This video features Iberia Romina Sosa, MD, PhD presenting on Consultative Hematology. This presentation was given at our April 11th New Directions in the Diagnosis and Treatment of Hematologic Cancers Symposium in 2023.
Thank you to the organizers for the opportunity to be here. Um I am going to be providing an ash 22 update on consultative hematology. On behalf of the Fox Chase Cancer Center, I have no relevant financial disclosures. So today we are going to do a review of some of the high yield abstracts that were presented at the 2022 ash conference uh for Consultative Hematology. We're going to focus on immune thrombocytopenic perra, cold lutin disease, thrombosis and parasal nocturnal hemoglobinuria. The first abstract we're going to tackle is immune thrombocytopenic perra. This is a plenary abstract for the efficacy and safety of intravenous epga mod in adults with primary I T P. This is the results of the advanced force study just to recall. Immune thrombocytopenia is an acquired autoimmune disorder characterized by a reduction in platelet count which can result in increased fatigue, risk of bleeding and decreased quality of life. I G G autoantibodies target glycoprotein expressed on platelets and mega Caro sites and they can result in platelet degradation, induced platelet apoptosis, impaired platelet production and sometimes impair impaired platelet function. We typically treat I T P with um steroids immunosuppression such as I T anti CD 20 therapies and splenectomy enter carga mod, which is a novel mechanism to treat I T P. Potentially, it targets the neonatal F C receptor that is found in the endothelial cell of the endos. And essentially, the mechanism of action we hope to achieve is um to prevent um to increase lysosomal degradation that often um does not occur whenever we have the F C um neonatal receptor um leading to um um I G G homeostasis and recycling of the immunoglobulins. So essentially, um if F carga mod binds the neonatal F C receptor here, then that prevents the antibodies from being saved in the endos soe and eventually just increases the likelihood that they're going to go to the limo lysosome and end up getting degraded. So, the advanced four trial was trying to look at patients that had chronic or persistent I T P patients that had um platelet counts of less than 30,000 with a screening of two different platelet counts of less than 30 K. During this time period. 100 and 31 patients were randomized to either get F carga mod for a period of 24 weeks at 10 mg per kilo of I V at a 2 to 1 ratio versus placebo in the placebo arm. These patients um had, could have concurrent I T P treatment um As long as they were on a stable dose that did not have any changes in the dose during the period of the study for the patients. The eligibility criteria were adult patients and also patients that had had at least two prior I T P treatments or one prior, one prior I T P treatment with one concurrent treatment or placebo were given as a weekly dosing from um for four weeks. And then thereafter, from four weeks to 15 weeks were either giving weekly or every two weeks based on platelet counts. And then a fixed dosing uh was assumed after 16 weeks with uh end points being measured from 19 to 24 weeks and an option to advance to the open label extension. Later on overall, the baseline characteristics of the patient population were very similar among the aortic mod and the placebo arm times. His diagnosis was anywhere from um 10 to 11 years. Uh patients with a history of splenectomy, um At least one third of those patients in both the ear tiga mod and the placebo arm. And these patients were heavily pretreated with at least two thirds of the patients having had at least three prior I T P. Therapies. Therapies that were um reported were cortical steroids T P O medics as well as other immunosuppressants. In terms of the efficacy endpoints, the primary endpoint was the proportion of patients with sustained platelet count. Um greater than 50,000 in greater than 4 to 6 week uh visits during the week, uh weeks of 19 to 24. And you can see that the aquatic mod arm um did reach this primary endpoint in comparison to placebo. It also did very well in terms of some key secondary endpoints, meaning the number of cumulative weeks of disease control, the sustained platelet count as well as a durable, sustained platelet count. Looking at this in a different way, Carma also resulted in higher response rates from the international group uh Working Working Group uh criteria when compared to placebo with at least 50% of patients or greater um achieving an international working group response um namely consecutive visits, greater than seven days apart, with platelet counts of greater than 30,000 twofold increase from baseline in the absence of any bleeding events. Um Whenever compared to the placebo arm, since the mechanism of action is to improve the clearance of I G G, you can actually see here the placebo arm in terms of I G G and the ear mod arm and how the majority of patients by week four had achieved at least a 60% reduction of I G G levels. Um Whenever compared to the placebo arm and these were maintained during um and sustained across the time. Um when the study um was uh conducted in terms of art adverse events that were of any concerns. There were no