MPN News From ASH 2018: Perspectives From Leading Experts

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Topics include: Treatment and Understanding

As part of Patient Power’s coverage from the 2018 American Society of Hematology (ASH) annual meeting, a panel of experts in myeloproliferative neoplasms (MPNs), including Dr. Srdan Verstovsek, Dr. Abdulraheem Yacoub and Lindsey Lyle, as well as Andrew Schorr, gathered to discuss the latest news and developments related to research and treatment of MPNs. The experts shared their perspective on the exciting progress made and “buzz” from this year’s meeting in San Diego, including updates on JAK inhibitors in development, news on interferon, diagnostic testing, the story that somatic mutations tell, and the overwhelming interest in the study of MPNs. 

Sponsored by Incyte Corporation.

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Transcript

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Andrew Schorr:

Hello, and welcome to Patient Power. I’m Andrew Schorr. We are on location in San Diego, which is my home county, at the American Society of Hematology meeting, where there are thousands of physicians and physician assistants, and researchers, and some patients like us here talking about blood related conditions.

And we’re talking in this discussion about MPNs. I have one—myelofibrosis. We’re also talking about essential thrombocythemia and polycythemia vera. And we have a great panel to talk with. So, first of all let’s start with one gentleman here who’s been my doctor along the way, Dr. Srdan Verstovsek. And what’s your title now at MD Anderson?

Dr. Verstovsek:

I am a Professor of Medicine in the Leukemia Department. And I am going to be there I hope for the rest of my life.

Andrew Schorr:           

Okay. All right. Thank you. And next to him, is someone where they work together for years, Lindsey Lyle.

She’s been on our programs of course before. And you were working with Dr. Verstovsek, and now what’s your position these days?

Lindsey Lyle:  

Now I am a senior instructor with the Division of Medicine at the University of Colorado.

Andrew Schorr:           

Okay. All right. Thank you. And also, someone else has been on our Patient Power programs. Now let’s go to Kansas. Okay. Not for the Wizard of Oz, but for Dr. Yacoub. Introduce yourself.

Dr. Yacoub:     

Hello. I’m Abdulraheem Yacoub. I’m an Associate Professor of Hematology/Oncology in the Department of Malignant Hematology and Cellular Therapeutics. I’m also a director of Hematology Clinic Program as well.

Andrew Schorr:           

Okay. And all of them work hard for those of us dealing with myeloid conditions and of course specifically MPNs. So, we want to get the news headlines here. So, let me just start with you, Srdan. Overall, in MPNs, is there a lot to talk about?

Dr. Verstovsek:

There is. There is always so much going on. In our last 10 years since we met, there has been so much progress.

It’s just incredible how much progress has been done in the drug development, in understanding of the biology of the disease, and thinking proactively of what to do to perhaps prevent progression of the patients as they’re living with myeloproliferative neoplasms.

So, it’s not only what to do when it’s needed, but it’s also to understand the problem and to prevent change that would lead to untimely deaths or a progression of the patients. So, prevention is coming forward in many studies. Clinical studies, not just in biology. So, there is a lot to talk about this.

Andrew Schorr:           

Okay. And do you feel that the drug companies—I mean these are more rare conditions—that they’re responding with the development of therapies? I mean, there are some much bigger conditions that they’re focused on. But for our more rare conditions, there is actual drug development going on.

Dr. Verstovsek:

This is particularly evidence in the area of ssential thrombocythemia or ET, and polycythemia vera, PV. So, ET and PV.

We have a whole section almost on interferons—long-acting interferons, where the goal is not only to see about the control of the blood cell count. We should be then controlling the risk of blood clotting, which is the main problem—immediate problem—but also about the bone marrow change and the change in the molecular structure of the patient.

That would mean, basically, decrease in the number of cells with the mutation in the blood or bone marrow in patients that are treated. If that decreases, we call this the JAK2 mutation allele burden. If that goes down or goes away, you would say that this is the biologically targeted therapy that has a potential to change the overall outcome of the patients based on the—affecting the underlying problem. It’s not just like a chemotherapy that kills cells that are growing fast. It is affecting the biology of the disease.

And so, the whole area of interferons in ET and PV is so hot, and we have so many other presentations here to hear about it.

What is the real potential of these therapies?

