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The Leading Edge of Myeloproliferative Neoplasms Treatment

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Published on December 4, 2020

Expert Shares the Latest News in MPN Treatment

Are you seeking the latest information on myeloproliferative neoplasm (MPN) treatment? You have come to the right place! In this segment from a recent Answers Now program Dr. Srdan Verstovsek, world-renowned MPN specialist and Director of Clinical Research for MPN in the Department of Leukemia at MD Anderson Cancer Center, will share the latest news on MPN research — including the emergence of cutting-edge treatment methods!

He is joined by Patient Power co-founder and two-time cancer survivor Andrew Schorr and Patient Advocate Ruth Fein. Together, they explore the latest developments in essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) treatment including new and exciting combination therapies and the future of immunotherapy for MPNs.

This program is sponsored by Incyte and is produced in partnership with the MPNRF. This organization has no editorial control. It is produced by Patient Power. Patient Power is solely responsible for program content.

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Transcript | The Leading Edge of Myeloproliferative Neoplasms Treatment

Ruth Fein: Hi and welcome to our MPN Answers Now program. I'm Ruth Fein, a health writer fortunate enough to live in beautiful Saratoga Springs in upstate New York. And I'm a patient advocate for Patient Power. I'm also someone who's lived with each one of the MPNs: ET, PV and now myelofibrosis for the last 25 years. So, you could say that I'm sort of a patient pro at this point.

Today we're talking about cutting edge treatments with a world-renowned MPN specialist, Dr. Srdan Verstovsek, Professor of Medicine and Hematologist/Oncologist at The University of Texas MD Anderson Cancer Center. Dr. Verstovsek, thanks so much for taking time to be with us today.

Dr. Verstovsek: It's a great pleasure to be on the program. Thank you very much, Ruth, for having me. I am sure that we are going to have a lovely discussion that will benefit everybody and I'm looking forward to it.

Ruth Fein: I'm also joined by another very special guest, Patient Power Co-Founder Andrew Schorr. Time to dig in. Let's begin with ET. Dr. Verstovsek, I believe that most ET research is still concentrated on cardiovascular health, limiting the risk of bleeds and clots, what we call thrombotic events – which I know all too personally. Where do you see breakthroughs in ET research?

What Is the Latest News in Essential Thrombocythemia (ET) Research?

Dr. Verstovsek: We know that patients with essential thrombocythemia have predicted normal life expectancy. We know that the main reason for dying is complications of cardiovascular nature, the thrombotic events. That's why we separate the ET patients in two groups, the low risk and high risk for thrombosis and treat appropriately. But we also know that there is a risk of progression to myelofibrosis or acute myeloid leukemia, which are then deadly complications for these patients because they come with a much shorter life expectancy.

So, we are moving from assessing the thrombotic risk and treating it properly, and there are new ways of doing that, to looking at possibly decreasing the transformation risk or progression risk by decreasing or even eliminating malignant clone that would look at a molecular response. Not only at the complete hematological respond meaning, control of the blood cell count, which is, therefore, control of the thrombotic risk, but also looking at the molecular response, seeing whether malignant clone that drives the disease can be decreased and possibly eliminated, which would be then a probably highly active in terms of progression-free survival — meaning preventing complication in some patients that may lead them to untimely death.

Andrew Schorr: I just want to see if I make sense of that. So, Ruth was worried about thrombotic events as an ET patient — stroke, bleeding, et cetera, as all our ET patients worry about that. But you're saying now there's something superseding that to deal at the molecular level that could eliminate or slow progression. That sounds great.

Dr. Verstovsek: Yes, that is correct. The second step in our assessment of what really needs to be done short of eliminating disease first would be to control the thrombotic risk because we don't want patients to have a stroke or heart attack or something that would be compromising their life and make it really bad or lead to untimely death. We all agree on that, and we have standard medications like hydroxyurea (Hydrea) or anagrelide (Agrylin), but we also have been using when possible the Interferon of different preparations. With development of much more friendlier, I would say, safer and less cumbersome to give Interferons, and I'm talking about particular one called Ropeginterferon, which is given under the skin as a biological agent, as injection every two weeks and possibly even once a month.

We are talking about not only controlling the blood cell count, which Interferons can do, we all know that. We are talking about long-term delivery of these biological agents that can then affect the bone marrow activity, improve bone marrow in terms of the elimination of that malignant clone, number of cells with the mutation in a bone marrow. Which, for example, is the JAK2 mutation in 60% of ET patients. We can track that, and it can go lower and lower and lower, and in some patients perhaps go away. That would be complete molecular response. We see something like that with this particular medication, Ropeginterferon in polycythemia vera patients.