significant adverse events that were different between um the TGA arm and the placebo arm. Importantly, the most common adverse events that were reported were headache, pete and hematuria. But these were not necessarily significantly um worse or different than um the placebo arm take home points is that the benefit of targeting the neonatal F C receptor and lowering total I G G levels were demonstrated by clinically and statistically significant improvement in plate that counts compared with placebo. It was a well tolerated drug and most of the adverse events were mild to moderate with no new safety signals that came out out of um the study. The results supported both weekly and every other week administration. And we are excited to see how those patients that advance to the open label extension advanced plus are going to do and the patient reported outcomes that we expect to come out of this particular study. We're going to switch gears and we're going to look at the update on saab used in the gluten and disease. This is abstract 31 this is looking at the part B um extension of the Cadenza study just to remind us the Cadenza study was one of two studies including the cardinal study as well. Looking at patients that had cold of gluten and disease to determine whether cylia um dosed every two weeks. In comparison to placebo um improved hemoglobin levels and transfusion um outcomes um for patients um with cold alu and disease. This is um the part a has already been previously reported, we are going to be summarizing part B or the open label extension period just to summarize part A was the efficacy of Seima. And it is important to note that 54% of patients in this particular trial noted that there was an increase in hemoglobin with red blood cells greater than two g per deciliter improvement or greater than 12 g per deciliter at um improvement um that were reported in this particular um in, in patients that were receiving cylia and this has led to the FDA approval of this particular drug in the part B. What the um what the study uh personnel was hoping to achieve was to look at the long term effect of the uses of tilea whenever we think about patient related outcomes. So the open label extension of Cadenza, the follow-up media treatment was over 99 weeks with a range of 22 to 100 and 77. And the patient related outcomes that were looked at were a variety of fatigue and severity scores. You can see here, this is the part A, this is the Cylia arm and this is the placebo arm. You can see the corpo patients with a fat fatigue score that they maintained um during part B of the extension, they maintained a good performance in terms of uh clinically relevant change for the fa fat fatigue score. A clinically important change was determined to be a change of five points after week one for those patients in the placebo arm. Once they were enrolled in part B and they were able to get suya, there was a dramatic improvement in their facet fatigue scores from baseline in a variety of other uh fatigue assessments. S F 12 and E Q VA s with, with um reported clinically important changes. You can actually see that overall um patients in this um in the extension actually did um improvement um did improve in terms of patient related outcomes. This is actually quite important because it supported the idea that there is a benefit associated with the Tilia when it comes to fatigue and overall quality of life. So, not only are we improving hemoglobin but potentially also improving um patient related um quality of life. The benefits are very sustainable for more than a year. And patients previously treated with placebo demonstrated a brisk patient related outcome improvement in part B not going to be reviewing two very important abstracts um that are very um meaningful in terms of thrombosis. The first abstract that we're going to be reviewing is the alive two study. This is a late breaking abstract um that is coming from the group in the Netherlands. The basis of this is that um in patients that have inherited thrombophilia and miscarriages. The question of the use and the benefit of heparin has often been um queried uh by a lot of us practitioners. We know that Heparin is very useful for patients that have recurrent miscarriage and antipas lipid syndrome. And there's been a beneficial use of low molecular weight heparin on live birth for those patients that have recurred miscarriage of unexplained ideology. Oftentimes, um we try to uh extrapolate from the anti phospho lipid and use low molecular weight heparin. We know from the alive study. The original study that was reported in the New England Journal of Medicine that there was no benefit for low molecular weight on live birth for anybody that has recurred miscarriage without um an explained ideology. However, there was a signal or a suggestion that there might be a benefit for patients that had inherited thrombophilia for the use of low molecular weight. Enter the Alive to study. This was 41 centers in five countries. The coordinating centers were in Amsterdam and Warwick. It was an open label trial and the inclusion criteria for this is the history of patients that had two or more miscarriages with a maximum seven weeks gestation age and that had a history of inherited thrombophilia. They were standardized to either receive standard