In this HealthTree for Myelofibrosis Podcast episode, we were fortunate enough to speak with Professor Claire Harrison about highlights from the ASH 2024 conference, which was held in December 2024. This is the largest hematology conference in the world, and people from all over the world travel to the event to hear about and share the latest in hematology. 

Dalton Bean (00:13)
Hello and welcome to the HealthTree Foundation for Myelofibrosis Podcast, a show that connects patients with researchers. I'm your host, Dalton Bean. In this episode, I had the pleasure of speaking with Professor Claire Harrison about highlights from the American Society of Hematology 2024 Conference, also known as ASH. During the conversation, Dr. Harrison shared what she felt were some of the most impactful studies shared at ASH for essential thrombocythemia, polycythemia vera, and myelofibrosis.

Professor Harrison is a graduate of Oxford University Medical School, became a consultant at the Guyus and St. Thomas Hospital in 2001, where she is now a deputy chief medical officer. The focus of her work is in myeloplasm neoplasms or MPNs for short, for which she has a national and international reputation. Some key areas for her research interests are clinical trials and associated translational research. Her work has led to the approval of new therapies such as ruxolitinib,

fedratinib, momelotinib, and pacrtinib. In the past 10 years, she has published widely and over 300 academic articles. In addition, she has a strong interest in patient advocacy and founded the UK MPN group, MPN Voice.

Dalton Bean (01:27)
Hi, Dr. Harrison. Thank you for joining me today.

Claire Harrison (01:32)
Hi Dalton, it's a great pleasure to be with you today from London, UK.

Claire Harrison (01:37)
Please call me Claire,

by the way.

Dalton Bean (01:40)
I'd love it if you could introduce the ASH conference to our audience that may be unfamiliar with it.

Claire Harrison (01:46)
So, ASH stands for American Society of Hematology. It's the biggest hematology conference and it covers the breadth of hematology from transfusion to sickle cell, bleeding disorders and malignancy. And it gets bigger and bigger and bigger every year. It's a massive conference. You have to be pretty fit and have loads of energy to go to this conference, believe me, right? So it had...

This time it had like over 30,000 delegates. And when you go to us, you may go as a doctor, you might go as a scientist, you may go as a patient, you may go as a farmer person, as a news person. So those delegates are all there with a different aim in mind. And the structure of the meeting is that it runs over several days. People submit their work and we usually submit our newest data.

Claire Harrison (02:42)
and our best data, we save it all up for the ASH meeting and it's our big treat as clinicians who are interested in furthering science and clinical knowledge. And we present it in a paper, which is about 400 words long, which is known as an abstract. And so there were 8,000 unique abstracts presented at the ASH meeting. They're submitted, they're peer reviewed, and then we decide if they're going to just be published as the little paragraph presented.

Claire Harrison (03:12)
as a kind of on a poster, which is literally as it sounds, a poster piece of paper that gets stuck on a board. And then we walk and we read the posters and we have a discussion or as an oral. And the oral sessions are very lively. There are a lot of them. You really need a sat nav and you need, you know, to do some forward planning to go to the meeting. in addition to that, there are several hundred separate workshops, educational sessions and around all of that.

We like to meet people we want to meet. We like to network and chat. you know, the person who goes to Ash, an average person like me might do 20, 25,000 steps a day. And it's pretty much going to make the most of it and be busy from maybe 6.30 AM until the early evening. It's a full on meeting. And for me as a European, I need a full night's sleep on the flight to recover on the way back.

Claire Harrison (04:08)
It's certainly a really exciting meeting and this year it was in San Diego and the weather was good, everyone was really engaged and it was a great meeting and we're all still basking in that post-COVID opportunity to meet each other face to face. We really miss that in COVID.

Dalton Bean (04:13)

Yeah, this was actually my first Ash that I've attended. it was, I kind of described it to a friend of mine as Disneyland for Hematologists. It is everything there and not just within the conference building, but all of San Diego is decked out in ash. The buses that you see going by, everything is ash. So this really is like the place to be for Hematology research and for

the latest, greatest research. you said, researchers, clinicians, everyone, this is where they want to go and present the latest work because this is the top conference for hematology. So in that vein, with this being such a big research hub for hematology, I'd love if you could share with us some of the highlights that you found at ASH for MPN patients. We can break it down by

ET, PV, as well as myelobibrosis, and just kind of go through what you think is really impactful and a good thing to take away for patients this year.

