MPN Clinical Trial update with Dr. Abu-Zeinah, from ASH 2021
by David Wallace
TRANSCRIPT | MPN Clinical Trials, 2022 Update
David Wallace:
Hello, I’m David Wallace, founder of PV Reporter and our nonprofit organization MPN Cancer Connection. And your host for today’s program, the American Society of Hematology 2021 update, is Dr. Ghaith Abu-Zeinah from Weill Cornell medicine in New York. Dr. Thank you for joining us.
Dr. Abu-Zeinah:
Thank you, David, for having me it’s a pleasure to be here.
David Wallace:
So there was a lot of excitement this year at ASH. What should patients with MF PV and ET be looking forward to regarding the new and improved treatment?
Dr. Abu-Zeinah:
It was an ASH packed with scientific developments in the field of MPN and other fields as well. It’s a little bit hard to summarize ASH in only a few words, but I will say that every year we look forward to the updates on several research studies, including clinical trials, including preclinical studies. So studies done in the lab about promising, you know, agents that could be moved forward to clinical trial. The, the clinical trial session, I think had several interesting results, many of them very promising and, and look to be effective treatment agents. And some of these drugs are phase two studies, so earlier in development and of course there are some phase three studies but generally speaking you know, the later phases are generally when the drugs have been shown to be safe and have gotten to the point where we’re looking at effectiveness.
Dr. Abu-Zeinah:
And some of these studies are randomized. Some of them are really single agent studies. So one of the studies we were looking forward to and we’ve heard about the past few years is the updated data on Pelabresib, which is a BET inhibitor for the treatment of myelofibrosis. And that study was presented this ASH and also previous years showing that this drug has actually a unique efficacy in treating the anemia of myelofibrosis. So patients who got onto this study who had myelofibrosis with anemia that may or may not have been transfusion dependent, we’ve seen actually some really good responses in terms of hemoglobin in improvement, becoming transfusion independent, also being a, a generally well tolerated drug with side effects that aren’t, you know, for the most part aren’t severe side effects and are not too frequent. So, so this agent actually not only does it seem to be effective in treating anemia in a subset of patients, certainly not everybody, but it actually had some of benefits in bone marrow fibrosis reversion, which is also kind of a unique finding in, in some of these newer drugs or the novel agents being developed.
Dr. Abu-Zeinah:
So the ability for a drug to reverse fibrosis is actually a promising finding because in, in the scientific community, we associate that with disease modifying activity or the potential for a drug to really reverse the ongoing process of disease progression and prevent it from happening. Now, I think it’s still early to say for sure you know, this drug has been in development for a few years, but you know, as we know, MPN are chronic diseases and require really long a longer follow up to determine if these drugs are truly preventing progression, but this agent is now in phase three of development, and we’re looking forward to hearing more about what the phase three data is looking like or what it’s showing, and it’s actually being expanded to the treatment of ET patients.
Dr. Abu-Zeinah:
So the study is also open for the treatment of ET. So that I think is one exciting agent to look at the data, if you wanna search it, it’s all published online or, you know, looking forward to the data to come in the next few years as well, another study or studies that came out that we’re also very promising the results of the study rusfertide the drug rusfertide which is a hepcidin mimetic for treating polycythemia vera. And this drug actually has a unique mechanism of action. It sort of works on regulating iron metabolism and sort of in layman’s terms really shutting off the axis of iron into the red blood cells to try to slow down the red blood cell production. So this drug in the phase two clinical trial whether used alone as a monotherapy or in combination with another cytoreductive agent that patients may have already been on, but continue to require phlebotomy, it appears that patients treated on this trial with this drug have for the most part become phlebotomy independent.
Dr. Abu-Zeinah:
So the vast majority of patients who required at least three phlebotomies within six months from starting this study have no longer required phlebotomies. And there may have been a few who needed one or two phlebotomies here and there, but overall, very, very exciting to hear. The patients can really be free of phlebotomies with this treatment. So I think that would be second on the list. And, and certainly there are a few other studies that are, you know, unique agents with different mechanisms of actions targeting different pathways. Some of the pathways that have been particularly interesting to look into and target are, you know, one, the TGF beta pathway TGF beta or tumor growth factor. beta is a sort of a cytokine signaling pathway that really, you know, is overactive in MPN, particularly with myelofibrosis. So drugs that have worked on trying to target that access have shown various sort of efficacy results in treating not only NPNs, but other myeloid neoplasms, you know, for instance, there is a drug approved for MDS known as Luspatercept, which targets that access to and has shown to be very effective in treating anemia of myelodysplastic syndrome.