pregnancy care alone or to get a low molecular weight heparin. In addition to standard pregnancy care, and this could be Delta parent, an ox Aparri Narain or tin aparine. The primary outcome was to obtain a live birth, secondary outcomes also included miscarriage or adverse obstetric outcomes and safety signals were also included. Overall, you can see that both of the groups were very evenly distributed in terms of age, the number of miscarriages and the different thrombophilia noted um from this particular study that in terms of the primary outcome, low molecular weight did not increase the risk. The the benefit of having an increase in live birth rates. It was 71.6 um for patients in the low molecular weight arm and 70.9. For those patients receiving standard of care, there was absolute difference was not um was not significant enough um to merit the use of low molecular weight heparin. Also, um there was a difference in adverse events, although these um adverse events were minimal, there was easy bruising skin reactions at injection site and minor bleeding. There was an a greater increase of those in the low molecular weight arm um when compared to standard of care. So overall the live birth rates for patients that had standard care practices nowadays is at least 70% in patients that have thrombophilia, which is actually quite good and low molecular weight did not improve on this. So, the recommendation um from this group based on this randomized study is not to treat patients with low molecular weight to prevent miscarriage if they have a thrombophilia. And also not to test in the absence of any therapeutic implications as it is not likely to improve the rate of life birth for these patients switching gears a little bit. Um instead of looking at pregnancy going into something that we do in our cancer center, which is um looking at the cancer, the venous thromboembolism risk in those patients that are treated with immune checkpoint inhibitors. So this is actually quite important because we are seeing an increased use in cancer patients of immune checkpoint inhibitor therapy. But as we are seeing this, we're also seeing an increased rates of venous thromboembolism observed in clinical practice of approximately 10 to 25%. The prothrombotic effect of immune checkpoint inhibitors is not currently clear, but we do know that several of the risk scores to determine the risk of venous thromboembolism in our patients with cancer tend tend to underperform whenever we're using immune checkpoint inhibitors. So ranta score, for example, is not as useful in this particular scenario. Um whenever we're talking about immune checkpoint inhibitors, so we need something better. Hence, the Vienna group decided to examine um the early c reactive protein dynamics in immune checkpoint inhibitor therapy, immune checkpoint inhibitors induce a systemic inflammatory response. And we know this and there has been several reports. Now looking at c reactive protein elevation after the initiation of the immune checkpoint inhibitors, the rationale is that they may serve as a biomarker for mortality and treatment response when we are using immune checkpoint inhibitors with higher baseline C R P S associated with poor outcomes and early C R P dynamics being described as a potential bio marker for treatment response. The way that the study was designed was a retrospective corporate study coming out of the use of immune checkpoint inhibitors at Medi Uni Vienna. They were looking at the duration of immuno of of immune checkpoint inhibitor therapy until subsequent anticancer therapy deaths or maximum of three months after the last cycle of immune checkpoint inhibition. During the periods of 2015 to 2018, the end points were Venus thromboembolism, whether it was pe D V P or catheter associated. They, they specifically focus on the C R P dynamics, the measurement of the C reactive protein at study baseline and then within four weeks prior to immune checkpoint inhibitor and longitudinal measurements throughout the statistical analysis was based on the risk of venous thromboembolism. So when we talk about C R P dynamics, we're really looking at these different and um at these different patterns here, we're talking about AC R P flare which is a rise in the C R P level to 2.5 times or greater within the first month or the first four weeks of initiation of an immune checkpoint inhibitor. Those patients that are flare responders are going to have a decrease as time progresses. Um then there are those patients that are going to continue with this flare and are going to not have a response or an improvement in baseline of the C R P. Then there's also the patients that are going to not be responders, they're not gonna have AC R P flare and those patients that have a reduction in the C R P but didn't have the obvious flare before. What does this all mean? Well, it actually means that in terms of looking at the C R P levels and looking at the risk of venous thromboembolism in this particular population, we see that patients that had AC R P flare were more likely to actually have an incidence of a venous thromboembolism versus those patients that did not have an early C R P flare. Furthermore, there was also in those patients with AC R P response within the first three months after therapy initiation