Claire Harrison (05:36)
Sure, I'm always really happy to do that because I know as a patient, it's really important to know that people are dedicating their time and networking and sharing as most they can to try to get progress. And that's what that meeting is all about really. And so I first of all want to say that when I first started going to Ash, it was your first Ash this year, Dalton, but it was my...

Maybe 26, Ash. I'm so long in the teeth. The first one I went to was pregnant with my first child. So that's how many I know I've been to. the first time I went to Ash, there was perhaps one session on myloproliferative neoplasms, MPN. This year, there were more than 10. And those sessions were packed out. They were full of old people like me.

also loads of young, fresh people who are really interested in science. Also, we want to engage with industry because they often have a lot of resource, they're developing drugs. So, you know, it was really good, really vibrant. The sessions were full and there was a lot of interesting data. and some of the data related to science. So there was some quite nice data on science.

I'm going to try to put that in a kind of fun context. just sort of two, two to three things to talk about for science. First was some lovely work that came from Anne Mullally, who's based in Boston now. And she started off by talking about some work from the UK bio-resource where we've been collecting samples and data from people who live in the UK. And what we've noticed is that

there's a correlation between the number of people that have a low level JAK2, JAK2 being one of the commonest mutations that's associated with NPN. So low level JAK2 mutation and having a higher body mass index. So that's your body weight over your height. So it's less common to have JAK2 if you've got a higher BMI. So what she did or her group did in a lab was they used a mouse model

of a low amount of JAT2 and they had some mice which they fed a normal diet and they kept them nice and slim. And they had some other mice that were fed all those things that we know we shouldn't eat like ultra processed food type stuff and fat and everything. So those mice were obese. And then what they looked at was what happened to those mice over time. So we expect number of JAT2 cells to build up and then the mice to develop a high hemoglobin and then unfortunately to have a shorter life.

What they saw was that the obese mice compared to the normal size mice, they either didn't develop the phenotype of PV, so high hemoglobin, or if they did, they developed it later and they lived longer. Now, I don't think our listeners today should go out and go, yay, that's great. And Malali says I could go and eat as much rubbishfood as I want because it's really good for me if I'm JAK2 positive.

I think that's telling us about inflammation and the role of inflammation. And it's telling us something about it's not just about the JAK-2, it's something else. There are other factors that are leading to that. Other scientific facts that came through, just if it's okay to mention a couple of other ones. First of all was some really interesting data looking at persistence of stem cells. So again, mutations at a low level.

and what happened to mouse model of disease. And these workers were looking at interferon, which is one of our staple drugs. We know it reduces the JAK-2 allele burden in some patients, but it's not so good at reducing spleen size in myelofibrosis. And then one of our JAK inhibitors, which is approved called Fadratinib. And what they found was that whilst the two drugs independently did address different aspects of the disease,

You had to use really high doses of interferon, pegolated interferon to reduce the clone. Whereas if you combined the two, fadratinib plus interferon in a mouse, then you actually reduce the number of cells that were able to recapitulate disease, suggesting that you were modulating the disease. So that's really interesting. We have seen some studies already looking at the combination of JAK inhibitors and interferon and some readouts. So my great friend and colleague Jean-Jacques Kylasjean from Paris, he's done the Roxo PEG study, which was presented at ASH a couple of years ago. And there's been a study in Denmark, but there may be something different about Fadratinib. It has a slightly different profile. It's more JAK2

than JAK1. Remember that JAK is a family of four protein. And so we sat up and listened to that because actually we're doing that trial in humans in the UK.

So we're really interested in that. So our study is called Fedora after the funky hat. So that was interesting. And then lastly, some work done by our group looking at amount of mutation. So I know loads of patients are asking me now about what's my VAF, what's my allele burden? What does that show? And so we know a lot about JAK2 VAF, but we don't know very much about cal reticulum, which is our second most common mutation seen in ET and MF patients for our listeners.

What Z Ng, who is an Australian fellow with our group, did in collaboration with colleagues from France was to look at the quantitation of calreticulin mutation over time, what happens with different treatments, and whether there were any correlates. And in brief, we found that Ruxolotinib and Interferon were able to reduce the amount of calreticulin.

and agrelide treatment, which is a treatment we use specifically for ET patients, was associated with significant increases in caloriculin and burden. None of this correlated to clinical events, but we only looked at 143 patients and we didn't look over a very long period of time. So we might expect to see something, but it is interesting to see these differences in therapies. And also what's also interesting is we've known for some time that anagrolide is associated with an increase in fibrosis. So it's tempting to draw the line between those two scientific facts. And of course, it's really relevant in this era where we are testing mutation targeted therapies. So, there are two or three caloriculin-targeted therapies that are being tested at present and indeed at ASH.