Andrew Schorr:           

Mm-hmm. And I’ll mention that we’ll also have a separate interview with two of these folks, Dr. Yacoub and Dr. Verstovsek, specifically about what’s happening in interferons.

Lindsey, so let’s go on with you. So, I’m living with myelofibrosis. I’m on Jakafi (ruxolitinib). I don’t know how long it’ll last—an extended time or not. And I’m living well. Not everybody benefits but a lot of people have. But we wonder, “Well, what’s next.” So, what do you feel the buzz is for those of us who are on a JAK inhibitor like this?

Lindsey Lyle:  

I think that’s a really great thing that you bring up, Andrew. Because as our patients are living longer with the invention of JAK inhibitors and these sort of other therapeutic agents, we really are coming up with this, “How long will this last?” and “How long will your response stay the same?” or “Are we going to lose some response?”

And so, I think that especially at this ASH, with the clinical studies that are being presented really, a lot of talk about combination therapies is really key for patients to know that this is happening. What can we add to maybe regain some of that response or improve the response all together?

And I think too, sequential therapies is becoming a big thing in hematologic malignancies. Meaning, if you let’s say, stop responding to something, what can be used next in a safe and hopefully effective manner? So, I think all of these are really on the forefront of this as well because that will become more of a question as people continue to do well for longer.

Andrew Schorr:           

Okay. Let’s dig in to that a little more, Dr. Yacoub. So, combining like, what kind of combinations?

Dr. Yacoub:     

It’s a great time to take care of MPN patients, better than any other time. We have a lot more understanding of some of the events that happened inside the cells that drive the cancer to behave in the way it behaves.     

And based on that new knowledge, we’re designing different trials with molecules that interfere with how the cells grow and continue to become a cancer. And based on that, we have a new era of molecules that are aiming at changing that. And actually, hitting the cancer where it hurts, where it actually affects the behavior of the cancer. And we try to think of them as a disease-modifying therapies rather than therapies focused on symptoms.

So, there’s been a very impressive work by a group of physicians that was presented today about a molecule that inhibits PI3K-delta. Which is one of the multiple efforts that we’re seeing in that pathway where we’re adding molecules that are active at killing cancer cells, in addition to what has been approved previously with ruxolitinib to get a much deeper impact, more of a booster to the current therapy right now.

And we’re seeing very good signals. And there have been multiple other efforts in the same access, trying to add more cancer therapy that is effective at changing how the cancer behaves and modifies future behavior.

Andrew Schorr:           

Hmm. Okay. I just want to go over that with you for just a second and get your thoughts. So, I’m on one drug right now, and then many other people are on one drug. And certainly, there are some people in trials on one drug. So, are you saying that maybe with myelofibrosis, maybe with more advanced PV even, that somebody might take two medicines?

Dr. Yacoub:     

Exactly. And that has been building up on the previous successes of ruxolitinib. So, ruxolitinib has been on the market for multiple years and has helped a lot of patients and have saved a lot of lives.

But now we’re starting to understand the ceiling effect of what we can do with one drug. So, there is now multiple combinations that have been presented today that show that you can improve on the response, or improve on the blood counts, or have a long-term investment where you might actually be changing the cancer behavior.

Andrew Schorr:           

Hmm. Okay. So, Dr. Verstovsek, we’ve been learning a lot about genomics. Like some of us have learned—we’ve had various testing, if we’re JAK2 V617 positive, or MPL or CALR. You know, we’ve been learning that maybe there’s one of these cancer genes that’s driving our MPN. Okay? So, we take a drug that maybe inhibits that, like the JAK2 gene. But is this the idea of hitting the cancer cell in more than one way, like coming at it, hitting it up here, hitting it here? Is that the idea with combination therapy?

Dr. Verstovsek:

Yes. Correct. We know that underlying biological problem in all the patients, ET or PV or myelofibrosis, is the activation of the signaling inside the cells called JAK-STAT pathway that drives the growth of the cells. But there are many other abnormalities that would lead to different outcome of the patients or aggressiveness of the disease.

In ET there are not matching of extra—that you can find by looking at the genetics. There are not too many patients that have any other genetic abnormality other than the driver mutations like JAK2 mutation. And they don’t have usually many of abnormalities in chromosomes that carry genes. In myelofibrosis that is rather the norm and that’s why this disease is more aggressive.

