Chapters Transcript Video Thrombosis and Hemostasis I'm really happy to be here today to talk a little bit over the next half hour about some highlights from thrombosis and human stasis abstracts that were presented during the ash annual meeting last month. And just to start off, I have no disclosures related to any of these presentations that were presented. And today we're going to cover a couple of broad areas um firstly reviewing the use of tran exam IQ acid to prevent leading in patients undergoing treatment for human biological malignancies, followed by reviewing the addition of micro fennel. It's two cortical steroids in the first line therapy for ITP and then go through the use of electronic coaching. Does apart Avec for the treatment of hemophilia B. And then I have a series of quick summaries of some of the other. He highlights that uh I think many will find interesting and I'm gonna start off by going through this was a plenary presentation. Uh the a tree trial. Looking at tran examined prophylaxis on bleeding outcomes in patients with the methodological lignin. See And so despite uh platelet transfusion therapy prophylaxis for severe thrombosis, Dapena and patients undergoing treatment there is still significant bleeding in patients of anywhere from 40 to 70%. And the a tree trial was designed to evaluate the effects of prophylactic tran exam IQ acid as an adjunct to platelet transfusion therapy and the patient population. Those receiving treatment for human to logic malignancy, the outcomes. They were focused on the bleeding and transfusion requirements. And this is a multi uh multi center double blind placebo controlled R. R. C. T. And the basis for this. Um In the plenary introduction that lisa Baumann gave was that we know the train exam IQ acid has a significant effect on reducing bleeding complications in a variety of scenarios. We know that it reduces death, do postpartum hemorrhage and all cause mortality due to bleeding and trauma patients. It has been evaluated and is used quite extensively in orthopedic surgery, particularly around joint replacement. But the benefits of training Islamic acid in patients with thrown beside opinion and huma to logic, malignancy was unknown. The groups were stratified into chemotherapy and auto versus alot stem cell transplant. And these were patients that were undergoing treatment expected to have a platelet count less than 10,000 for at least five days. Patients were excluded if they had a history of VT need for concurrent anti coagulation, which would necessitate a higher platelet transfusion threshold. Patients with a PML, given the severe kogel apathy that is often seen, um, and patients with severe urine near dialysis, The treatments were tran examine Cassidy was given either intravenously as one g or 1.3 g orally versus a placebo every eight hours. And the study drug was started. Once the platelet count dropped below 30,000, It was continued for at least 30 days or until Platelet Recovery. Or if any of these other uh events occurred. And the standard platelet transfusion practices for prophylaxis greater than or less uh less than or equal to 10,000 was used. patients were monitored for 30 days after activation. Um And bleeding assessment was on the W. H. O. Scale. So as was mentioned previously many patients without um many patients were just receiving prophylaxis. Experience grade two or higher bleeding. The demographics the patients, the mean age was in the 50s. Um a slightly more predominance towards male patients and um pretty evenly stratified across different therapeutic groups. And when we look at the time to first W. H. O. Leading um event of two or higher or death, this is very easy to see that there is no significant difference in this uh in this primary outcome. When you look at this it was 48.8% in the placebo group and 45% in the TX a group with an odds ratio crossing one very similar outcomes. Even looking at the stratified groups. When you look at three am biotic events, there seemed to be a slightly higher rate of thrombosis in the train exam it acid group particularly around line inclusions. Um And so we know that lines are particularly difficult um object to work around in terms of prophylaxis and thrombosis. And so it seems that that was probably what was driving this higher rate that was seen when we looked at non catheter related events. It was very similar following the safety outcomes in the long term follow up. Um The overall robotic events um through 120 days were very low. V. O. D. With within 30 days of the last dose. Also very low and all cause mortality was equally balanced. And so in conclusions Dr Gershman who presented these data uh noted that training Islamic acid as prophylaxis. In addition to routine platelet transfusion did not decrease the rates of W. H. O. Bleeding. Um In severely thrown aside Penick patients. There were additional data presented during her presentation that um platelet and red cell transfusions did not differ between the two arms and the increased incidents of central line inclusion. However this was only looking at use of train exam it acid in the prophylactic setting. Um And it is still believed that T. X. A. May have a role in the