Listen to Hanny Al-Samkari, MD, discuss key findings from select studies in nonmalignant hematologic disorders presented at the 2025 ASH Annual Meeting, including perspectives on the clinical implications of the data for patients with ITP and vWD.
In this episode, Hanny Al-Samkari, MD, gives his thoughts on 5 key presentations from ASH 2025, and provides perspectives on the clinical implications of these data for patients with nonmalignant hematologic disorders such as ITP and vWD, including:
Presenter:
Hanny Al-Samkari, MD
The Peggy S. Blitz Endowed Chair in Hematology/Oncology
Co-Director, Hereditary Hemorrhagic Telangiectasia Center of Excellence
Massachusetts General Hospital
Associate Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Content based on an online CME program supported by educational grants from AstraZeneca, BeOne Medicines, Genentech, Geron Corporation, Incyte, Johnson & Johnson, Lilly, and Novartis Pharmaceuticals Corporation.
Link to full program:
https://bit.ly/48Ye45N
One of the late breaking abstracts at ASH this year, which I had the pleasure of presenting myself was the VAYHIT2 study, which was a randomized double-blind Phase 3 trial of inolimomab plus eltrombopag versus placebo plus eltrombopag and patients with primary immune thrombocytopenia, or ITP, who failed first-line corticosteroid treatment.
What is inolimomab? Inolimomab is a novel monoclonal antibody directed against the BAFF receptor. The B cell activating factor receptor. BAFF is critically important. It is a cytokine that is critically important in the maturation, differentiation, and survival of B cells.
That includes the autoreactive B cells that drive ITP. This drug is being evaluated in a number of different autoimmune diseases. They have already published some positive findings in Sjogren's syndrome. There is trials going on in lupus. It is being evaluated in autoimmune cytopenias in particular ITP in the VAYHIT1, VAYHIT2, and VAYHIT3 studies, as well as autoimmune hemolytic anemia, and the HIA study VAYHIT.
VAYHIT2 is a pivotal phase III study that asks the question, if we add this potent monoclonal antibody ianalumab to standard of care eltrombopag in people who have just failed their first-line corticosteroids, can we give patients a nice stable, durable duration off of any therapy? Can we do that safely? If we intervene early before the disease becomes very immunologically complex, and we know that ITP becomes more complex from an immunologic standpoint, the longer people have it, people develop oligoclonal T cell clones, for example, that drive refractoriness.
If we give this very potent drug early, can we modify the course of the disease? In some fraction of patients? Can we defang ITP? Can we take people who would otherwise have chronic relapsing disease course, where they have crashes over time, very typical course of ITP. Can we turn that into a mild ITP? Which is a lab abnormality of mildly reduced platelets without any significant crashes or at least much less likelihood of having a significant crash.
This study looked at all of those things. The key findings of the study were that, yes, adding inolimomab to standard of care, eltrombopag, whether it is a high-dose or low-dose of inolimomab, did prolong the time to treatment failure in people with ITP. This study used a novel endpoint called Time to Treatment Failure, or TTF, which was the time from randomization until the first occurrence of any of the following. Platelet counts less than 30,000. Use of rescue therapy beyond eight weeks of randomization.
Start of new ITP therapy at any time and inability to taper or discontinue eltrombopag, or death. All of the patients in this study were treated with eltrombopag, but they were required to taper off eltrombopag by the end of month six. Patients received four infusions of study drug either inolimomab 9 mg/kg, 3 mg/kg higher versus lower dose, or placebo during the first four months. These are given once every four weeks.
The study showed that the time to treatment failure was both statistically significantly and clinically significantly prolonged in people receiving either high or low-dose inolimomab versus placebo. The drug did this without any significant safety signals. The most common treatment-related adverse event was neutropenia, which was very transient, lasting literally days to perhaps a week or two.