Alex Rampottas, who's a scientific investigator again from the UK.

presented a CAR T cell. So these are targeted T cells. So he presented some data showing that he could make a CAR T cell, one of the most powerful immune therapies we have in our fight against cancer. He could target one of those against CALR as well. So this is important data that we need to gather together as a community and that generated a lot of discussion. It was really good. So I think that's it from a science point of view. Any comments from you?

Dalton Bean (13:10)
Yeah, I love getting an update on the science. For the listeners that may not know, I have a background being a hematology researcher. I was

A lab rat myself, I did three years on the bench top doing this sort of research. Getting kind of that snapshot into what's going on in the research side of things. I think it really provides a nice glimpse into what could be coming for the future. Obviously these are all early. Nothing is for sure, but I think it's a really good thing for people to hear of research doesn't stop. It's not, we have Jack two inhibitors. These work really well.

we're happy where we're at. Researchers are constantly pushing to figure out what's next, what's better. So when you speak to your physicians or hear about research going on, these people are dedicating their lives to driving the science forward and making a change. So thank you for sharing this science with us. Something that patients don't often hear about just because it's not, maybe not related to something that's going to affect them within the next year, but

Who knows in the next five to 10 years, these could be options for patients. So I love giving people an early glimpse like that.

Claire Harrison (14:28)
I think it's really important and I think it's really important as well to understand that there are so many really talented people looking at this data and we share and we discuss from across the globe. It will really give us some really good insights and we're able to do the science much more quickly now than when I was doing my thesis in the lab.

pouring a gel, taking a week to do something. We can sequence. I can order a whole genome to be sequenced on a patient in London and I will get an answer in six weeks. It's amazing what we can do now. It's fantastic.

Dalton Bean (15:09)
It's incredible. The speed that science moves is, it's pretty amazing. Obviously everyone wants it to be faster, but I think you do a really good job bringing it into perspective that realistically, 20, 30 years ago, a lot of the techniques that researchers are using now may not have even been developed. research is only going to continue to accelerate and it's a really exciting time.

for the research space because new tools are constantly being developed and opened up and yeah, it's just incredible. There's so many amazing minds that are working towards a common goal. So it's really exciting.

Claire Harrison (15:51)
So just a comment from me then, I think if you're listening as a patient or as someone who gets approached to take part in research, even if it's just agreeing for your data to be used or agreeing to give a sample and MPNs are a great model for research because we can sample your cancer by just sticking a needle in your arm, right? So we learned such a lot.

So please really do think about it really hard. There's a lot of ethical boundaries around research. Your data will be kept, you know, protected, but it's really, really helpful for us. And what we do know is that, you know, patients who are involved in research often feel more engaged in their care and actually oftentimes also have better outcomes. So I'm really grateful when my patients say yes to participating in research.

So shall we go on and talk about ET and PV?

Dalton Bean (16:46)
Absolutely.

Claire Harrison (16:48)
So I've got three main topics to talk about. I picked out three highlights when I was thinking about our conversation, Dalton, if that's okay. One is for ET, one is for PV, and one is for kind of

all MPNs. They're all from Europe, sorry about that. So the first one is about the prognostic value of controlling all aspects of the blood count.

Dalton Bean (17:07)
It's okay.

Claire Harrison (17:18)
So, and this is in ET, Essential Thrombocytemia, and this was done by a group from Spain, and the senior author was Alberto Álvarez-Loran. And in Spain, they have a really good network and a really good database for patients. So they, and they use a lot of hydroxyurea. Now, many of us use interferon, but their data is based on hydroxyurea.

It's probably translatable to other treatments, but let's just hear what they did. So what they did was they took patients with ET and they collected data on their treatment and whether they achieved a complete hematological response. That means normal white count, normal platelets, nothing to do with JAT2 allele burden, nothing to do with spleen.

nothing to do with symptoms, it's just all about the blood count. And what they showed, interestingly, was that for those patients who achieved this control, they were less likely to get a blood clot, so thrombosis, arterial or venous. They were more likely to have better survival, and they were less likely to develop myelofibrosis. So,

This is really important in some ways because we knew the stuff about blood clotting. That's primarily why we treat with these treatments, right? And when I'm talking to a patient about treatment is I'm usually saying, I want to do this because I want to reduce your chance of having a blood clot. And I often say, and there is some data that suggests we might affect your risk of developing myelofibrosis, which we know that some, but not all patients with ET develop.