treatment of active bleeding or may have benefit in patients who are refractory to platelet transfusion. Um In spite of ongoing efforts to H. L. A. Match for instance and procedure prophylaxis. I think this was an interesting presentation to put into the plenary given that it's essentially a negative study. But it was an important question. Um And I think these data were very important to present broadly because it has such wide ranging implications given the amount of bleeding. And so it will be interesting to see if there are further groups that may benefit from this. I'm going to move on to two talks that were presented during the late breaking abstract session. Um Late breaking abstract number two was a multi center randomized trial of adding michael Fennelly to first line corticosteroid therapy. And this was called the flight trial I. T. P. As we all know is a rare autoimmune condition social with bleeding risk and fatigue is a very common complaint in patients that correlates uh platelet count and first line therapy across many of the guidelines is the use of high dose corticosteroids. Um It can be institutions specific as to whether predniSONE or dexamethasone is preferred. I will say that our practice here is to uh use decks and methadone is a pulse fashion um due to similar rates of efficacy but lower rates of side effects is compared to long a month of predniSONE for instance. But we still have frequent side effects and there are variable response rates, high relapse rates And when you look at long term remission from cortical steroid alone it really is only about 20% in the U. K. Michael Fennell. It is often used as second line treatment. And so retrospective data and I tP suggested efficacy of 50 to 80% in this in this role with fairly good tolerable. It ep but responses could be delayed. And so the flight trial was designed to test this hypothesis about combining mmF with cortical steroid and first line therapy. And so this was also a multi center open label randomized controlled trial. Enrolling I. TP patients over the age of 16 with a platelet count. Meeting ash guidelines of less than 30,000 for initiation of treatment, patients were randomized 1 to 1 corticosteroid or corticosteroid with MMF With the primary outcome time from randomization to treatment failure um defined as a platelet count less than 30,000 and clinical need to move to second line treatment. There were secondary outcomes including side effects and patient reported outcomes across one year. And using the SF 36 and several fact questionnaires. There were 100 and 20 patients with a mean follow up of 18 months. Um about 50%. Men with a mean age of 54 the mean baseline platelet count was 7000 and so, as you can see here, um pretty evenly distributed amongst the two treatment art when you look at the primary outcome, dr Bradbury who was presenting this noted significantly fewer treatment failures in the patients assigned to MMF. And uh with MMF added, there were significantly more patients who responded overall and considered to be less refractory in terms of treatment. Side effects similar rates between the two groups, particularly around um the ones that are commonly associated with these therapies, including weight gain, difficulty sleeping, um mood changes, um steroid induced diabetes and low rates of hypertension is associated. Dr Bradbury noticed, noted that this was the first randomized controlled trial using MMF to treat I. TP with good efficacy and tolerable ITty. And there were a number of patients that were elderly, uh defined as over the age of 70 and so um about 30% over the age of 70 in about 15% over 75. So a population that we worry about use of many of these therapies in um the major benefits seem to also be associated with having the risk of refractory or relapsed I. T. P. Um And that considering mmf as first line therapy with the corticosteroid. Um for some patients something that I don't have here but was mentioned is that they're actually seem to be worse, slightly worse quality of life outcomes reported in patients getting mmF. And so that is part of the reason why um it needs to be considered as part of the overall therapies and may not make it as a standard overall first line for most patients. Mhm. The second thrombosis human stasis talk um presented in the late breaking abstracts was very exciting. Data from the phase three. Hope be trial looking at a training coaching does apart AVEC um which is an adam associated virus padua factor nine variant. In patients with moderate to severe hemophilia B. And so um this therapy is an investigational gene therapy. The Padua variant is very interesting um in that uh it's a hereditary factor nine variant um that is associated with much higher factor nine activity than just the circulating antigen. Um And what this is being utilized for in this effect um is that you with many of the gene therapy trials in human ophelia, you have difficulty achieving a high enough dose level with the vector to change significantly change factor levels. Fortunately, most patients with hemophilia A. And B. You only need to move them From less than 1% up to five or 10% to significantly reduce bleeding. You don't need to normalize