And so, one of the factors, for example, it’s a good example, this PI3 kinase. That’s the enzyme inside the cells that appears to be very active, and another factor that would perhaps lead to disease progression or a refractoriness to the ruxolitinib in myelofibrosis patients.

So, understanding the biology of the disease and identifying other factors that are not normal that would be amenable to the therapy that we are developing with the sponsors, with the commercial sponsors, then we would be aiming to tackle the disease process in two different ways.

One would be with JAK inhibitors to tackle the JAK-STAT pathway. PI3 kinase problem with PI3 kinase inhibitor. The fibrosis with antifibrotic medications. The genetic expression with so-called hypomethylation agents. The anemia problem with anemia drugs.

So, there is a whole slew of combinations that are being studied in the clinical arena, with either the normal agents that go after some biological abnormality or some even commercially available medications. Like today we heard about azacitidine (Vidaza) or thalidomide (Thalomid) being added to ruxolitinib (Jakafi) to tackle the anemia or bone marrow response.

So, we are learning a lot and we are trying to address those clinical needs by looking at biology and adding biologically active drugs. We are not using chemotherapy here.

Andrew Schorr:           

So, Lindsey, some of these drugs he’s mentioned, these are approved for other cancers?

Lindsey Lyle:  

Correct.

Andrew Schorr:           

So, is that the learning that happens at a conference like this, where there’s research that’s presented with approved drugs that have done well for other cancers? Thalidomide for years has been used in multiple myeloma and other blood-related cancer. So, whether these drugs can be combined with what had been approved for MPNs. Is that the idea?

Lindsey Lyle:  

Correct. Right. So, this is happening across all cancers really, because it’s going after cellular production in a way different mechanisms that seem to go awry in a variety of malignancies but maybe the outcome of those abnormalities are different, such as the disease looking different. But so, kind of using what he have or what we know works well in other things.

So, for example, azacitidine, which we know works very well in myelodysplastic syndrome and also in some AML patients, trying to use that in combination with ruxolitinib. So, I think that the bigger thing to take away from when you’re talking about using therapies that are already approved for other cancers is, number one, how is that going to affect the myelofibrosis patient, because just because that does work in another cancer, number one, it may not have the same affect, but also is the toxicity or safety profile acceptable?

So, these are all the things that the researchers are looking at in combining agents that are already approved for other diseases.

Andrew Schorr:                       

Hmm. Yes, Srdan?

Dr. Verstovsek:

You can look at that in a simplified way of saying, “Okay, we have a medication, ruxolitinib, that is credible for a duration of the time in majority of people by improving quality of life or spleen, and maybe people live longer. But it doesn’t last forever.

So, the major area of unmet needs you would say, it is after ruxolitinib, what do you do? But you can think differently. You can say, “How do I expand the value of what we already have? How do I bring additional benefit to it so that maybe combinational will not last only a year or two or three, like ruxolitinib does?”

Let’s say a combination’s going to last five years, or 10 years, or perhaps we get lucky and get the cure with combination. But let’s control the disease and not let it sleep under the ruxolitinib alone. And let it cover for much longer. So, that appears to be major focus, I would say, of this meeting. There are not too many actual presentations of second line therapies. It’s many, many more of combinations.

Andrew Schorr:           

Combinations.

Dr. Yacoub:     

Correct. And that comes in in multiple waves, so I’m sure we’re going to hear more about some of the molecules who will be investigated after ruxolitinib has done its part and stopped working.

But the other observation I’d like to add to what Srdan has mentioned, is that the clinical trial designs are becoming more patient-centric. They are focusing at any points that actually mean a lot to patients—their quality of lives, their symptoms core, their improvement, their fatigue. So, it’s not just about measuring cancer markers by inches and by numbers. It’s really about how patients perceive it.

So, we want to have medicines. We want to combine drugs, but we don’t want to have an active combination that ends up being disadvantageous in the quality of life of patients. So, we’re trying to balance activity along with quality of life to try to give patients the best possible combination of active drugs. And probably be more individualized to their diseases and their specialized molecular markers.

Andrew Schorr:           

Yeah, look, so I’ve been living with myelofibrosis since 2011 and been doing well.