But this is data that now suggests that treatment not only reduces the risk of blood clotting, but it may also reduce the risk of progression to fibrosis, which makes sense because we are suppressing blood count production. we're suppressing, you know, the interaction between abnormal cells and the bone marrow environment. And I think it's really important. we can't necessarily translate it to other treatments.

Interestingly, last year, so 2023, we showed the same is true in PV in the second line setting. Regardless of the treatment, that if you achieved a complete hematological response, then patients had a better event-free survival, which was thrombosis, hemorrhage, transformation, death. So here it is now for ET, which is a more diverse condition. So

It does speak to the importance of, you know, looking at your blood count and targeting it. It may speak in the future to the importance of in bringing a using a treatment at an earlier stage. you know, listeners will know that we usually only treat high risk patients with drugs and high risk is about thrombosis. And increasingly, we've been having this debate in PV. Well, should we actually we know that the risks to patients are more than

just for high risk patients. So should we be treating all patients? And if we have safer treatments that we know are effective, then that's a good argument. So I think this is powerful and interesting data. I don't know what you think, Dalton.

Dalton Bean (20:44)
.

Yeah, I think that that's super powerful, super interesting. I feel like the conversation when you're dealing with more of these chronic conditions, the conversation often turns to when is the right time to start treatment? As you mentioned, it's typically only in more aggressive or high risk individuals, but, and I've gotten in conversation with different patients, I've gotten

lots of questions about is there any work being done looking at low risk and evaluating is there benefit to starting treatment earlier? as you said, this is early and we can't, we don't ever want to jump to conclusions, but I think it should be reassuring for these low risk patients to know that there is research that is starting to evaluate this and that it'll likely, I would imagine, spark some more interest in the field to really see

if we're able to develop less harsh treatments and we can prevent the progression of disease, that I think is a really interesting topic for research. And I would imagine that will be pretty hot in the next couple of years.

Claire Harrison (22:11)
I think so too. And I also like to say that a lot of people get very worried about safety of hydroxyurea. And not everyone can take interferon, it doesn't suit everyone. And so this also speaks to long term safety, I think to some extent, because, you know, we're seeing a good benefit of the treatment. So that's also important. Those benefits were also seen for survival anyway, in intermediate risk patients, according to one of the prognostic schools.

Dalton Bean (22:24)
Hmm.

Absolutely.

Claire Harrison (22:40)
It's really interesting. So the next thing I thought I would talk about is some totally new treatments. So this is a lot of what Ash is about, totally new treatment. And this is about a drug called divesseran, which is very clever. So it's clever because it is a small inhibitory RNA. So you just

Dalton Bean (22:42)
Interesting. That is fascinating.

Claire Harrison (23:09)
to remind people that our genetic code is DNA and that gets changed into RNA, which makes proteins. And DNA and RNA lock together according to their sequence. So this is so-called SI, small inhibitory RNA, targets a specific part of the DNA or it targets RNA.

And so it targets a specific gene which is involved in Hexidin and Hexidin is important for iron. So not only does it target the specific gene, this Divesaran has a sequence on it attached to the small inhibitory RNA that targets it to the liver. So it's targeted to the liver. It gets internalized into the liver cell.

And then the small inhibitory RNA goes off and it binds to the genetic code for this gene, is called, it's complicated, TMRSS6, which then leads to increase in hepsidine. And so this is about avoiding the need for phlebotomy or venous section for PV patients. So it's given by injection, it's given, I think it's every four weeks, and there was a dose finding study and...

This was initial results from a phase one, two study presented by Marina Kremenskaya, who is from Mount Sinai, showing that this drug basically pretty much stopped the need for venus section for patients. And it's well tolerated and it's entering into a clinical trial. And we know that phlebotomy takes a long time for patients. It's painful. Your veins aren't great afterwards. You get iron deficient, so you get tired. So this is important and a new compound potentially targeting this treatment.

Dalton Bean (25:15)
Yeah, that's a really exciting new compound. And I love how, probably inadvertently here, but we spoke about how science progresses so quickly. SiRNAs, haven't been around all that long. This is a

Like you said, this is a new therapy that just is being developed, presented at ASH this year. And if you were to ask researchers 20 years ago, this is a concept that they would have said, we don't know how to make that happen. That's not likely to happen. Like the speed that science is happening and that this research is happening is truly incredible. And

I know you didn't do that on purpose, but I just wanted to highlight for our listeners here that these are like, this is truly groundbreaking work that's being presented at this conference. This is stuff that for some of these patients when they first got diagnosed, this, if you would ask their doctors then, it may have sounded like science fiction at the time, but it's becoming reality.