them. And so while with factor eight you're using very high dose amounts to get above 10%. Very small doses are needed with this variant because it will generate a much higher factor nine activity. Okay. Um and that was seen in the phase to be study that it provided a mean factor nine activity at 41%, which is phenomenal and would be dramatically changed the lives of patients who get this therapy. And then although most gene therapy trials exclude patients with preexisting neutralizing antibodies to the camp said um some of the earlier studies suggested that um this may not prevent successful transaction with this product. And so the hope the study was looking at male patients 18 years or older with a factor nine activity of 2% or less. Um and those essentially requiring continuous prophylaxis for at least two months suggesting that they would have the greatest benefit from increasing their levels and be able to potentially come off of therapy. Um patients that had Factor nine inhibitors um active hepatitis B or C infection or HIV that was not well controlled where exclusion criteria, there was no prophylactic immuno suppression used. And after the screening visit there was a lead in phase a dozing visit and then post treatment follow up. The primary endpoints was looking at factor nine activity at 26 weeks after dozing as well as 52 weeks. And secondary endpoints looking at rates of bleeding. Um Factor nine product consumption and antibody tigers and safety. 75 patients were screened with 67 going into the lead in Phase 13, discontinued prior to dosing due to concomitant comorbidities, other medications that were needed. Um and some patients actually withdrew due to the COVID pandemic. The 54 patients received the therapy, The the mean age of 41. Um and as you can see, most patients actually had a factor nine level of less than 1%. So a severe category with moderately severe between one and 2% Nearly 50% of these patients had prior hepatitis C infection, which is actually very common uh in the hemophilia population given the use of blood products prior to adequate screening. Um And so that's always a concern for comorbidities. E um if these patients have significant fibrosis or cirrhosis, a number of patients had detectable neutralizing antibodies at baseline for the the primary outcome. Looking at over the overview of factor nine activity. Um at 26 weeks, you can see that there was a significant rise in these patients and the change from baseline was about 36%. Again, when I talked about if we can move one of these patients up above 5 to 10% that will change them essentially from severe to mild haemophilia, that they may not need prophylaxis and significantly reduce bleeding events. And when you look at the bleeds in the 1st 2026 weeks in the lead in phase, prior to dosing their 123 leads, 107 meeting treatment um reduced to 21 leads 10 needing treatment um uh in the 1st 26 weeks And there was a significant number of patients in the lead in phase of 30%, but 72% having absolutely no bleeds after they had their dose. There were a number of treatment related adverse events. Um In the post treatment period, 53 patients had 324 adverse events. Um The majority of the treatment related adverse events were considered mild Nine patients required steroid treatment for trans emanates elevations. All of them are able to discontinue steroids prior to two week 26. Uh with giving steroids we worry about um potentially stopping uh the effectiveness but even those patients were preserved in the mild range of 8-39%. Um one patient discontinued after getting 10% of the dose and the other six patients with infusion reactions successfully completed it. And as dr pipe was presenting this during the late breaking abstracts, um This was the first Phase three study in hemophilia B with the largest gene therapy trial cohort with mean factor nine activity significantly increasing to near normal levels by 26 weeks. Meeting the first co primary endpoint. Um patients were able to discontinue prophylaxis, which is a major benefit for quality of life and for cost associated with hemophilia therapy. Um bleeding was abolished the majority of these patients. Again, even if you're on therapy, if you're having bleeding into joints, you have continued joint damage which leads to long term loss of function. So by stopping bleeding it allows us to minimize ongoing damage. The most common safety finding is trans emanates elevation requiring steroids. Um And this was consistent with the early phase studies and dr pipe noted that they are planning a final analysis at one year to support marketing authorization. What? Over the next 10-15 minutes I'm going to go through. Um some quick summaries of seven different abstracts that were presented that have direct relevance I think for our clinical work. The first one um was this very interesting therapy that's being explored to look at inhibiting contact activation of the contact pathway and device thrombosis issues. And so a. b. 0. 