Alice Ma, MD, discusses Acquired Hemophilia and Hemophilia, explains ITP, and also provides an update on Von Willebrand Disease.
Back to Symposium Page »
It is now my pleasure to introduce Dr Alice Ma. Course director for the hematology block in the medical school and fellowship director for the hematology oncology program at the University of North Carolina School of Medicine, who will speak on the most relevant clinical bleeding developments in the last 12 months. Dr. Martin is a good friend of this conference who is participating our conference many times and has always enthusiastically received. Please welcome Dr Alice Ma. If you have questions you would like to have her address, please use the ask a question chat function to ask your questions during the presentation. Questions will be addressed during the panel session. Hello. It's a pleasure to be back virtually in La Hoya, although I'd prefer to be, uh, in La Hoya in real life. And maybe next year we'll be able to meet again. I'm Alice Ma, and I'm going to be talking today for an update in bleeding disorders. I have some disclosures, which are that I have received honoraria and a research grant from Takeda for speaking and doing research on acquired haemophilia, and I will try to point out where that plays into this, uh, where this plays into this presentation as an outline I'd like to speak about acquired hemophilia, Um, a little bit about I t. P um, a little update, which is not a good thing in one, well, a brand disease. And if there's time a little bit about hemophilia, I'd like to start with a case. A 78 year old man with coronary artery disease, insulin dependent diabetes, hypertension and emphysema presented with gross human urea and an elevated A PTT. At 78 seconds, the patient was found to have acquired hemophilia A and was found to have a factor. Eight level of 1% with the Bethesda tighter, quite elevated. At 104 the patient was treated with recombinant porcine factor eight for six days with excellent bleed resolution, according to the U. N C Protocol, which I'll be presented shortly. And our protocol uses less recombinant porcine eight than the current package insert recommends. We also started immuno suppression with rituximab. So here is our protocol, which we have just published in blood advances. Instead of the 200 units per kilo in the package insert, we start with half that dose as a load we start with 100 units per kilo and then we go ahead and we get a an immediate recovery somewhere between 10 and 15 minutes after that dose and then we depending on the level that is achieved, we go ahead and give a second dose. So if all is well and the patient is at goal somewhere around 100% factor eight activity, we go ahead and we give a second dose at four hours of 50 units per kilo. But before that, we will draw a trough at four hours. We don't wait for the trough, but we continue dozing by the target trough. So given the recovery at 100% and a subsequent dose of 50 units per kilo will dose so that we achieve a target trough of between 30 to 50% or a little higher for life threatening or severe bleeding. If there is no response and that's the box down at the bottom where we get zero recovery, then we'll move and say recumbent porcine eight didn't work, and please, at that point, consider using a bypassing agent. If the level is less than 100% maybe 40 or 50% will then go ahead and consider giving a repeat dose of 100 units per kilo. If the dose is significantly higher than 100% then we'll draw trough levels every 6 to 8 hours and then continue dozing by the target trough Again. We've published this just recently. This, uh, schema uses significantly less recumbent poor sign eight and um leads to excellent bleed resolution. So this patient did well, but subsequently his human urea Rickard. Within the next two weeks, he also had developed a left forearm hematoma. At that point, his repeat Bethesda tighter, was lower. At 68 he had gotten a couple of doses of rituximab by this point and he had not gone on to develop a poor sign factory inhibitor. He was again treated with recombinant porcine factor eight. While he was in the hospital. He completed his, um, his 3rd and 4th doses of rituximab. And after insurance approval was achieved, we went ahead and started prophylaxis with Mrs a mob and no further episodes of human urea occurred. So I'd like to talk about this new agent and this is a mob. This is a by specific antibody, which binds to factor nine a and factor 10 and thus mimics the action of activated factor. Eight. It's approved for use in patients with hemophilia A with or without inhibitors to factor eight, and it's been approved to give sub Q once weekly for a load 3 mg per kilogram weekly for four weeks and then 1.5 mg per kilogram per week. Um, although it can be spaced out so that you can double the dose and give it every two weeks or quadruple the dose and give