Claire Harrison (26:27)
And it's super targeted, as I described, right, targeted to the liver and then just targeted to that gene. So the idea is then that you just take away any off-target, so side effects potentially. So really cool. All righty. And then the last thing I want to talk about is data from 6,000 patients, 6,000 patients from the German registry.

And this was presented by Susanna Isfaw, who comes from Hanover. And we speak about this in MPN quite a lot, the dissonance, so the difference between what a patient thinks about their symptoms, and what a doctor records or registers about their symptoms. So it speaks to communication, I think. But there are some other important facets here. So this is a really powerful registry.

They use MPN 10, is one of our common symptoms scores that we've developed with Ruben Messe and others. And it's validated in multiple languages and we use it for drug approval, et cetera. And we asked the patients about six key symptoms, fatigue, itching, fever, night sweats, weight loss and pain. And we asked the patients to score them one to 10. And the physicians were asked in Germany, does a patient have that symptom? Yes or no.

So it wasn't about is the score the same? It's does the physician recognise that the patient has a symptom? So there was some not so surprising things even in 2024 when this data was collected and presented. That fatigue is the most common symptom. We know that for MPNs and that's true also of many other diseases too. 80 to 85 % of patients and physicians recognize that across all disease types and across all the symptoms, the patients reported a higher prevalence than the physicians but that the concordance say the agreement yes there is a symptom got better once the score went over four out of ten a high score being worse symptoms and there was no trend to better recognition of symptoms over time from physicians.

And that's also true about even things that you could actually measure like weight loss as well. So that we know that there's nothing really surprising there. But what is important?

Claire Harrison (29:01)
And I thought and the reason I've selected that in my mind to talk to you about today, because there were lots of abstracts, of course, is that the presence of any symptom that a physician recognized and a severe symptom that a patient recognize was associated with a higher hazard of death. Sadly, in the highest kind of most rigorous statistical analysis, which is called a multivariable model, you

know that Dalton. So we take all of the different variables like age, sadly, older people are more likely to die than younger people. And so all those things are adjusted for and still the presence of symptoms was associated with that risk. So it speaks to for me.

Physicians, you need to take note more about your patient's symptoms. Patients, you need to make sure your physicians listen to you about symptoms. And although they're difficult to assess sometimes, there are tools that we can use, and they are important. We know they're important to our patients. We know they impact on their quality of life, et cetera, but this speaks to other facets. Now, I don't want people to get really worried and go,

I always score my fatigue 10 out of 10. That means I'm going to die. You know, it doesn't mean that at all. This is looking at 6,000 people. And what I might score as 10 out of 10, Dalton, you might score as three out of 10. It's very individual, right? But it just talks to the fact that, you know, we as physicians need to improve our dialogue. And we did all listen to this.

And I've been talking to patients and physicians about it in my post-hash talks like we're doing today.

Dalton Bean (30:49)
And I think that that's something that's really good to bring up is, ASH isn't just a place to go and learn about the newest therapies that are coming out.

This is a place where physicians get together and they talk about what can we do better for our patients? Can we listen better? Does this sort of treatment work better? Like this is really a place for the experts in the field to come together and say, this is what we're doing and how can we do better? It's amazing. Claire and I actually, the way that we met was

The Health Tree Foundation sponsored a peer view session. And peer view is a continuing medical education session that happens at ASH where they bring in some of the top experts from around the world. They're sat in on this, or she was one of the presenters for this session, as well as two other myelofibrosis experts. And they shared to a room filled with physicians about

This is what's changing. This is what we can work on. This is what the data is telling us. So it is really, people go not just to share their work. They go to hear from about other work that's being done, but also to better themselves as doctors. And I think that that's really, really cool that everyone has kind of that humility to do that, to say like, yeah, I'm good at what I do, but I can always be better.

Claire Harrison (32:29)
Yeah, that's absolutely true. And I also want to say that another thing that's quite common is people come with their difficult cases and they catch you and go, can I just ask you about this case? Because people are passionate about their patients, right? And in real life, things are difficult. So yeah, thanks for mentioning that. was a great session and it has a big function around education too. yeah. In the UK, we've set up

an app actually for patients to record their symptoms. And we did present some data at ASH and we're collecting, we're using a little wearable device like this one and looking at how much our patients are walking. So we're using that to do some education too. So we were happy about that. Yeah, that's cool. So have we got time to talk about myelofibrosis then Dalton?