Thank you very much. And it’s worked well for me. I’ve had great doctors and good treatment. So, we’re hoping to go to New Zealand. That’s a month-long trip. Even from California here. And I do not want my MF to get in the way. I want to have energy.

Dr. Yacoub:     

Correct.

Andrew Schorr:           

And I want to be able to enjoy life. And I really appreciate you saying that, recognizing what’s so important for us. It’s not just the number.

Dr. Yacoub:     

And I keep being reminded by a patient that actually shadowed with Srdan, who has gone through every single therapeutic option she’s ever been able to receive. And then she enrolled in a Phase 1 clinical trial that we presented this meeting. And now she has had such a remarkable improvement in her life and quality. And two years later she’s done every cruise I have heard of. She’s been around the whole world and there’s no signs that this going to slow down anytime soon.

Andrew Schorr:           

Wow. Well that would be great. Now, Chris, you know, over the years, we’ve talked about, “Well, if ruxolitinib stops working, or doesn’t work for you, what else do we have like as a JAK inhibitor?” Okay? And now you’re talking about a combining a—or a booster to ruxolitinib.

But let’s not leave out, are there other JAK inhibitors in development? Because for the last couple years, we’ve heard about trials for this, that. I’ve talked to Claire Harrison about this trial and that trial. But we haven’t heard a lot lately. So, where are we, Srdan?

Dr. Verstovsek:

Well there are other JAK inhibitors in development. There are still other JAK inhibitors in development. Some have actually been resurrected that were put on a shelf by one company and now picked up by the new company and are put back in development. A case in point is the fedratinib.

Andrew Schorr:           

Fedratinib. Yeah.

Dr. Verstovsek:

Which is the one that most recently was obtained by a company called TargeGen, where we understand that there will be an attempt to get it approved in a short order.

Although there are plans to do more studies with it, even Phase III comparison studies to base valuable therapy like it was done in the past with some other JAK inhibitors. But I think the time to improve another JAK2 inhibitor whether it would be fedratinib or momelotinib, is another one that was recently resurrected from the dealer who failed to develop it in the Phase III studies.

The second drug that has been resurrected, or even pacritinib that is still in the development. So, three of them are still in contention here. I think the time to improve over the next one, and that would be in the second-line setting after ruxolitinib, is shorter and shorter and I think it’s going to happen soon. I can’t really say 2019 or not, but we are expecting that there will be some development because we put all together—patients and doctors and the companies—much effort in developing another line of a JAK inhibitors.

Andrew Schorr:                       

Okay. Go ahead.

Dr. Yacoub:     

And I think those new trials are a lot more wise and more carefully designed, so all the previous and rigorous studies were not completely wasted. We gained so much knowledge on how those studies were not positive. And the newer generation of clinical trials have been designed more carefully, more focused in the right type of preparation, the right kind of patients. So, we’re very optimistic about those trials resulting in different outcomes than the other trials.

Andrew Schorr:           

Okay. He mentioned earlier antifibrotics. So first of all, just so we understand, for me with myelofibrosis or generally with MPNs, we’re developing scarring or fibrosis in our bone marrow. Did I get it right?

Lindsey Lyle:  

Correct.

Andrew Schorr:           

Okay. Now would somebody with ET or PV have that as well?

Lindsey Lyle:  

Well, it can be on a continuum a little bit. So, generally, in ET we don’t see fibrosis in the bone marrow.

In polycythemia vera you may see very slight degree of that. But generally, it is diagnostic for myelofibrosis.

Andrew Schorr:           

Okay. So, antifibrotics. So, we talked about JAK2 inhibitors existing and in development. What about antifibrotics?

Dr. Yacoub:     

So, again, there are different schools of thought on whether the pathology that you see in the scarring in the bone marrow is actually the problem. Or is it an aftermath of the original problem? So, there have been a few efforts trying to treat the cancer at a much earlier phase. And prevent the scarring by actually treating the mere problem rather than targeting the scarring itself.

So, there are newer molecules that target myelofibrosis at the more early phase of the stem cells and have resulted in normalization or change in the morphology of the bone marrow with the scarring.

I think that might be a very wise approach. Srdan has been very involved in the antifibrotic agents and I will delineate to him to share some of those results, probably what presented from last year.

Andrew Schorr:           

Yeah, go ahead.