it every four weeks. What's really interesting is the indication is for patients with hemophilia A. It doesn't specifically say congenital hemophilia a and, in the past year or so a number of case reports. And then, in this, um, article a case series of patients with acquired haemophilia being successfully treated with Mrs um eb have started to appear. Yeah, so this article by Dr Noble presents 12 patients with acquired him affiliate from the University of Vienna. These were newly diagnosed patients. Um, most of them had severe bleeding. Some had surgeries, muscle hematomas. These were an older group of patients with significant comorbidities as our scene with the typical patients with acquired haemophilia. A. These patients all were diagnosed with a factor. Eight inhibitor of about 22 ranging between nine and 80. The factor eight level was less than 1%. Usually, although the high was 1.5% they all received him a static treatment. The eight, who had severe bleeding, were treated with bypassing agents. And then the treatment was assessed by an independent board of coagulation physicians who were well acquainted with the treatment of acquired hemophilia. A. And so the conclusion in these patients from either insufficient response adverse event after bypassing therapy reasons that they couldn't get approved him a static therapy, Um, some patients with very high inhibitor typewriters, some of them having surgery. The conclusion was that conventional acquired haemophilia a therapy in Europe which usually consists of bypassing agents and then immuno suppression with corticosteroids plus minus cyclophosphamide, Um, they this board decided that this conventional therapy was going to be associated with a high rate of complications, and that, perhaps, and this is a mob plus reduced intensity. Immuno suppression with rituximab could be a better option, and that led to some shared decision making between the physicians and patients. And the decision to go ahead and use em misses a mob plus single agent Rituximab. So these patients were treated if they were on a PCC, they stopped for at least 48 hours because you cannot use a PCC with Mrs a mob safely. Um, and so these patients were subsequently switched to recumbent seven a in those who are having ongoing bleeding. And then they got their first dose of Mrs A mob. And if they needed, um, subsequent bypassing therapy, they got recombinant seven a at a lower dose. Now, in order to keep the total dose of cynicism AB down, they gave weekly, eh, Mrs um ab for another two or three additional doses. So a total of three or four weekly doses and then they dose reduced and then gave that in intervals up to four weeks, so significantly longer, um, interval, then usually would be given to a congenital patient. And then they used monitoring, which we don't typically do in the US they measured a chroma genic factor eight using human re agents. And when that um, level is exceeded 10% they thought that that would represent an approximate mysticism and plasma concentration of 20 mics per mil and 10 patients. They started immuno suppression with a little course of steroids. Some patients, um, uh, didn't get corticosteroids. Everyone got rituximab. And then So how do we monitor? And how was Mrs um have monitored? Well, it turns out when patients are ah, nemeses, um ab the normal way we check out PTT and a factor eight s a using a one stage PTT. These are absolutely not reliable. And so the PTT's get really shortened. And the factor eight essays look like they're usually over 400%. And that is absolutely not what's going on biologically. So in order to monitor and this is a mob, you have to use a chroma, Jenna CASS A again, If you use human re agents with his chroma genic essay, it might give you some idea of the effect of the and this is a mob. And if you use a chroma genic ass A with bovine re agents that will pick up the patient's own endogenous factor eight or any exogenous factor eight that might be given, um, therapeutically, it will not reliably pick up porcine factor. Eight. Mhm. So the initial him a static therapy was started, usually within a day after the initial bleeding event, Um, and three patients were initially treated with a PCC and then switched to seven A. Because of an either because of an insufficient response or an adverse effect. Seven patients got up front therapy with Rick Competent seven a. The first dose of cynicism EB was given pretty close to after the start of the initial bypassing therapy, and it turns out that a median of five doses of EMI were given the last dose after a median of 31 days. And so this is not very much. Mrs um, Eb One patient ended up getting repetitive doses of seven A because she needed little surgeries to close her abdominal wound. What's really cool is that even in patients with severe bleeding or surgical wounds, a clinically impressive improvement of bleeding was