This was short-duration neutropenia. Most importantly, the fact that this drug is immunosuppressive in and of itself did not lead to any increase in the rate or severity of infections during the treatment period or the post-treatment period. This study is following patients for a long time. It is actually following patients for over three years from the time the last patient was randomized. The median follow-up at this primary analysis was between 11 and 13 months per group, so pretty good duration of follow-up now, but the study will continue to follow patients.
Of the goals of the study, giving people a nice duration off therapy without the need for chronic controller therapy. That goal was met. Doing it safely, that goal was met. The third goal, which would be really groundbreaking in ITP because we have no disease-modifying therapies, would be true disease modification. We are going to find out how disease-modifying this drug really is over that long duration of follow-up.
Inolimomab is being evaluated in ITP in a number of different clinical trials. This is VAYHIT2. VAYHIT1 is a similar study, but looking at patients in the first-line, in combination with corticosteroids, rather than in the second-line in combination with eltrombopag. Truly newly diagnosed patients that have just been treated in VAYHIT1. In VAYHIi3, which is already reported out, is looking at inolimomab by itself or some patients could enter that study with chronic low-dose steroid or low-dose or a stable dose of TPO-RA.
VAYHIT3, that was a study that already read out. This was in relapsed refractory patients, third line and beyond. It was a phase II study, so a non-randomized study, and that study showed that the drug was also safe and effective in that population of patients. Actually, one of the other abstracts presented at ASH this year was a follow-on analysis from the VAYHIT3 study. This was presented by Dr. Phil Choi. This study was really interesting in that I showed the results of many of the secondary endpoints and subgroup analyses.
There was not a specific population of patients that clearly lacked response to inolimomab in this study and subgroup analyses. The time to confirmed response in patients who achieved a confirmed response to inolimomab in this study was a few weeks. Rates of bleeding events and their severity improved in patients over time over additional follow-up.
The B cell depletion induced by inolimomab in the study was rapid and profound and similar to what was seen in VAYHIT2. The level of IgG dropping was actually very minimal, which is very reassuring when it comes to use of an immunosuppressive drug and maintaining your responses to various vaccines that the patient has already received. There were no severe infections observed in the VAYHIT3 study, except for a grade 3 event of clostridium difficile infection reported as not related to inolimomab by the investigator.
This gives additional supportive evidence for this drug in ITP. If VAYHIT1 is similarly successful positive study, then we may be seeing inolimomab added to our ITP therapeutic armamentarium and potentially in ways that disrupt the treatment paradigm. Addition to corticosteroids in the first line or addition to eltrombopag in the second line.
Now I am going to talk about another abstract, also in ITP, but in a distinct subtype of ITP.
This is immune checkpoint inhibitor-induced ITP or ICI ITP. This is a very problematic entity that we see in patients with cancer receiving immune checkpoint inhibitors, which are obviously a mainstay of cancer therapy now. There are multiple different classes CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, LAG-3 inhibitors, and there are now 12 immune checkpoint inhibitors approved in the US for treatment of over 20 cancer types. One of the things we know happens with these drugs is immune-related adverse events or IRAEs.
Immune-related adverse events, while they normally target skin, GI tract, and endocrine glands, they certainly can target blood cells. We can see autoimmune hemolytic anemia. We can see ITP. We can see autoimmune neutropenia, aplastic anemia, pure red cell aplasia. These are all potentially possible, but we do not have very much data, at least before this study. We did not really know what the rate of ICI ITP was in all patients receiving immune checkpoint inhibitors.
We did not know much about how it responded to therapy. The prior data was in very small groups of patients, smaller case series. This was an observational study conducted over seven different large academic centers, including many hospitals. It found that the incidence of ICI ITP was 0.25% of all patients receiving immune checkpoint blockade, or one in 400 patients. Not hugely common, but also not all that vanishingly rare.
Three-quarters of patients who developed ICI ITP did recover from the ICI ITP, usually after treatment with glucocorticoids, IVIg, and/or thrombopoietin receptor agonists with similar response rates. Despite the choice of therapeutic, around 60% response for any of these therapeutics. This study included over 200 patients with ICI ITP, which is far greater than any of the other studies evaluated before.