2 3 um was evaluated in end stage renal disease patients receiving hemodialysis phase two. Double blind placebo R. C. T. And this contact activation inhibitors humanized I. G. Four and it binds to factor 11th A. Two domain. So it inhibits factor 11 activation by factor 12 A. And the contact pathway but not by thrombin. So it's it's almost quieting down the process by which factor 11 is activated. It was given as a single dose infusion um and what they saw was that there was no change in the pro thrombin time. The bleeding times that were assessed on these patients. There was a prolonged partial from a plastic time, the PTT. Um and reduced the complexes of thrombin with anti thrombin. So it was it was interesting to see this but most importantly when you look at clotting and the dialyzers units, significant reduction in clotting in the units. Um significant reduction in need for saline flushes which are used frequently to keep these lines open and looking at need for circuit change outs. Um And so the question really comes up is how beneficial will this be, not just in dialysis but looking at many circuits that we commonly worry about thrombosis and uh think about cardiopulmonary bypass uh circuits, patients on ECMO and patients potentially in C. V. V. H. In the unit. The next abstract this is presented by uh dr Brooke Sadler from Washington University. Um genetics of low von will bring factor activity and heavy menstrual bleeding. When we look at heavy menstrual bleeding, this affects 1/3 of adolescent women and heavy menstrual bleeding. Um If you just ask somebody if they have heavy periods, it's very hard to get accurate answers because nobody has a context for what that means. And even asking within a family, Well if there is a hereditary issue, many women only have the context of family members. Um So it's really asking things like do the periods last more than seven days, do you have to wear double products? Have you ever missed school or work because of your menstrual bleeding? Um uh you have to change your product more than every two hours or always make sure that you're getting up in the middle of the night. And when you actually quantify this, it correlates with about 80 mils of blood loss in a cycle. And so a third of adolescents women actually experienced this. But when you look at two thirds of um of uh women who undergo hysterectomy for abnormal uterine bleeding not to do in an atomic defect. Two thirds of them actually have low von will bring factor levels. And so they explored this group between 30 and 50% who had heavy menstrual bleeding and did whole exam sequencing. What they found is that a number of patients had um mutations in bleeding control genes or genes associated with various disorders. 36% had a sequence variation in Van Wilburn factor. Um And then there were also interestingly these rare pathogenic variants with certain anemia related genes um including spear psychosis, vanco knees. And so um further research that's going to come from this is going to try to explore whether or not there's actually some effect that these anemia genes have online will bring factor. We know that now you can't explain all of one will bring factor variation simply by um mutations in the gene itself on the other spectrum of von Wilburn factor. So not having to not having enough. Now we moved to having too much fun will bring factor um due to loss of atoms T. S. 13 activity leading to acquired through robotic from beside the Penick purpura. And so uh in the last 18 to 24 months, the FDA approved capitalism ab for patients with acquired TTP, it's a nano body that inhibits platelet and john Wilburn factor binding um particularly the highest weight multi MERS molecular rate Baltimore's which are the most human statically active. And so what it induces is essentially the equivalent of a of an acquired von Wilburn syndrome that mimics type two um Von will bring disease, but because they have too much fun will bring factor. The attempt is to move them back into balance team of stasis. It is only a bridge therapy. It doesn't address the underlying auto antibody. So that's why you need to use things like riTUXimab and corticosteroids. In addition to the therapeutic plasma exchange, The cost right now is estimated at about $270,000 here in the United States, um for one month of therapy. And that's how it was studied in the trials in this study, Dr. and colleagues at Yale Uh did a cost effectiveness model to evaluate Catholicism and plus standard of care corticosteroids and plasma exchange with riTUXimab. Um to see whether or not capitalism that by reducing length of stays or need for therapies might be cost effective. And when you look at a full 30 day course, what you saw is that the incremental cost effectiveness ratio was $1.5 million life-year quality. And so by standard willingness to pay thresholds. This was not considered cost effective. One of the things that has since come out since the initial trials on which this model was based is that patients who have ready access to Adams. CS 13 testing may be able to stop therapy sooner than 30 days once you know, that their levels are above 10%. And so whether or not it's going to be cost effective in that situation is unknown. Um Subsequent to this study coming out, there was a statement from the United Kingdom's National Health Service that they had negotiated lower prices um for capitalism ab to the point