Dalton Bean (33:13)
Very cool. Yeah. Yeah, that's super cool.

We always have time to talk about myelofibrosis

Claire Harrison (33:25)
So I would say most of the most of the talks that actually were actually about myelofibrosis. And for once there was not a new prognostic score. There's like enough more prognostic scores myelofibrosis and I've got fingers and toes. There was a lot of talk about TP53 mutations and what we do with them and and you know, P53 is really important in

the kind of cell death. So wonky or really diseased cells, they're supposed to die. And if p53 isn't working, then usually they don't die. So that's really important. And it's a common gene that gets affected in cancer. So there was a lot of discussion about p53. What does it mean? If you have a small amount of a p53 change, is it bad or isn't it? And there was, there's still

Claire Harrison (34:22)
I can't say that I can present a definitive story on that. And I know that a lot of patients and probably some listeners are having a lot of gene mutation tests and this might come up, but you know, don't panic. Talk to your doctor. It may well have been there for a while. A small amount of that mutation can sit there for years and years and years. We've understood that from some of the work that's been done more recently. So,

One of the things I want to touch on is then just something about prognosis and a difficult decision that some people with myelofibrosis have to make, which is about transplant. And we know that very few patients will undergo a transplant and we know it's a really difficult decision because it's a toxic treatment. And so what was done in this data-based analysis was to look, to try to generate

effectively a randomized trial transplant not transplant using data from 1800 myelofibrosis patients treated with Roxolitinib or Jacovi, which is one of our Jack inhibitors, which has been around now for like 12 years. In fact, I remember that Ash when it was we were presenting data and it was approved and all the taxi cabs had Jacovi on them. It was really weird. And yeah, so that's what you mean about San Diego being decked out for ASh.

So this was a very complicated piece of analysis and it basically tried to help us to decide using some prognostic scores.

Let's say one of the ones we use is the dynamic IPSS score dynamic international prognostic score using the mutation and karyotype enhanced score. And then a transplant score, which looks at how well a patient's likely to do after a transplant, which is called MTSS.

And what was produced was an algorithm that says, these patients can delay a transplant decision, and these patients need to go soon to transplant. So it's a bit too complicated to describe in detail, but it tries to give us a framework for these discussions. It was a little bit controversial, nonetheless good. And what I really hope one day is that I'm sorry for any transplant colleagues, but that we can avoid the need for transplant and we can.

We've come a long way. We've got treatments that really prolong patients life and they prolong life and improve quality of life. I'm talking here about the Jack inhibitors predominantly, but we still got a bit of a way to go. So it's a tough decision and, but it helped us to put a framework around it. then just so lastly, maybe if it's okay to talk about some data with two JAK inhibitors.

and then just some other new therapies. So the newest JAK inhibitor to be approved is Momolotinib, which is otherwise known as OJARA in the US and OMJARA in Europe. And what we know that we recruit a very selected population of patients for clinical trials.

And so what we really like to look for is real world evidence. And so what was presented at ASH, which was important for me to see in brief was at least three different sets of data, one from Italy, one actually from the UK and one from US centers about patients in real world. Real world people who might not be eligible for a clinical trial because their kidneys don't work quite well because

they've got high blood pressure because they had a cancer in the last year. And what they showed actually was that momolotinib worked.

for those patients. So it does what a JAK inhibitor does, it reduces spleen, it reduces symptoms, but it also improved anemia and made some patients no longer need to have transfusions. And it did it without any new side effects being reported. So that is really important. The other piece of data that was presented with regard to JAK inhibitors was with fedratinib or in-drebic. And we recently published

the last randomized study with that drug called Freedom 2, which was where we looked at fadratinib as a second line drug versus a basket of different therapies. But for most patients, was roxalitinib or Jacovi. And Haifa Al Ali presented some data where we analyzed that study and we looked at patients with platelet counts between 50 and 100 and then over 100.

If your platelet counts low, sometimes means that you can't have quite as big a dose of a Jack inhibitor because these drugs lower the platelet count and then we start worrying about bleeding risk. So this data is really important because it showed that fadratinib worked often at full dose for patients with platelets in what I would call the gray zone, 50 to 100.

