relapsed/refractory, among the most relapsed/refractory of any ITP study that’s ever been done. So a difficult population. And they received 4 infusions of ianalumab 9 mg/kg.

And 44% of patients in VAYHIT3 had a response, a confirmed platelet response, and of those patients about a total of a quarter of the patients that were enrolled in the study ended up having a stable response at 6 months. These numbers, they are very — you might say a quarter, about 24%, that’s pretty similar to rilzabrutinib in LUNA3, and you’d be right, right? So these patients are tough to treat. It’s very common to have these kind of longer-term response rates in that 20-30% range.

But one nice thing about ianalumab is it does it with 4 infusions and not a chronic therapy as is often required with other — in the other different therapies that are being evaluated. It also caused a lot less bleeding, right? It really reduced the bleeding, which is obviously the main thing that we have concern about in these patients.

So all in all, a smaller study but a very informative study and one that helps us also — helps me to say when I have this drug available to me why I’d also like to use this in patients that have difficult disease and have failed a number of prior therapies.

DR LOVE: So this will come up with these cases, but you hear a lot of cases of people on TPOs and they’re still having some relapses, maybe it’s once a year, twice a year. Sometimes there are big problems, not big problems. How do you judge whether or not hey, maybe it’s time to try something else like ianalumab or rilzabrutinib for that matter? If you could, would you ever consider continuing eltrombopag and adding in ianalumab?

DR AL-SAMKARI: Yeah. So I’ll take the question about combination therapy in later lines first, which is that this is something that we have certainly looked at with more salvage-type therapies, like adding mycophenolate to a TPO, for example, or adding azathioprine or something like that. And there is some value in this. You can sometimes get a response where you otherwise couldn’t, but the prospect of adding ianalumab or rilzabrutinib to a TPO in later-line settings I think is really interesting and one that we don’t have the answer to, but one that I would definitely try in people that are not responding to 1 agent alone, right?

In terms of the other — the first question, the time that you might say well, you’re on a thrombopoietin receptor agonist, your platelets are good most of the time, but you’re in the hospital once or twice a year, I would say that for that patient, that type of patient, I would try them on something else because I mean being admitted to the hospital on a regular basis is — even if it’s every 6 months, every 8 months, having a major crash, right, we really, really want to try to avoid that. And maybe it will be different on the alternative drug or maybe it won’t be, but the only way to know, right, is to try. And I would — I would definitely look to switch patients like that to one of these newer therapies.

Improved health-related quality of life and bleeding scores with the oral Bruton tyrosine kinase inhibitor rilzabrutinib in the open-label period of the multicenter Phase III LUNA 3 study for adults with ITP

Cooper N et al. Improved health-related quality of life (HRQoL) and bleeding scores with oral Bruton tyrosine kinase (BTK) inhibitor rilzabrutinib in the open-label (OL) period of the multicenter phase 3 LUNA3 study in adults with immune thrombocytopenia (ITP). ASH 2025;Abstract 1254. 

DR LOVE: So do you want to talk about the data from the Phase III LUNA study presented at ASH?

DR AL-SAMKARI: This was a secondary analysis from LUNA3 that looked at ITP-PAC not just at the end of the double-blind period of the study, like the initial publication did, but also looks at it after a number of weeks of the open-label extension and shows continued improvement in fatigue over time, right? So something that we like to see, that the longer you treat patients the better you get the disease and the inflammation caused by the disease under control, and that is what was seen.

Additionally, right, as patients continued into the open-label period they had less bleeding, right? So their median bleeding scores were slowly declining and declining and declining over time, which again is representative of continued good and improving disease control of their ITP.

DR LOVE: And do we know anything about the mechanism of the fatigue and why it seems that you see benefit here? And also, if patients on rilzabrutinib require surgery do you need to stop it ahead of time and afterwards?

DR AL-SAMKARI: That’s a great question. So in terms of the mechanism of fatigue, it’s not fully understood, right? We believe that it’s multifactorial, that it’s related to systemic inflammation from the autoimmune disease itself, as we see in many other systemic autoimmune diseases. We know these patients, right, because they’re at increased risk for bleeding, and particularly women of childbearing potential who are menstruating, they’re at increased risk for iron deficiency and iron deficiency anemia, and that’s often missed. Certain thrombopoietin receptor agonists, like eltrombopag, chelate iron, and they cause iron deficiency, so that’s something that has to be paid close attention to. It's believe that rilzabrutinib helps with this fatigue primarily through anti-inflammatory effects, but that is still — that still needs to be really proven in studies that are designed to prove that.