Dr. Abu-Zeinah:
That’s also being investigated in MPN, and there are other agents who that are similar to targeting these pathways. So one of those studies actually was a single center study by the MD Anderson, where they used a drug called sotatercept to target that access and found that there was benefit in terms of treating anemia. So as you can tell, you know, there’s sort of a variety of agents in different pathways, targeting different mechanisms and the different subtypes of MPNs generally myelofibrosis is where the majority of clinical trials are run. And sometimes these active agents, when they do have good activity in myelofibrosis they’re used in ET, or sometimes PV PV does have a potentially sort of a unique pathophysiology that we don’t see with the others, including, you know, things like iron metabolism. And so that drug is really only active in PV as far as we know rusferitide. So, yeah, I mean, I think that kind of summarized the clinical trials. You know, there are certainly many others out there that are worth, you know, reviewing and looking at. There are some that were presented as an oral presentation and others as posters, but definitely it was a very exciting ASH and a lot of advancements in the field.
David Wallace:
Okay, excellent. So I’m seeing artificial intelligence or AI play really kind an expanding role in MPN research from clinical trial matching to bone marrow histopathology. So, first of all, tell us what is histopathology and how might AI be used to gain a deeper understanding of MPNs from the various gene mutations?
Dr. Abu-Zeinah:
That is a very, very good question, David you know, artificial intelligence has become a major, a hot topic in the field of medicine and really many other fields in our day to day lives. You know, understanding artificial intelligence is understanding that the human brain as fascinating as it is, has some limit. And although we have our own neural networks we, don’t always, we’re not always capable of swallowing in very large amounts of data and making sense of it, even when we put our minds together. Sometimes we, you know, there are certain patterns that we don’t, you know, we just don’t see our brain doesn’t see, or our eye doesn’t see artificial intelligence really works to try to synthesize as much data as there is available, you know, including microscopic data that dye, doesn’t see, you know, things that show up on histopathology, meaning bone marrow biopsies, looking under the microscope at very high power, trying to look at these microscopic cells how they appear and how they interact with their environment is part of that.
Dr. Abu-Zeinah:
There’s a lot of data in there about how these cells look like in the bone marrow, what type of cells there are, what percentage of them how they’re organized, sort of what the architecture is. What’s the degree of fibro this, for instance, you know, all that kind of data. If you try to put it together the probably the best way to do it nowadays is to use machine learning and artificial intelligence to synthesize all that information. Not only from one patient, but from several patients who have these diseases and try to make sense of patterns or trends to say that there is a common trend or a common pattern in how these bone marrows look like that can potentially tell us some information about how the disease is going to behave or how it will potentially respond to a specific treatment. So, you know, as the amount of data we have nowadays increases we really have to think about how we can capitalize on artificial intelligence to help us help us figure out not only a prognosis, but also treatment options and even help us establish a diagnosis a little bit better too.
David Wallace:
Can you shed some light on what actually is histopathology?
Dr. Abu-Zeinah:
Yeah. So histopathology is really looking at sort of how the cells look like under the microscope. So it is essentially, you know, for instance, bone marrow biopsy is a good example of where we look at histopathology. So when bone marrow biopsies are processed they’re usually stained for different markers that allow us to look at these cells under the microscope. And, and it sort of gives the cells certain colors. And it allows us to identify what these cells are and how they look in their environment and how that appearance can be associated with a particular diagnosis. So the way we diagnose myeloproliferative neoplasms is not only by looking at the mutations like JAK2 and the blood counts, but also by looking at the histopathology of the bone marrow, you know, maybe another term to use is bone marrow morphology. How does, how does the bone marrow look like under the microscope after all the staining is done?