We’re not talking about them yet, but the drug Ropeginterferon is approved as a therapy in Europe for polycythemia vera patients. And in that study that led to its approval it was able to eliminate in a good number of patients, the malignant clone, the JAK2 positive cells went away after about five or six years of therapy.

We are now facing imminently a start of a global study with Ropeginterferon for possible approval in ET patients. So, I'm looking forward to see what can we achieve with the same drug that is approved for PV in Europe, in patients with ET on a global level. We expect control of the blood cell count, which would be decreasing thrombotic risk. And I expect that over time that malignant clone of JAK2 positive cells will decrease and possibly go away.

Are we talking about the cure? I'm not that brave to say it, but I'm talking about a functional cure where we are minimizing the disease so much so that perhaps in some patients if we are successful, we will not be able even to detect it. That is where we are looking for in the future, and that will be preventing progression.

Are There Any New Options for Essential Thrombocythemia Patients Receiving Treatment for the First Time?

Ruth Fein: Yeah, that's great news and very exciting for those who have ET. So, talk to us about today. We understand what's coming down the pipe, that's exciting, but ET today, are we looking at something different when we're beginning treatment, are we looking at something as an option today that's different that might've been just a few years ago?

Dr. Verstovsek: The therapeutic options for ET have not really changed much over the last few years. Hydroxyurea is a number one choice, even by now, new published or updated NCCN United States guidelines for therapy of patients with ET, that is the chemotherapy that you take by mouth daily to control the blood cell count. We still have anagrelide there. Interferon comes as a choice, but it's not prominent in the therapy of ET, particularly because we don't have any approved drug, tolerance is poor, the insurance coverage is really not there for its use, and that's why I highlighted that possibility of developing Ropeginterferon in this setting.

There are other medications that are being investigated as a therapy for ET in a so-called pilot studies, smaller group of people that are not responding to standard therapy like investigational agents, navitoclax or bomedemstat. They have relatively funny names. These are really investigational agents that just are being explored as a possibility for development as a therapy in the future. But in terms of the standard practice that has not really changed recently.

Can You Tell Us About Combination Therapy Studies for MPNs?

Ruth Fein: Let's talk about JAK Inhibitors and where they're headed. That's ruxolitinib such as Jakafi for those who only know it by that name. It's already approved for myelofibrosis and for advanced PV after hydroxyurea. What's really exciting is the number of advanced drug combination trials. They can provide the symptomatic relief of a JAK Inhibitor and they start to look at the biology of the disease, right? So what combination studies are you involved in? Talk to us about what's happening there.

Dr. Verstovsek: The combination studies are becoming a norm, particularly in drug development of new medications for myelofibrosis. But if we want to just move from ET over to PV to myelofibrosis, let's just address the issue, is there a role of the JAK Inhibitors in ET? Since we started with ET. The role of the JAK2 inhibitor in ET exists in patients that are really suffering from the symptoms related to ET. There were studies with the ruxolitinib, a JAK Inhibitor that, as you said, has been approved for particular patients with PV and for myelofibrosis. There were studies showing that it can really control well the symptoms and to some degree, a blood cell count in advanced patients with ET. It's not officially approved, but it has a role in this particular setting.

What Are the Latest Developments in Polycythemia Vera Treatment?

Now, if we move on to the polycythemia vera, in that setting we also have development of the Ropeginterferon in United States. And as I was describing, it was approved in Europe last year; the company that produces it has applied for approval in United States for Ropeginterferon as the first-choice therapy for polycythemia vera.

But to connect it to your question about the combinations, because the expectation is that this drug might be approved in United States as is in Europe, the intent is now to see how can we optimize its use? And it's in the combination, right? There are a number of combination studies between the Interferon preparations, Ropeginterferon is one of them. And the JAK inhibitor, ruxolitinib. Remember the JAK inhibitor ruxolitinib is approved for polycythemia vera after hydroxyurea. So-called second line, but if you combine it with Interferon, maybe it's going to do the trick and make it much better, right? So, combinations of Interferon with ruxolitinib.

There are at least three studies underway that I know of trying to combine things together to improve the quality of life, control the malignant clone, decrease the thrombotic risk and make that life much more enjoyable for much longer periods of time when we talk about polycythemia vera.

In myelofibrosis, the combination strategies are the bread and butter of the clinical trials that are underway. We know that we have valuable medications. When we talk about JAK Inhibitors, ruxolitinib and fedratinib (Inrebic) approved as therapies for myelofibrosis. They are very effective in controlling the signs and symptoms of the disease. They control the big spleen, the liver, quality of life, people gain weight, albumin goes up, the kidney function improves, a lot of benefits.