observed within three days, um, of start of empiricism eb. One patient had that mild bleeding associated with the surgeries as we mentioned before, but also in the five patients who had really failed bypassing therapy. The bleeding stopped within the first four days, they got no new bleeds and no breakthrough bleeding events were observed after day two, and so even low dose cynicism ab, um, seemed to protect from bleeding in patients with acquired haemophilia. Um, this just shows the graph of the factor eight activity measured with the bovine re agents. And what you'll see is that, um, the levels are all coming up after immuno suppression, although some patients take, um a while to maybe even 200 days to get their levels above 50%. And so during that time, we hope that they are protected with the m s is a mob. There were some adverse events that occurred. The 61 year old guy with chronic inflammatory bowel disease ended up getting a bowel perf and really died. Several, um um, days after this whole thing started, immuno suppression was otherwise pretty good. Um, one patient got a stroke on M s. Is a mob during co medication with this seven A. And then five days after, eh? Mrs. Um ab An older man developed an end steamy after six days on a PCC therapy again. Usually we try very hard not to give a PCC with with Mrs A mob. And so, in conclusion, um, which patients with acquired hemophilia should be considered for M s is a mob and Rita CSA mob treatment. And the answer is the older, more frail patients who have contra indications to bypassing therapy. Those with a high inhibitor tighter who are going to take a longer time to resolve and those who've had multiple admissions. We're going to have a paper coming out showing that you can reduce the number of admissions if you start using M s is a mob. There are some other considerations again you do not want to use. And this is a mob with a PCC. You need special monitoring the chroma genic factor eight essays with bovine re agents in order to detect when the patient is entering a remission. Once you use M s is a mob the use of recombinant porcine factor. It is more difficult since the levels of porcine factor eight won't be able to be accurately measured. There may be insurance issues, but we have not had any in the four or five patients we've treated at UNC and then we really don't know how to optimally treat breakthrough bleeds or surgeries other than to say, um, that recombinant seven A seems to be a little safer than a PCC. With that, I'm going to move to the next case. And so the next case is a 24 year old man who has a history of chronic variable immunoglobulin deficiency and childhood I. T. P. He has been maintained on L Trumbull peg 75 mg daily for the past seven years, and he came to me on l Tremble Peg his platelet count vary somewhere between 10 and 60,000. Um, and my fellow was initially pretty perplexed by this, but it turns out it's because he's variably well, actually non adherent to the L Trumbull peg diet. His favorite foods are milk, cheese and ice cream, and, um, he travels. Or he used to travel for work and really lived on Oreo Mcflurry. Um, and you can talk about how much dairy is in that, but it's probably not the best thing to wash down your l tremble peg with this. He had previously failed therapy with Rituximab than Christian and splenectomy. So based on a Phase three randomized study of Abba Trumbull peg that was published in the British Journal of British Journal of Hematology. Um uh, described here this was a, um, screening followed by, uh, comparison with placebo. Random ization. Um dose titrate nation reduce reduction of the I t p concomitant medications and then maintenance patients were then subsequently eligible to enroll in the extension phase. Um, 100 patients were entered into study. 49 were randomized, um, and treated 32 with a view Trumbull peg and 17 with placebo. I should mention avid Trumbull. Peg is an oral small molecule, uh, similar to l Trumbo Peg, but with significantly less drug, drug and drug food interactions and, um um, somewhat lower. Um uh, a es experienced by patients. As you can see, the dark line above is compared to the lighter line, which is placebo. More patients treated with active drug were able to maintain a good platelet count, and this extended into the extension phase. And based on this and as well as the fact that a s were all comparable with or lower than patients treated with placebo, the FDA approved ABBA Trumbull peg for treatment of patients with chronic I t P in June of 2019. The dose tea tray Shen is a little interesting. You dose titrate every couple of weeks. You start at 20 mg once a day, and you either go down or up, depending on the platelet count. This is out of the package insert. Um and this is now a nice adjunct, uh, to patients with chronic I t. P. Especially in the era of covid right now where we are trying really