Okay, so this first abstract let's talk about low molecular weight heparin versus a standard pregnancy care for women with recurrent miscarriage age and inherited thrombophilia. ALIFE2, which was an open-label phase three randomized control trial.
As studies have shown an association between re. Carriages and inherited thrombophilia. And usually we just put the patient on ox if they have miscarriages, plus the proven thrombophilia. And then we go until the end of the pregnancy with ox. And so that's prac what is now commonly practiced.
But there, this is not based on evidence. There, there has been no clinical trials to evaluate this, to see does it really improve the outcome of pregnancy or not? If you use the. The lovinox in these cases. So there studies a trial which was investigator initiated, was International Open Label involved 15 hospitals in Netherland, US, Belgium and Slovenia, and also about 26 sites at uk.
And it was registered in Dodge Trial Registry and Euro C Clinical. So basically the participants were 18 to 42 year old females who were pregnant less than seven weeks or were trying to conceive. And they had documented confirmation that they had either factor five, one of the thrombo thrombophilias factor five Lidin trobin gene mutation.
C and anti trauma. And if they were more than seven weeks pregnant, they were excluded from the study or if they had any allergy to any of the low molecular weight heparin products. And then they were randomized one-to-one for one of the subcutaneous available such as an exocrine delta, Parin, heparin, and anine.
What, whatever was available. At the time of that study. And then when the urine test was positive for pregnancy and patient was less than seven weeks pregnant, they would start the the low the low molecular rate heparin until the end of the study. Primary outcome was to look at live birth rate in patients who were on LMWH versus those who were just a standard of care.
Just monitor. Safety opt outcome also was being looked at including bleeding, thrombocytopenia, skin reactions. There was also some secondary outcomes also were looked at as, adverse problems during the pregnancy. So the resource was that be between the year 2012 to 2021.
They looked at 10,000 patients and only 428 patients would qualify because most of these miscarriage people who had miscarriage, they actually didn't have thrombophilia. So only out of 10,000 people, only 428 were registered. And then 326 were randomized. For this trial, 164 were assigned to low molecular weight, and then the rest were assigned to the the Standard of care, which was monitoring.
And as the most common was was factor five. Lidin was the most common. Thrombophilia, 56% and 70% of patients had more than three miscarriages. Aspirin was only used in 11 pa, 11% of patients. And what it showed this study was actually live birth is was not different between people who were on patients who were on OX versus those who were not on ox.
So I didn't change anything, putting them on low molecular rate, parin and also adverse events was actually more in a group that was not group that was on low molecular weight heparin. The conclusion of this trial would be don't they don't recommend screening people when they have miscarriages for thrombophilias because as you see, out of 10,000 people, only 400 had thrombophilia.
And also the second one is that doesn't seem like putting patients on. Low molecular rate heparin does change the outcome of live births, and doesn't improve. It also doesn't improve the adverse events that may happen during pregnancy. It can even be more than patients who were monitored.
The second study this is for p and h as 50% of. More than 50% even of patients who are on PN who have PNH H and are placed on anti C5 inhibitor compliments. They still have extravascular hemolysis, but and then many of them still are transfusion dependent. So for these patients there is no, there was no other.
Solution. This study looked at monotherapy with Iptacopan, which is a factor B inhibitor, and is oral twice a day. And it, it was a phase three trial, randomized, open label. So this study so patients who had hemoglobin less than 10, they were on Rab or Eculizumab more than six months, and they were randomized to Iptacopan versus whatever they were.
Prior to en being enrolled in this study eight to five. So there were more patients randomized to Iptacopan versus a standard of care. And the endpoints that they were looking as the primary endpoint was increase in hemoglobin more than two grams, and also percent of patients who had more than the hemoglobin reached to more than 12.
In the absence of transfusions, and they also looked at a secondary endpoint. Look at fatigue using facet FS score, changing hemoglobin breakthrough hemolysis and also major adverse vascular and infections. So this study so there was 62 patients on iptacopan versus 35 patients on RZ or Eculizumab.
57% of patients were on transfusion and primary endpoint 51 out of six patients Were treated with, who were treated with oc. They had increase in hemoglobin more than two grams compared to those who were on a standard of care. And also about 42 out of 60 patients, the hemoglobin went up above 12 gram per deciliter.
So there was really fascinating results. Now, secondary endpoints was there was superiority in transfusion avoidance and change. Baseline hemoglobin Iptacopan arm compared to ex standard of care. The other thing was the safety issues that that was also, I think important. And then the study was for 24 weeks.