Below 50, we have to adjust the dose. Often we're adjusting the dose of ruxolitinib at that limit and we saw that those patients benefited from spleen and symptom responses which I think is really important.

Dalton Bean (39:47)
I think that that is super important. Platelet count is often a concern of patients when they go in and they get their blood draws. I can look within five minutes of on the internet or speaking to patients and I will have someone telling me their platelet counts. It's something that patients keep an eye on. So it's nice to know that it's researchers, physicians are paying attention to this.

and that therapies are being developed that really do have this in mind.

Claire Harrison (40:22)
And of course, pacritinib is, you know, you can use percritinib specifically for patients with platelets below 50. And, you know, we've seen some nice data emerging with percritinib. There was some metabolic data at ASH. We know it improves hemoglobin as well. And momolotinib can be used for patients with platelets down to 25. But it was nice to see that data with fadratinib because we do need more than one JAK inhibitor. Every patient is different. They handle different side effects differently.

So it's good to have these four drugs. It's really important. So, and then I just want to talk a little bit about some combination stories, if that's okay. So combination has been where it's at. And we've been trying to combine drugs to get better responses with Jack inhibitors, deeper responses, modify the disease and define what modified disease means. And so

Ash, we saw the 48-week data from the manifest study with Pelabresib continuing to show spleen and symptom improvement, no new cases of leukemia or accelerated phase, which is a little bit of a, I would say it's a minor safety concern, but the FDA is keeping an eye on it with that combination. So it was really important and it's reassuring for patients that are taking that combination still in that study.

You know, we are watching you closely and we haven't seen any new cases. So my view is, I think that risk is probably a bit overstated, but it's important to keep a watch.

And John Mascarenas, he presented data on the imetal stat, which is a telomerase inhibitor. And we've known about that for a while in myelofibrosis. We tested it in ET and he's been launching a study looking at Roxolitinib in combination with imetal stat.

And boy, that's the study we've wanted to do for a while. So it's nice to see that data well tolerated and yes, spleen and symptoms, but also reduction in molecular burden and reduction in fibrosis. So that's really exciting. There is a study for people who are listening with Imetalstat on its own, which is a randomized study. It's nearly recruited. It's a really important study and it's the only study where we're looking at

trying to change survival for patients. So big share tap for that study. If you're interested in that drug, it's given us an infusion every three weeks. And then on the subject of bet inhibitors, there is a nice new bet inhibitor made by Opna Pharmaceuticals that we've been doing a little study on in the UK. That's given continuously less issues with taste disturbance. So we presented some preliminary data with that.

And then quite a lot of data on new agents for anemia. So targeting Hexidine, the iron pathway again, data with LOX inhibitors, and then an update on the Keros data with the drug Her050 called Elriticet. Have to practice that before you say it. So that's also looking really exciting. And we know that anemia is a big problem and it often goes hand in hand with low platelets.

What we saw with Elriticept was that patients often had stable or improved platelet counts, even those with low platelets. And this drug targets TGF-Beta, which is a bad chemical that we know is linked to pathogenesis, so causing fibrosis and causing problems with blood cell production. So we really hope that that drug will be taken forward and lead to benefits for patients.

So I think that is really important. And then just lastly, I want to talk about two agents that are currently in trials in the frontline setting. One is selenexor, which has been approved for myeloma, which is a totally different type, a different family of blood cancers, but it's potentially interesting in myelofibrosis because it...

target JAKSTAT, it targets a pathway called NF-kB and it may keep drugs within the nucleus and keep them on target. So it's an XP01 inhibitor and there was some data presented from China where I find out from somebody who's been in our department for six months they can give cell an XOR. So they were able to show us some kind of real world data from China that this drug works but it is in an upfront study

called the export study comparing selenaxyl plus roxalitonib versus roxalitonib alone upfront. And then lastly, I want to talk about Navto-Madeline. So I'm coming back to p53. So we spoke about p53 earlier, didn't we Dalton? Yeah. And coming back to p53, going to test the audience on that. So if you remember, p53 is important.

Dalton Bean (45:28)
Yes, bringing it back around.

Claire Harrison (45:39)
And it's important that it's active because it means that disease cells die. So they undergo cell death, which is called apoptosis. Now, Navtomablin works on a protein called MDM and it inhibits MDM, which in turn inhibits P53. So if you've got high levels of MDM, P53 doesn't work well. And guess what? Patients with myelofibrosis have high levels of MDM.