that it made it considered a cost effective therapy and they're modeling so more to be seen about how this affects the pricing. Here in the United States. I can't talk about the robotic microalgae apathy this year without talking about covid 19. Um we know that it's very common for these patients to have thrombosis. These genetic mutations that we know uh in the last 1 to 2 years have learned are associated with complement, needed T. P A T. M. A. And also uh catastrophic anti fossil lipid syndrome with complement mediation. How does this all connected to covid 19? We think that Covid 19 is complement activating. And when they looked at patients who had the most severe forms of covid, they found that in their cohort, many of these patients had pathogenic variants and complement regulatory proteins, interestingly enough, there's some protective miss sense variants um that are known in complement factor B, which actually add extra breaks essentially to complement activation. And these patients that had these did not require the ICU even though they developed covid so more to come on the role of compliment and whether complement inhibiting therapies such as a collision mob um may be beneficial in this population. Um There are trials ongoing right now to look at that. The next several abstracts talk about venous thrombosis, embolism and the cancer population. Um We've done quite a bit of discussion nationally about diversity equity and inclusion and that um I think it's very important, particularly in the cancer VT population. We know that VTS common in cancer patients and general population data actually says the VTS more common in african americans. And so um this group looked at the California cancer registry and also combined with er utilization data and discharged data across the state of California, adjusting for a variety of factors that we know are associated with the t including age, sex, cancer stage types of therapy. And also looked at neighborhood socioeconomic status insurance type and co morbidity. So, a lot of adjustments to these data and what they found is that even when adjusting for all of this, when you look at the 12 month cumulative incidence of DVT and PE, it is much higher in african americans than non hispanic whites. Hispanics and asian pacific Islanders. Um, and so this really does go to show that there are um uh, increased rates in this population. How much of this is biology? How much of this is um structural issues in the health care system and the delivery system um has yet to be really defined. But we know that it is an area that needs special attention. We talk about VT and cancer. We also are starting to increasingly used Vox. We have several trials that have looked at this Hockey CVT cancer in the docks. Even Caravaggio, which came out last March for a picks. Even select is a pilot study for River Rock sedan and Adam V. T. E, also with the pick sedan suggested efficacy and safety. But there was a signal of concern with bleeding in Gi malignancy patients. This makes sense, particularly intra Luminal patients because of the fact that they have um uh disrupted uh and to fill in that is within the G. I. Tract and therefore that the site that the drug is being absorbed, you get much higher tissue concentration. This was a single center retrospective experience with 73 patients and showed that um that uh that dough axe do seem to be fairly well tolerated. Um, but extra Luminal disease, interestingly enough had a much higher rate of bleeding across six months. So we need to really do trials and Gi malignancy patients to figure out the appropriate dose. And the last of the abstracts I'm going to be presenting um is looking at VT and the Koran a score. We know that the corona score can risk stratify patients that might benefit from prophylaxis um particularly in Ash. Last year. The prior year, uh there were two studies presented the amplify Study, um, cassini and avert, sorry, that we're looking at Xarelto and eloquence prophylaxis in high risk patients. Um and what we see here is that you look at many different variables um that are participating in this risk and that the higher your corona score, the higher your risk. However, when we actually look at it um in a multi variable model, the corona score doesn't seem to do much better than just looking at the individual factors. And so um while the corona score is important, I think it needs to be used more widely than it currently is. Um there are probably additional factors other than what we are putting in the corona score that really helped us re stratify. So, in conclusion, um the addition of TX A two standard platelet transfusion thresholds does not reduce the risk of bleeding in patients undergoing therapy for him, malignancy, micro fennel. It may have a role in the addition of cortical to the addition of corticosteroids for first line treatment of ITP but may reduce quality of life. The training coaching does a part of that. The um uh had you a variant therapy um leads to significant increases in factor nine activity in patients with hemophilia. B Contact pathway activation is likely helpful to reduce device thrombosis. Think about von Wilburn factor, low von Wilburn