And we know with ruxolitinib people actually live longer for a few years, but it does not eliminate disease. It loses the control of these symptoms and these medications do not really improve the bone marrow function, the anemia persists, and it may be worse on the therapy with JAK inhibitors. So how do we improve that? There are a number of combination strategies to add a medication to JAK inhibitor, let's say ruxolitinib to improve what the JAK inhibitor does.

More of the spleen, more of the symptom control, which is not really trivial at all because for the prolongation of life, as I said, that is one of the benefits of ruxolitinib, you really need to make that spleen as small as possible. That is the key barometer that leads to the prolongation of life. The smaller the spleen gets on ruxolitinib, the longer people live. So, combination partners would perhaps boost that benefit and make it even smaller and improve quality of life with it, or you can think about alternative combinations. If the anemia is present or develops on JAK Inhibitor, you add a medication for anemia to ruxolitinib. One of the major studies that is happening in this particular field is the combination of ruxolitinib with drug called luspatercept (Reblozyl). Luspatercept is the drug that was recently approved for anemia in patients with myelodysplastic syndrome.

It's a cousin to myelofibrosis, and it was already started as an agent or medication for patients with myelofibrosis that were anemic. We are facing in the very near future opening the study on a global level of a combination of ruxolitinib and luspatercept to cover all three problems that we usually associate with myelofibrosis. JAK inhibitor will improve the spleen and symptoms and luspatercept, if it’s going to work, improve the anemia. So, that combination has a really good promise. So, these are the two main types of combinations improving what the JAK inhibitor does, all bringing additional benefit and prolong that benefit much longer of this combination overall, so that we don't lose that control, after average, what we know after about three years. We want this to work forever, basically.

Is There Any New Clinical Trial Research on Myelofibrosis (MF)?

Andrew Schorr: And then is there any other ones you just want to put on our radar, Srdan, any other trials or things related to these combinations that you're hoping to learn about for myelofibrosis?

Dr. Verstovsek: There are many, many drugs that are being developed, but since we are talking about this field in terms of... we are really talking about the phase three randomized study with these medications that may lead to their approval. That's what we are talking about. Phase three randomized studies means that you randomize the patients between standard of care and the combination, right? And for all these three drugs we are planning to do later this year. There are many other drugs that are being studied and some of them are actually in phase three studies also for approval but perhaps not in combination yet. You have medications called momelotinib, pacritinib, CAR-T that has no name, CAR-T 232, imetelstat.

These are all other four drugs that are being studied for possible approval. Again, in randomized phase three studies after JAK Inhibitors in a second line setting, for those that fail the fedratinib or fail ruxolitinib. So, we have a spectrum. We are talking about combinations, and that is the main focus, but realistically the most difficult situation for the patient is after JAK inhibitors, you don't have any benefit from ruxolitinib any more or no benefit from fedratinib. What do you do then? That is the most difficult situation.

Perhaps we don't have too many drugs in development there because we want, from the get-go to have that combination and make it work forever. But the real question is what do you do after ruxolitinib, after fedratinib? This is where these other drugs — momelotinib and CAR-T 232, imetelstat — that are being developed, and the pacritinib that I mentioned is being developed for patients with very low platelets below 50,000, for which no drug exists at all. So, you see the sub-grouping here. We have combinations in frontline, we have the second line drugs. We have drugs for specific problems. And for particular patients with specific characteristics — a lot of diversity because not everybody's the same, we need it all.

What Is the Role of CAR T-Cell Therapy in Myeloproliferative Neoplasm Treatment?

Andrew Schorr: Dr. Verstovsek, if I could just ask, some of the patients watching may be headed to transplant or have had one, and I know if my doctor said, well, the fedratinib or the Jakafi, or whatever it was, had sort of pooped out or there wasn't a good combination; they might start talking about transplant if I was fit, but I knew there's a mortality that goes with that as well. So, you mentioned just along the way a minute ago, about CAR-T, chimeric antigen receptor T-cell therapy, which is in trials for multiple myeloma and other blood-related cancer, chronic lymphocytic leukemia, and approved in some lymphoma. So would this be some kind of middle ground where people would not go on to transplant, but might have something like that?

Dr. Verstovsek: The role of CAR T-cells in myeloproliferative neoplasms or myelofibrosis in particular, any advanced phase where we are losing the response to standard JAK inhibitors or we don't have many other options with the pills or injections, is being looked at. There is no real, at the moment, understanding how would we position CAR T-cells in the myelofibrosis field?