At the end of the 24 weeks, 60 out of 62 patients were transfusion independent at the end of the study. Safety issues. Only one Iptacopan patient had ischemic heart attack. That, that at the end of eventually it was determined that it wasn't due to ioc. And there was some minor problems like headaches and diarrhea, which was more common in Iptacopan arm.
But infection was actually more common in revolut of and Eculizumab. It seems like this therapy is going to be game changer for these type of patients that they don't respond to Relu, zumab and equi and continue to need blood transfusions or lower hemoglobin of less than 10. The next one, this was the, and the, so those two were in late.
Abstracts. And then this one was in our in looking at health related quality of life in sickle cell disease patients and health equity concerns in patients who had recurrent vaso-occlusive crisis. And this was a long digital survey. Which was was done months zero three time points zero, three and six months.
But this abstract presence only the this the time zero so one of the time points. So this was a mixed method. The study meaning there was in person like one-to-one interviews with patients and also long. Survey. The survey was including different tools like Fact, bmt, fact G BMTs, and also ASCQ-Me, which is usually in all of sickle cell trials.
ASCQ-Me is used and the goal was to qu to. Check for symptoms, health related, quality of life and work impacts of patients with sickle cell disease. Basically looking at all these function daily functions that patients are supposed to have now. Also sim symptoms, comorbidities, treatment experiences, and out-of-pocket costs and out of pocket costs and time that patient was spending for taking care of sickle cell disease was also documented.
And reported by patient. The also, we looked at health equity concerns that patients had. In terms of equal getting equal care in emergency room or when they get admitted eligibility was that patients should have at least two vaso-occlusive crisis in one year, in the past two years prior to enrollment.
And yeah, the data analysis is only for the first time point, which was time. 142 adults from, so this was an international study, was from patients from us, uk, Germany, and Italy. Were enrolled in France. So majority of patients out of a hundred forty, two eighty five were from us.
70% were females. And 15% of these patients were only having a full-time. And 62% of them were taking hydroxyurea the months prior to the survey. And the time of admission, they, the 6% had so about the mean average of a number of VOCs in one year was six VOCs, and average time for admission was 14 days.
So of the, these various tools that we used for checking the quality of life, so the factI scoring. Which is from zero to 1 0 8, the higher the better showed that they they scored lower than US general population. So US general population scores, 80 patients with sickle cell disease were scoring 62.
And the most the most impact on patients with sickle cell disease were the physical and emotion. Wellbeing domains. The other the other. A tool, the EQ-5D-5L was showing that 89% of patients at the time of the survey were reporting pain which is quite astonishing.
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74% reporting anxiety, 72% were reporting mobility impairment, 46% self-care impairment. The Ask Me questionnaire showed that 42%, although they. Working. But 42% show that they had impairment in work and then 24% were like absentism 53% loss of productivity reported. And , the mean activity impairment was 52%.
And then the question about, okay, how comfortable you were feeling when you were admitted in terms of healthcare equity 63% of patients were concerned about and then they felt that they had been treated unfairly and they dis correlated with they thought 67% thought this was because of the race and ethnicity difference and also because they were requesting for more pain.
Another 64% were reporting that so we still have to work in the healthcare equity for patients with sickle cell. And despite all the treatments that are available now to sickle cell patients still quality of life in sickle for sickle cell patients seems like it's not. Even near 10 minutes. Okay I'll be fast. So despite all of we have for sickle cell patients, there is a still poor quality of life. So this is actually a gene therapy in sickle cell disease. So this trial is a single dose ex Auto, they, so they call it exel in sickle cell disease, as you see. There, this is a little bit complicated, I'm gonna tell you about this.
So these the very dark parts, which starts from here. Is the months that patients post gene therapy were voc free with occlusive crisis. And then on the left side, you see the number of VOCs they were experiencing prior to gene theradisease py. For example, the first patient was having seven VOCs with occlusive crosses in one year for 32 months was voc.
Post gene therapy. So Simz is very effective. And and then you can also see here when they became transfusion independent, this second line that you see here, the vertical lines, this is when they started becoming transfusion, EP independent. Post gene therapy. So seems to be very tolerated.
They reported it and also effective at least for 32 months follow up time that the study was following patients. But we need more data and more studies to for safety. All right. These are clinical trials that we have for Bo for benign hematology at uci. We, most of them are for sickle cell, and we have one trial that is both sickle cell disease and thalassemia.
So one of them is, A randomized double blind placebo control multicenter study that lu at in glaucoma, which is a p selecting inhibitor compared to a standard of care. The patients have to be have two to 10 vaso-occlusive crisis in one year. And that it requires pain medication. And then the p selectin infusion is about 30 minutes.