Dr. Verstovsek:

Yeah, so this was actually very good point to say that to couples with our early observation that we learn a lot over the years. Not just about how to utilize the medications or how to design the studies, but about biology. And the question is, is the fibrosis just a reaction to the presence of the malignancy? Do you need to go after the fibrosis as a part of the disease process? Is it not perhaps just a reaction? Or what do we actually do?

So, there are efforts in both ways, right? To tackle the malignancy that would lead to decrease in fibrosis, or to tackle the fibrosis actually as a part of the disease process. And the PRM-151 is the one that is tackling the fibrosis itself because it seems that fibrosis is part of the disease.

And you tackle the fibrous sites, the cells that make up the bulk of what you see in the bone marrow. Those fiber optic tissues are made up of these fibrous sites. And if you can prevent them from becoming a fibrous sites, they come from other blood cells, then you would over time decrease the fibrosis. And that would potentially lead to clinical benefit in improvement in the red blood cell production, platelet production, and perhaps quality of life, improvement in the spleen.

So, studies are tackling the biology that we are learning about in different angles. I don’t think there is one right angle. We are trying everything. We have so much going on, right?

Dr. Yacoub:     

And there has been very success for agents that results in very meaningful clinical improvement. And in both the patient’s quality of life and the disease outcomes, without affecting the fibrosis. So, we’ve been observing that you don’t have to couple what you see with what you get.

So, you might have, so—but then some newer generations of molecules that we believe to be disease modifying, they go into the provisional cells of the disease, and hid them there where the whole fibrosis process which could have been an aftermath, would not happen and might improve with time.

So, that would be—that is a new generation of drugs that we’re researching right now. And we don’t have a lot of that presented this ASH meeting, but there will be more coming soon, hopefully.

Andrew Schorr:           

Okay. So, I want to ask about acute myeloid leukemia, because we—particularly if we progress to myelofibrosis, know we have a risk of that. And different from people who develop AML as a primary diagnosis, for us it would be secondary. And I know that’s been tough to treat over the years. So, Srdan, two things.

One is, with many new drugs, I think like 6 or 8 new drugs in AML, does any of it apply to those of us who could develop secondary AML coming from myelofibrosis to give us hope if that? Or can we head it off at the pass, where if you see it coming, you can stop it?

Dr. Verstovsek:

Excellent. So, these are two different approaches. One is, “Yes, you have a problem, what can I do about it?” And the other one is, “It’s coming, you can see it coming, can I prevent it and treat it early?” So, once you have established acute myeloid leukemia, like with any other type of leukemia you would look at, and you ask a question about the genetic profiling.

Is there some genetic abnormality that we have a medication for? Like IDH inhibitors are now approved. Up to six percent of the patients with MF and MPN can have those mutations. I actually have couple of patients on these particular drugs—IDH inhibitors.

LF—FLT3 inhibitors are approved. There are a couple now. That is not as common, but you test for it. If it’s there you use that particular inhibitor for that particular mutation.

So, some of the new agents can be useful in the AML after myelofibrosis or MPN in general. Some of the other are rather non-specific, like Bcl-2 inhibitor or new compression chemotherapy. Perhaps less needs to be studied, because remember, this group of patients with ML after MPN is relatively small within the larger population of AML patients. So, not too many specific studies. And so, the experience will tell us.

But on the other hand, to tackle the other side of the coin, is the acute myeloid leukemia hardly ever—there are exceptions—happen overnight, right? You live with the PV, ET or myelofibrosis and you see blasts coming up. These are leukemic cells basically, and if you have more than 20% that’s acute myeloid leukemia. But you can’t see them coming up. So, we all agree that there is an accelerated phase which is in between normal, which would be up to 5 percent. So, 10 to 20 percent of blasts, is called accelerated phase.

And so, that’s inevitable progression then. And you intervene early. That is even built in national guidelines now.

Andrew Schorr:           

Correct.

Dr. Verstovsek:

You don’t wait. What are you waiting for, right? So, you intervene with the therapies that potentially can lower the blasts, are the commercial—the high methylation agents.

Andrew Schorr:           

Correct.

Dr. Verstovsek:

Or even studies are being developed for that particular area, like MDN1 inhibitor, right? So…

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Page last updated on December 11, 2018