So Navtomadlin reduces the effect of MDM, which releases P53 and then in theory, disease cells die. So we've been studying this compound for a while in myelofibrosis and what was presented again by John Mascarenes in a study called the Boreus study was Navtomadlin on its own after failure of Jack inhibitor in a randomized study showing

that this drug delivered spleen and symptom benefits, but also, and this is important for me to see changes in the basic biology, reduction in amount of mutations, reduction in fibrosis, and also reduction in CD34 positive cells, so that's leukemia cells or blast cells. So it's possible that we might see a new drug approved for myelofibrosis this year, and that drug might be Navtomadlin.

Who knows? Exciting stuff. Both of those drugs

Dalton Bean (47:07)
Exciting stuff. That is very exciting.

Claire Harrison (47:11)
cause a lot of gastrointestinal toxicity. So we have to learn how to use them. And if you wanted to potentially be involved in studies of Nabtomadlin, that's also in a study now called the POESIS study, which is being led by Serge Vrstovesec, who I've worked with a long time ago with the comfort studies. And so he's designed a study where patients get Roxalitinib

And then if they haven't benefited, then they get randomised to either stay on the Roxalitinib for longer. And we know responses get better over time, so that's perfectly reasonable. Or to get Navtomadlin plus Roxalitinib. And this is a new study design. So we're thinking about new ways of studying drugs. And it's also a way to test that drug, which we've seen works in a second line setting up front. So I'm super excited.

for seeing the results of this data.

Dalton Bean (48:07)
I am too.

I think as we close out, something that I love to highlight is kind of that call to action for clinical trials of if patients are interested, explore clinical trials. you, we touched on the cell and extra for my fibrosis actually hosted a podcast with Dr. John Mascarenas, whose name has come up a couple of times during this.

I hosted a podcast with him that is up on our website that's covering the sentry trial, is selenex or formalopiprosis. We're working on getting more accessibility into these trials so that patients can get a little bit better understanding. But I guess, what would you tell a patient that was maybe interested in looking into these trials?

Claire Harrison (49:04)
I would say really really think about them. Your doctor is not under any inducement to put you in a trial. They might offer it to you because they think it potentially will one benefit you. They may offer it to you even though you might not get the treatment at the beginning you may get the opportunity to have it later. I think

If I was a patient or I was sitting with a loved one or a friend looking at a study, what I would want to do is read the information carefully. Understand, is this an early phase clinical trial? Is it a first in man study? If it's not, what do we know about the safety? What side effects might I expect? And they will summarize that in an information leaflet that comes to you as a patient.

Claire Harrison (50:03)
Also, what will be in that leaflet will be information about how often you have to come to hospital. And frequently, unfortunately, patients on clinical trials have to come more often and may have to come and stay longer. So I had some patients having caloriculine targeted therapies today. One of them was there all day and one of them came yesterday as well. But, you know.

We want to test these benefits for patients. So understand that, understand if you'll get your travel expenses reimbursed and if someone can come with you. If you don't speak the language or read the language of the package insert, ask for a translation. We don't want to discourage people. We absolutely want to make clinical trials accessible for everyone who wants to take part in them.

Claire Harrison (50:54)
Not all clinical trials are sponsored by pharmaceutical companies. Some of them are academic clinical trials, some of them are data only, some of them you might give blood samples for. Always your data will be protected and will not be linked back to you and you will always see information on that. What I would say is though, take your time, think about it hard, talk to your friends and family about it.

talk to someone in the health team about it, but understand that you can always step away from a clinical trial. But for the most part, I would say patients benefit and what wasn't to Ash was data on these new CalR targeted therapies. And I expect that we'll see that and hopefully we can sit and talk about that next year. But you know, there are brave patients, maybe 60, 70 patients from across the world who've had these treatments as a first in human. And this is how we make advances in the disease. But you're not compelled to do it. But thank you to all of those people who do.

Dalton Bean (52:03)
Well, it's been such a pleasure talking to you, Claire. Your name is one that is so well known in this space that I am truly honored that you took the time to speak with us today and really just share with our audience. That's what we're designed to do is get that information out there and I couldn't have asked for a better person to do that than yourself. So thank you.

Claire Harrison (52:07)
Thank you.

You're very kind. was my pleasure. And I wish everyone who's listening to this podcast, the best health and take care of everyone. Thank you so much, Dalton.

Dalton Bean (52:40)
Thank you.

Dalton Bean (52:42)
Thank you for listening to the health tree for myelofibrosis podcast. Join us next time where we'll learn more about myelofibrosis research and what that means for you.