So it's an infusion every three months. So the difference between this p selectin inhibitor to Autodoc V, which is already FDA approved, is that they don't have to come monthly. And also it's every three months. . And also it's not humanized is much like human monoclonal antibody.
So it doesn't cause allergic reaction. So we don't even need pre-medication for this infusion. Now the other two trials are about a thyroid kinase. Activator which is called a Tavo Etavopivat. And then this study looks at the first one looks at sickle cell disease patients who haven't been transfused and they have two to 10 vaso-occlusive crisis.
And the other one is also avo, Etavopivat. But this looks at actually sickle cell patients who get blood transfusion for their stroke and also thalassemia patients transfused and transfusion in. Usually transfuse patients, sickle cell disease patients are all excluded from studies, but the goal of this study is actually to look to see if Etavopivat can extend the the interval between transfusion and decrease the need for transfusions.
In thalassemia patients we can include both transfusion, thalassemia and transfusion. Independent thalassemia, usually there is no trial for transfusion independent patients, so this is a chance for transfusion independent patient thalassemia patients who have hemoglobin less than 10. We also gonna have a, our opening a trial to open to look at brain iron deposition in thalassemia patients.
And we have a romi plasty for thrombocytopenia chemotherapy induced thrombocytopenia in patients with GI malignancies. So these all are open and enrolling. So if you have patients that you've tried everything and they still you're not satisfied with. Medications that are available, this is a way to go.
Now what is the background for this apo vivo and in glaucoma? As one of the mechanisms of pathophysiology of sickle cell is vaso occlusion. And then we used to say, okay, red blood cells in sickle cell, red blood cells are stiff. And then they don't go when they go through. Small areas of vasculature they cause they cause vaso occlusion and pain crisis.
But now we know that it's not just red blood cells are a sticky, it's also white blood cells, platelets, tic counts. And one of the targets is the p selecting that has been shown during crisis. The serum p selecting goes. So that's how they came up with the idea that if you use p selecting, it decreases the the crisis VA occlusive crisis by 60% and 60% of patients.
And we already have a p selecting inhibitor AUC V approved, but the problem is every month. In is supposed to be one upgrade to Avir, which is a p selecting the other one the other part of physiology we always ignore and patients walk around with hemoglobin of seven because of hemolysis.
But it's important to stop the hemolysis because studies have shown that. Those patients who have higher ldh have lower survival, and that's because intravascular hemolysis causes endothelial dysfunction and vasculopathy and nephropathy and retinopathy and all these complications.
It's not just vaso occlusion, it's also hemolysis associated with inflammation. Now, what is the the mechanism of how does. Pyro kinase activators work. As mial Etavopivat has been approved for pyro kinase deficiency. So subsequent studies on that that medication showed that in we know that in sickle cell disease patients, other than all these mechanisms that I talked about, there is also increasing 2,3 dpg, which results in decrease in atp, which also results in red blood cell membrane.
Instability. So it increases the risk of hemolysis in sickle cell patients and rest of other hemolytic anemia. So that's why we think it also works in thalassemia. And I'm gonna show you the thalassemia data for a tbo Etavopivat. So basically what thyroid kinase activators do they increase a p decrease 2,3 dpg improves hemoglobin or two binding for.
Oxygen affinity and decrease oxidative s stress, therefore decrease membrane damage and results in effective erythropoiesis increase lifespan. So should VA theoretically should work both in thalassemia and sickle cell disease or other like Spherocytosis and el lymphocytosis. All these rare hemolytic combs negative.
Disorders. So this is the phase one study that they looked at how atop Pivot works under the graph and a, which is the left side shows that when they, the different, so this was phase one, so they were trying to see which dose is more effective and they tried doses of hundred, 200, 300 and 400 milligram daily.
And they showed that when when they give. Etavopivat, actually, the 2,3 dpg went down, right? And then after they stopped it, after two weeks of daily dosing stop, goes back up the 2,3 dpg. And they also showed that when the medication starts, very, so this actually happens very fast. The ATP goes.
and then after 14 days when they stop the medication it still remains. As you see, the ATTP takes time to go down, although the DPG goes back up fast. That was one study and then here also they showed that so these are again different dosing and this one shows actually P 50 means the oxygen pressure where 50% of your hemoglobin gets saturated.
The lower, the better, right around 24 to 28 is normal. As you see sickle cell blood red cells, they had. High P 50 high pressure. But when they were exposed to AVO Etavopivat, after 24 hours, it came down to normal. Basically. So these vis boxes, the red ones are 24 hour. After exposure to avo, pwa and then the best it seems like after a certain dose it was the same amount decreased.