People ask, can you rechallenge a patient with an immune checkpoint inhibitor after they developed ICI ITP? You can. Doing so results in recurrent ICI ITP in about 30% of patients in this study. Of those patients that were rechallenged, again, about three-quarters recovered after a second round of treatment, and ICI, ITP, and its severity were independently associated with a higher risk of death.
The worse your ICI ITP, the higher your likelihood of death. This was an independent predictor in evaluation in a multivariable analysis. This is important for oncologists and hematologists who are referred patients with ICI ITP.
Now I am happy to talk about a study of a novel protein S antibody in patients with von Willebrand disease. This drug is called VGA039. This is a subcutaneous every four-week maintenance drug similar to emicizumab in hemophilia given subcutaneously on an every so many weeks basis. This was a phase I, II multidose study of this anti-protein S antibody and von Willebrand disease.
Why might a protein S inhibitor be good in von Willebrand disease? It enhances thrombin generation to restore hemostasis in patients that have a deficiency of a critical coagulation factor, von Willebrand factor. This drug, in theory, could be effective in multiple different bleeding disorders.
The first bleeding disorder that is being evaluated in substantial effort is von Willebrand disease, and the VIVID-1 and VIVID-2 studies. VIVID-1 was healthy volunteers, and VIVID-2 was patients with von Willebrand disease, all types represented. Then VIVID-3 was the study that was presented at ASH. This was an open-label phase I, II study of multiple doses of subcutaneous VGA039.
This study enrolled 16 participants, of whom eight had completed dosing and were reported on efficacy-wise, and eight were ongoing, and so safety was reported in all patients. Efficacy was reported in the patients that had completed dosing. No patients had withdrawn on therapy. There were no thromboembolic events, no injection site reactions, no concerns about increased D-dimer. No concerns about any really significant thromboembolic predisposition from this early study.
With rather substantial improvements in the annualized bleeding rates after treatment with VGA039, like 75%, in some patients really substantial improvements, including in those that were previously receiving recombinant von Willebrand factor as prophylaxis given via intravenous infusion once to twice a week.
This is a subcutaneous drug given once every four months. This drug is promising in von Willebrand disease. The phase III study of this drug in VWD is currently enrolling. We will look forward to seeing the final results from this study VIVID-3 the phase I, II, and hopefully this will provide a nice prophylactic maintenance option for people with von Willebrand disease.
Lastly, I am going to talk about one of the plenary abstracts. It was called deciphering the dilemma intravenous iron use in iron deficiency during acute infections. This is presented by Dr. Sohail. One of the things that many of us recognize is that people have anxiety about giving intravenous iron in hospitalized people with infections because they are worried that the iron, "feeds the infection or feeds the bacteria." Many bacteria are siderophilic.
They like situations of high iron. This has really influenced hospital policies and influenced providers to not give intravenous iron. This study that was presented as one of the plenaries, was a very large study using the TriNetX Research Network, a global federated EHR network with de-identified data from 275 million patients across the world, updated every two to four weeks, providing aggregate, real-time counts and built-in analytics.
This was a more sophisticated, large database study effectively. The results were relatively striking. Basically, it did not matter what the type of infection was. People receiving IV iron had better survival than people not receiving IV iron. They had better survival. They had lower rates of requiring red cell transfusion. MRSA bacteremia, pneumonia, urinary tract infection, colitis, cellulitis, it was many different infection types. It did not really matter.
The hemoglobin improved. Not a surprise. The amount of red cell transfusion required went down, but survival improved. I have never had any personal concerns about using intravenous iron. I have always called it urban legend to use intravenous iron in patients with active infections. Obviously, blood contains plenty of iron, and giving people blood transfusions is also immunosuppressive.
I would much rather give people IV iron, but it is really nice to have a big study and a study presented as a plenary at ASH that reinforces this, and that gives us good data to say, "No, in fact, it is totally fine to use intravenous iron. In fact, it may be beneficial to use intravenous iron to treat anemia and iron deficiency anemia in these patients."