were numerically lower venous thromboembolism rates observed compared to the remainder of those patients. This was adjusted in a multi variable analysis for cancer type stage age sex and charleston comorbidity index. The take home points of this particular study is that the early dynamics of systemic C R P are associated with the risk of venous thromboembolism during immune checkpoint therapy. The highest venous thromboembolism risk is observed in those patients that have an early C R P flare and the lowest risk is in those patients that had a drop of greater than 50% in their C R P with no prior flare. This is actually really quite interesting because it, it, it, it um gives us a potential link between the use of immune checkpoint inhibitors and systemic inflammatory responses and being a thromboembolism. And it could potentially be a way for us to determine who is going to be at higher risk and may benefit from prophylactic anti regulation. So more to come on this but definitely something to keep a look at it on and potentially start using or looking at in our particular patients. And then finally, I'm going to conclude by just reviewing a new um therapy that is possibly coming for parasal nocturnal hemoglobinuria. This was another late breaking, abstract looking at IP taco. So just to remind us that P N H is a disorder of complement disregulation. It is a rare disorder characterized by intravascular hemolysis, thrombosis risk and bone marrow failure. It is caused by the somatic mutation, pig aging resulting in a lack of GP I anchored protein CD 55 CD 59 which allow for um destruction of red blood cells by a membrane attack, complement uh membrane attack complex. It is important to know that we've actually had huge improvements in the rates of intravascular hemolysis as well as thrombosis risk in patients when we use C five inhibitors, namely Eliza and Raval lua. However, up to third, two thirds of patients have residual anemia due to um emerging extravascular hemolysis that occurs because of C three sin and fays enter um IAN A first in class oral not ID selective complement factor B inhibitor that shows promising safety and efficacy based on phase two data. So this is going to be the applied P N H study which is an open label randomized multi center phase three, investigating IP taco pan monotherapy in P N H patients with residual anemia. The patients that were looked at and enrolled in this particular study were adults with a diagnosis of P N H and clinically significant extravascular hemolysis with a mean hemoglobin of less than 10 g per deciliter. They were randomized 8 to 5 to either received monotherapy with oral IP taco 200 mg, B ID versus standard of care with either Ecoza or Raval Luima. There was a 24 week randomized treatment period, a 24 week treatment extension period and the opportunity to go to the rollover extension program. The primary end points were an improvement in hemoglobin of greater than two g per deciliter in the absence of red blood cell transfusions or a hematologic response of greater than 12 g per deciliter. Secondary endpoints included transfusion avoidance, facet scores and the occurrence of clinical breakthrough hemolysis and major adverse events. Overall monotherapy was superior to standard of care for both primary endpoints, meaning there was an increase from baseline of hemoglobin of two g per deciliter in a majority of patients with Ian and there was a hemoglobin of greater than 12 in the absence of red blood cell transfusions for a majority of patients on Ian as well. From a secondary efficacy standpoint, we were always um transfusion avoidance um was successful with the Tapan monotherapy. The adjusted mean hemoglobin change from baseline. For those patients on a taco pan was approximately po more than 3.59 g per deciliter. Whereas for those patients that were on standard of care, it was approximately the same or a little bit lower at minus 0.4 IAN was also superior at reducing patient reported fatigue from baseline. Overall. From a safety standpoint, the adverse events were deemed to be equivalent in both groups with headache and diarrhea being more likely in the Ian group and COVID-19 infections and breakthrough hemolysis being more likely in the standard of care group. Um There were no serious infections caused by encapsulated bacteria. No patients discontinued due to um severe adverse events. There were no deaths and there was a major adverse event that was reported in the Taco arm, a transient ischemic attack on a patient that had six sinus syndrome. This was not determined to be related to steady treatment and the patient continues to receive the treatment. Overall. Oral of taco monotherapy seems to be very successful at reducing both extravascular and intravascular hemolysis and achieving clinically meaningful end points in terms of hemoglobin. It was well tolerated um with a favorable safety profile and no serious breakthrough hemolysis. Single agent of taco pan may provide a practice changing oral outpatient regimen um for patients with P N H. This concludes my discussion of the um high yield abstracts presented from quantitative hematology. Um in the uh ash 2022 conference this year. Um I thank you for your attention and if you have any questions, I'd be more than happy to answer questions at this time.