This was in intervention study. So do that was phase one. Now this is phase well, Dr. F Fleshman, you give a lot of time to malignant guys, so I deserve five more minutes. Yeah, . Yeah. So Aviva was tried in sickle cell patients and they showed that it actually decreases the inflammation.
So this one shows the hemoglobin. So in 15 patients, they gave the atop of vva baseline hemoglobin was 8.9. It went up to 10.5 and there was 12 percent change from baseline. So it works, it decreases the hemolysis and p-value was sign. Same. So arc is acute re count sorry, absolute retic count.
So absolute retic count was at baseline was 234, and after exposure to a Etavopivat for two weeks, it went down to hundred thousand. So it was dig went down by 46%. So it decreases the hemolysis, increases the increases the hemoglobin and also improves. P 50. So at baseline, P 50 was 30.9, and then after two weeks, exposure went down to 26, which is normal.
And there was 13% decline. So I'm not gonna go through the rest. These are some of the quality improvement in red blood cells membrane and all those things. . So that's too much detail, but that shows that there, there is improvement. Now these are the inflammation markers. So as we talked, hemolysis increases the inflammation in sickle cell patients like increases, interleukin 60, TNFs, all these things.
So this study also showed that two weeks of 400 milligram once daily ET avo Etavopivat, it decreased by 26% the TNF alpha. It decreased by 33%. The C r p also decreased the markers of hypercoagulability such as the dier trombone trobin complex and TROBIN 1.2. These are general markers, so by 60%, so the hypercoagulability went down by 60% and tissue hypoxia, they.
They used erythropoietin to show improvement in declining tissue and declining erythropoietin as a marker of tissue hyper. So at the baseline there was 2.6 normal value, let me see, erythropoietin. So baseline was 140 and then it went down by 42%. So improved, but then it seems like there was no significant change in P-value.
So probably we need more more number of patients. This was only fifth, seven or six patients. But now there are these The trials that I show you as open at uci enrolling more patients to show that. Now I wanna show you the Metabo Etavopivat. So the difference between Metabo, Etavopivat and Avo Etavopivat is that meta Metabo is twice a day oral.
And also it's a aase inhibitor, so it affects the hormones, but mipi is more specific, so it's not aase inhibitor. And I'm pointing this out because a lot of patients are concerned about fertility and all these issues. So mi EVO Etavopivat is like upgraded Mevo Etavopivat, which has already approved the safety in PK deficiency.
This pyro kinase deficiency has already been demonstrated. So this is the data in transfusion independent thalassemia patients that they had hemoglobin of 8.4 at baseline. And after 72, Weeks it went up to 1.2. The median improved by 1.2, and also erythropoietin went down by 35. Ferone is a marker of we use it as a marker of hyperactivity and bone marrow.
Which went down by 3000 went down from 10,000 to 5,400. And then also marks the markers of iron and reticulocyte counts. Decreased in in bilirubin, decreased, and hepcidin also actually went up because in, in transfusion, independent thalassemia patients, hepcidin is suppressed due to increased ery ferone which shows bone marrow mass increased.
And then it increases the iron absorption because it suppresses the hepcidin. So despite not being on transfusion these transfusion implemented patients. Do continue to accumulate iron. So this is a very important point that we always forget about transfusion. Independent patients worry about iron overload and that ferritin underestimates iron overload in these patients.
So you may miss iron overload in tosin, intermedia patients if to, if you just rely on your Fein because of suppression of hepcidin. Yep, that's it. So if you have any patients that you think they would benefit from clinical trials, you can always email me.
Dr. Zahra Pakbaz is a board-certified hematologist specializing in non-cancerous blood diseases at UCI Health. Her areas of clinical interest include thalassemia, sickle cell anemia, iron excess, coagulation problems, and low or high platelet and white or red blood cell counts.
Iran's Tehran University of Medical Sciences granted Pakbaz a medical degree and an internship. She completed an internal medicine residency at MedStar Union Memorial Hospital in Baltimore, Maryland, and an adult hematology fellowship at the National Institutes of Health (NIH) in Bethesda, Maryland.
Pakbaz has produced over sixty scholarly articles and lectures on sickle cell anemia, thalassemia, and iron metabolism. Her discoveries have improved the prognoses of sickle cell and thalassemia sufferers. Her efforts to sickle cell research and care have earned her a multitude of honors. She collaborates with primary care physicians and other specialists to provide patient-centered treatment to those with blood problems.
Pakbaz serves patients in the Orange, California, UCI Health Chao Family Comprehensive Cancer Center.