very hard not to give rituximab which will block the effect of any vaccines such as a covid vaccine for a period of about six months. So we're trying really hard to use, um, from the poet in receptor agonists and I v i g if we can to treat I tp reserving more stronger immuno suppression and potentially rituximab until after our patients have been vaccinated. I want to talk briefly and say that there have been some ash and I s t h n h f and World Federation of Hemophilia guidelines for von Will grins just published in the last month, there are 21 in diagnosis and one for treatment. Um, just to highlight a couple of things from the diagnostic um, guidelines. And there is a The take home message is that the guidelines are using a lot more emphasis on genetic testing. Um, specifically, um, when one is trying to diagnose either type to be von will brands or type to N von will bronze, they move genetic testing ahead of the functional testing that we are usually used to. And then I'm moving to case three. So this is something that a number of us are seeing around the country and in fact, around the world. So I have a 36 year old woman with type one Von Will bronze disease. She is responsive to Desmond present, and she needs to have a tooth pulled now. Normally, she would go to the dentist. She would take her Stein eight nasal spray as well as tronic stomach acid before her procedure. And Styx Mate is the brand name for 100 and 50 mg per micrograms per mil of Desmond present. The problem is that Styx Mate Nasal spray has been on manufacturer's recall due to, um, an inaccurate concentration of Desmond present in the vial. It's actually too concentrated and therefore causes too many es. It is not expected to be available until at least 2022. There is no generic, and there is no alternative. UH, Desmond Press and nasal spray of a similar concentration. So what are we telling all of our patients who usually takes time? Eight. To do so? Options to replace intra nasal Desmond present include one Desmond present given peremptorily so we can give. And the dose of Desmond Crescent is usually 0.3 micrograms per kilogram. Given Ivy at the Infusion center. Or, um, for our patients who are a little more medically savvy, those who might be nurses or health care workers or no nurses or doctors. Um, we have actually prescribed um, vials of G D A, V P and syringes. Um, and patients are taught how to draw up Desmond present um, and then give it in a series of sub Q administrations no more than one cc per injection. It's really dilute. And so patients end up giving themselves a series of sub Q administrations, um, prior to procedures or for treatment of bleeds. Additionally, patients may end up having to take von will brand factor concentrate, and this can either be done at an infusion center prior to procedures, um, or by home nursing or patients may learn how may have to learn how to do self administration. As you can imagine, all of this is a lot more bother. Um, a lot more painful than using intra nasal G d a v p. And we cannot wait. Um, we have several hundreds of patients at our center who are having to do all of this. Um, so we can't wait until the international d d a v p is available again. The last thing I want to talk about is gene therapy for hemophilia. Um, so hemophilia A was thought to be the first, um uh, hemophilia. That was going to be, uh, that was going to have a gene therapy product. Villach to Jean Rocks apart. Pelvic um, which is the product that was developed by BioMarin, uh, went to the F. D A and the F. D. A approval was denied, or at least delayed. The FDA wanted to see more data, given that there were falling factor eight levels seen in the 14 patients treated in the phase 1 to 2 trial. They asked to see more advanced data from the phase three trial patients. Um, and so it is not currently FDA approved, Even though, um, I think biomarin really thought they were going to get FDA approval. So hemophilia is currently on the back burner until we can get some more data. Hemophilia B. There are a number of clinical trials with promising data. Um, for a number of products, Um, and those are all getting themselves lined up potentially to go to the FDA. Uh, so really watch this space because who gets eligible and how you end up deciding when patients should be treated with gene therapy? What are what can who are the optimal candidates for gene therapy? These are all going to be targets of a number of best practices and and, uh, expert opinions, um, coming up. So there will be a number of trials that will start to be getting reported, including one that was just reported at the plenary session at Ash. Um, so again, sometime in the next year or two gene therapies are expected to roll out for hemophilia, which will provide our patients with a number of new, um, options for therapy. With that, I'd like to close and thank you for your attention