In terms of your other question, for patients going to surgery there is no — based on the platelet aggregation studies for this drug there is no impact on platelet function, and so even though for other BTK inhibitors we do hold usually for a couple days around surgery, it’s not specifically indicated to do that with rilzabrutinib. So that is — I would err on the side of not because I would rather not threaten the patient’s platelet count. I’d rather not potential precipitate a drop in their platelet count given that this drug should not be impacting their surgical hemostasis.

DR LOVE: Interesting. So I don’t know. Maybe I’m the last person to know this, but what do you see with the sed rate in ITP?

DR AL-SAMKARI: It’s something that’s been studied, but it’s not predictive of fatigue. Some patients have elevated sed rates, some patients don’t. These are studies that were done many decades ago looking at sed rate, looking at CRP. These nonspecific inflammatory markers are often normal in patients with ITP despite the fact that they have ongoing fatigue and are believed to be under a systemic inflammatory picture.

Romiplostim for chemotherapy-induced thrombocytopenia in patients with colorectal, gastroesophageal and pancreatic cancer: A global Phase III randomized, placebo-controlled trial

Al-Samkari H et al. Romiplostim for chemotherapy-induced thrombocytopenia (CIT) in colorectal, gastroesophageal, and pancreatic cancers: A global, phase 3, randomized, placebo-controlled trial (RCT). ASCO 2025;Abstract 12007.

DR LOVE: So let me ask you something, I noticed you had several publications on the issue of thrombocytopenia related to chemotherapy, do you want to talk a little bit about that?

DR AL-SAMKARI: Yeah. Yeah, Neil. Chemotherapy-induced thrombocytopenia is a really, really common problem, right, in heme/onc practice worldwide. It’s just a very common thing that we see. And unlike chemotherapy-induced neutropenia, where we can give G-CSF, and we use it routinely to improve patient’s neutrophil counts, and we don’t have to reduce the dose intensity of their chemotherapy, CIT patients often have reduction in dose intensity of their chemotherapy, and likely to the detriment to the patient, right? We know that reducing relative dose intensity of chemotherapy is bad for many patients, particularly those being treated for curative intent and those being treated for long-term palliative intent. And so we want to do something about it.

And so this is an area of study in evaluating thrombopoietin receptor agonists that I’ve been very closely involved in, as well, and the use of drugs like romiplostim and avatrombopag to treat patients with CIT, who develop persistent CIT, they’re platelet counts are low when they show up for the cycle day 1. They haven’t recovered. You have to dose reduce. You have to delay the therapy by a week, right? You see this all the time.

And using a drug like romiplostim, as we did in the Phase III pivotal, randomized, controlled RECITE trial, which I had the pleasure of presenting at ASCO this last year, using romiplostim in these patients is quite effective at improving their platelet counts, and it’s quite safe, right.

We didn’t see increased thromboembolic risk. We didn’t see any concerns for development of MDS or things like that. What we saw was a much higher rate of people being able to maintain the relative dose intensity of chemotherapy with very, very little adverse event attributable to the romiplostim, right? The adverse events here is from the chemotherapy.

And so that study showed a tenfold greater odds of being able to avoid reductions in relative dose intensity if you got romiplostim versus placebo, higher platelet counts, higher platelet nadirs.

People feel much more comfortable and confident because the last thing we want a patient with cancer to have is a major bleeding event that we know dramatically reduces their survival. It lands them in the hospital. It slows down everything. If they survive the event it’s hard to get them back on good therapy, right? So this is, I think, an element of supportive care in cancer that has been somewhat forgotten about, relatively speaking, compared with other cytopenias that we are much more easily — we can much more easily manage.

Platelet transfusions are — they last for a few days. They’re a scarce resource. They’re not a good solution for chemotherapy-induced thrombocytopenia, but thrombopoietin receptor agonists appear to be quite a good solution for it.

DR LOVE: This concludes our program. Special thanks to Dr Al-Samkari, and thank you for listening. This is Dr Neil Love for “What Happened at ASH 2025? ITP Edition.”