factor in women with heavy menstrual bleeding, Capitalism and probably is not cost effective at 30 days. But we really need to see do shorter courses do it. Covid patients uh that had the most severe disease may have uh germline mutations in complement regulation may benefit from complement inhibition in very select cases, particularly severely ill patients. But try to enroll them in trials and lastly in cancer related V. T. E. When we look at factors associated with thrombosis, there appears to be higher incidents and african americans. Even when adjusting for many other factors that may affect these rates, does max have similar bleeding rates in patients with gi malignancy and the corona score can help risk stratify patients. But it probably is probably not the only set of factors associated with the tea. And with that I will end and take questions. Thank you. All right. Thank you so much. That was fantastic. Um A couple of questions with regard to the I. T. P. Data first. What was the steroid regimen decks versus predniSONE or was it was there an option for either and in what clinical study would you think about adding michael Fennell it? How to how do you factor in other drugs, like for tucks a mob or anti cd 20 and a body therapy? Yeah. So in the trial it was either um so patients could receive either predniSONE or dexamethasone. Um and so, you know, I think my personal preference would be decks and methods own based on the randomized data from prior to this publication. Um The patients I would consider with the addition of micro family at this point. Um Our patients that I'm worried due to potentially other autoimmune disorders may have uh decreased response rates. Um I I actually pulled the trigger fairly early in riTUXimab. Typically my my rate. I give decks and methadone every 2 to 4 weeks for 4 to 6 cycles. Testing platelets weekly to make sure that they're staying up in between cycles. If somebody drops before their fourth week in between cycles, or they're requiring their cycles sooner or they're they're really not achieving great platelet counts, I give them were toxin ab early. Um the guidelines really are all over the place and there's a lot of still preference for splenectomy, but I I try to preserve the spleen in many patients. One other question on that abstract how long was the micro finally given for in that trial? Um I have I have to go back and look, but I'm pretty sure it was for at least 30 days. And so it was uh you know, predniSONE in these trials has always given for at least 30 days. So I'm thinking it was, you know, at least 30 days with those patients. And if they had a response, they were maintained on it through six months. That made a question about the gene therapy trial. Was that put on clinical hold. And if so, why is that? Um in terms of a clinical hold was driving toxicity. Yeah. So there was there was at one point a pause that was concerning mainly around the The trans am in Itis. And then the patient who had the infusion reaction about 10 minutes in my understanding is that that was reviewed and felt to be not uh not concerning enough to warrant holding the trial overall. Uhh let's see. Um we have a question from DR Stone. Does the how do you think about uh you know, caprock acid? Uh you know that we sometimes use uh in malignant him when people are bleeding and around the site of Penick. I think we tend to use that more than trans economic acid, which is used I think more on the O. B. And and surgery realms. Um You know ju are we doing anything by using that agent? You know, I I think the big difference with them is it's really more of a binding site peace between tran exam IQ acid and epsilon amina caprock acid. I mean they're both serving as anti fiber analytics to block the action of plasma. Um In in pretty much every study in which they have been compared to each other retrospectively, they seem to have similar efficacy and safety. Um So you know, it really comes down to being institution specific. Um You know, train examine acids a little bit easier to take in terms of oral therapy, it's less nausea inducing. Um And the car has a shorter half life. And so it has to be given as Ebola us and then we give these continuous infusion. So it really does depend. But I think it's either one is probably going to be beneficial in a patient who is bleeding, particularly with new coastal bleeding, given fiber analytic activity. Maybe one last quick question about Catholicism. Ab are you using it? Um, and when So um, it is not currently on formulary within our system. Um, but it is something that we think about. And so where I typically am considering capitalism ab are upfront in patients who have the most severe presentations neurologic dysfunction, you have to balance against bleeding risks. I wouldn't use it. Anybody who you're concerned about cNS bleeding. For instance, the other place would be in patients who have particularly refractory courses. You've been exchanging them for a couple of weeks, you've given them riTUXimab to work on eradicating their inhibitor and you can't taper them from plasma exchange. So it may be a good bridge in that case, until they actually recover enzyme activity. Published Created by