The problem is that cell types or preparation of the cells requires particular marker on the surface of the malignant cells that would kind of drive those cells to kill or eliminate malignant clone preferentially over the normal cells. We are not there yet with myelofibrosis. However, this whole field of what I call cellular therapy, you're giving cells to a patient, right? They may be engineered in different way, for CAR T-cells you need the marker, but there are other types of preparations. At the moment here at MD Anderson, we have a study with re-engineered cord blood cells.

There are immunologically naive. You can infuse yourself, please don't do that. But it can be given to a patient without much of a harm. That's the whole idea, right? And maybe those cells will boost the immune system and help fight immunologically the myelofibrosis or some other similar conditions like aplastic anemia. That kind of cellular therapy is being investigated, as we speak, since we don't have that specific marker for CAR T-cells that require those markers for us to be more specific. So, we are moving in that direction. Let me mention a new way of looking at what we can do.

Lack of the marker that would distinguish between malignant and normal cells impacts another huge area of new drug development, which is antibodies, right? Antibodies are proteins that we all make that attack specific malignant cells or pathogens. And this is how we protect ourselves. So, the ideas are to try to find the markers for which we will be developing antibodies as a therapy for myelofibrosis. One study is underway here with the Anti-CD123 antibody to see whether this would preferentially kill malignant cells. So, we are going outside the box and looking for alternatives — cellular therapy, antibody therapy — something that has not been around until a year or two ago.

What Is the Role of Immunotherapy in MPNs?

Ruth Fein: Thank you. How close are we to having immunotherapy as an option for people with MPNs? So, is immunotherapy something we've already been talking about and not using that term? Or what is it exactly? If you could explain that to the audience.

Dr. Verstovsek: The term immunotherapy may mean a lot of different things and this is what you are actually alluding in your question. How can we objectivize the term? What does this really mean? And if we start from the Interferon that we said is immune booster in normal person, that is in a sense immunological therapy for patients with myeloproliferative neoplasm because it can, through this activity of enhancing the immune system, alter the bone marrow function and improve the control of the blood cell count that decrease the thrombotic risk. So, in essence, you can even call Interferons as the immunotherapy.

Now the alternative is what Andrew said about CAR T-cells, that will be immunological therapy in terms of looking at the specific markers and eliminating that through the cellular therapy, some call that immunotherapy. The many times, however, we are asked about immunotherapy as immuno-checkpoint inhibitors. I unfortunately bring another terminology. This became a hot topic about five, six years ago.

And even a Nobel prize winner was announced who is a doctor here at MD Anderson Cancer Center for developing of this particular strategy of attacking the malignancies, right? Unleashing the immune system by un-checking the checkpoints that are preventing immune system from the donor, from the host to attack the malignant cells, right? So, these are immuno-checkpoint inhibitors that allow again, enhanced immune system response to the presence of malignancy in the body.

This is now leading to a revolution in the field of solid tumors and cancers. And many drugs are being developed for many different solid cancers from the lungs to the GI and so on. Not so in MPN, as of yet. It seems that the immune system is really, really suppressed by the presence of advanced myelofibrosis, where you would be testing these medications. And giving patients these immuno-checkpoint inhibitors in two studies so far did not lead to enhanced immune system response to the presence of myelofibrosis.

So, there was no real clinical benefit. This is the real immunological therapy for me, where you are trying to enhance the host, the patient's immune system to act and contribute to elimination or malignancy. It didn't really work well so far, and we are not understanding how is this even possible, why the immune system is not enhanced and why it's not contributing. It's going to give you another door to open and learn about the immunological system in MPN to our benefit at the end, I always see the benefit at the end. We will learn what to do and what other medications to develop as immune therapy in myelofibrosis. This is another avenue where the field is going.

Ruth Fein: So, Dr. Vorstovsek, thanks so much for joining us today. It's been so helpful. I know to us and, and all of us who are online today. If you left us with a one sentence hopeful message at the end, what would it be?

Dr. Verstovsek: So, education is one aspect of what I would like to say for all of us and our patients to be aware of what's happening and understanding that, and then participation in clinical studies. Because hope is, like from your own case, that we are going to make in very near future, massive progress in understanding the biology that will lead us to combination strategies or even triplets for our patients, like yourself, to have a very well controlled disease. Make it chronic, as chronically possible so that you have a good life for as long as possible, likely forever.

And that is my goal, a realistic goal in my lifetime to achieve, to develop therapies that and I think soon that will make me worry less about dying and much more about making that quality of life and that spleen and anemia controllable for decades to come.


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