ASH 2016: MPN News and Updates From an Expert Panel

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Topics include: Treatments and Understanding

As part of our coverage from the 2016 American Society of Hematology (ASH) annual meeting, MPN experts Dr. Catriona Jamieson, Dr. John Mascarenhas, Dr. Stephen Oh and our own Andrew Schorr, gathered to discuss the latest updates on treatment and research for myeloproliferative neoplasms (MPNs). In this fruitful discussion, the experts shared their perspectives and optimism for the future, reviewed treatments in development and results from recent trials, the role of genetic testing, and advice for patients related to seeking the best care and therapy.

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Andrew Schorr:

Hello and welcome to Patient Power. I'm Andrew Schorr, and we're on location at ASH '16, the big American Society of Hematology Meeting, meeting this year in San Diego and researchers from around the world and practicing physicians, some patients—like us—come to hear the latest. And with us are three leading experts in the MPNs. To my right is Dr. John Mascarenhas. He is from New York City, and he is from the Mount Sinai School of Medicine, but he's also a leading expert in MPNs. He's Associate Professor of Medicine in Myeloproliferative Disorders at the TISH Cancer Institute. Thanks for being with us.

Dr. Mascarenhas:               

Thanks for inviting me.

Andrew Schorr:

And, to his right, is my doctor at UC San Diego and the Morris Cancer Center, is Dr. Catriona Jamieson. 

She is a Professor and Chief of Regenerative Medicine. Did I get it right?

Dr. Jamieson:      

That's right.

Andrew Schorr:

Thank you so much for being with us, Catriona. 

Dr. Jamieson:      

My pleasure, Andrew.

Andrew Schorr:

And then, to her right, is Dr. Stephen Oh, who's from the Siteman Cancer Center and the Washington University School of Medicine. You're an assistant professor there assigned in myeloproliferative conditions. Thanks for being with us, Stephen.

Dr. Oh:

Happy to be here. 

Andrew Schorr:

Catriona, let's start with you—right in the middle, here. So what are you excited about? You get thousands of people together, and more and more of them are talking about MPNs. They didn't years ago. So you have more to talk about and you, being a specialist in that area, there are more people in the room and there are more things to talk about. What do you think you're excited about for your patients and the patients watching worldwide?

Dr. Jamieson:     

I think what I'm excited about at this meeting is the power that patients have had to exact a change in the field. So we actually study real patients, we do real sequencing—both at the DNA level and the RNA level—in patient samples rather than trying to infer how the disease evolves. I think that has been a very powerful change in our field. A lot of us did experiments in reductionist model systems or mouse model systems and tried to say that mice are the same as humans and, of course, we're a little different. We, hopefully, will live over 80 years—mice have to live two years.

So there are some essential changes or differences between mice and humans that have really come to the fore recently—for example, how we handle RNA. We splice, we make different pieces of our RNA which, if you think about it, if you're going to remodel your house, the DNA is the blueprint. That's what the architect set up, that's what the basic building blocks for our genes are, he RNA is the engineer's interpretation of that blueprint, and then the protein is the builder. So there can be three things that go awry in myeloproliferative neoplasms, and, now, we're really able to look into all those three.

And it's not to say that the model systems that are being presented aren't really important—they give us really essential insights—it's now that we can dig deeper with real patient samples. And then the other thing that I'm very excited about is shape—how do we look at DNA and RNA from a topology standpoint, from a shape standpoint? So it turns out the three-dimensional structure of DNA and RNA really matters for function. So that's what's coming out of this meeting. It sounds very basic science, very abstract, but it's going to matter very quickly for the MPNs, I think.

Andrew Schorr:

John, you're nodding your head. You're a scientist, too. And what I'm trying to understand is, for us patients, we're in partnership now—will this pave the way for us?

Dr. Mascarenhas:               

I hope so. Listening to Catriona talk, I look at it from a different perspective. So I'm a clinical investigator, so in the translational world I sit on the other side and the insights that are gained—both at the molecular level and the biological level—I look to see how those can be translated effectively into therapies for patients with MPNs.

And I would say that, in recent years—and ASH this year—we're beginning to see more and more translation from projects in the lab that then help benefit patients in the clinic, and that's really where the excitement is. And it starts early on, in early phase studies, testing small cohorts of patients with drugs that have biologic rationale. And then, hopefully, if there's a signal of activity and not a signal of toxicity, they can progress to more mature type of clinical trials.

Andrew Schorr:

Okay. So as you're gaining these insights into—I don't want to say into the nooks and crannies, because it's not that—but a much sharper level. Do you feel that's going to lead to more precision medicine for us in the MPNs? 

Dr. Mascarenhas:               

I think so. I think we're already seeing that happen in leukemias, in general, but MPNs included. And one of the things that Catriona said, I totally agree, is one of the opticals we have is that many things look very promising in a mouse—in a murine model. But then don't necessarily—you can't really recapitulate that in a human being, because the humans are much more complex.

At every level, they're more complex. So understanding the complexity or being able to tease that out to better tailor therapies based on whether it's mutation profile or other cytokinetic profiles is where the direction is moving—where research is moving towards.

Andrew Schorr:

Hmm. Okay. So, Stephen, so people want to know—a patient comes to you in St. Louis and say, "Okay, you're doing this really cool science, and you're looking at things in a much sharper way—in a nano way, if you will—what does that mean for me?" What are you telling people? 

Dr. Oh:

Yeah, so I think a good example of that question is, with regard to the different genetic tests that are now available—not just testing for JAK2 or calreticulin but these 30, 40 or more gene panel tests that are out there from commercial labs—I would say, if you rewound three or four years ago and a patient asked me, "Is this something that I should be tested for?" I would say, "Well, we're doing a lot of research in this area, but it's not really practically useful at this time."

There are still really caveats and much to be learned about the implications of this kind of testing but, for me, at least, there's been a big shift in the past couple of years to using these tests more and more frequently and with more confidence as to what the results might mean. 

Andrew Schorr:

Okay. So, Catriona, you've sent tubes of blood of mine—the other day, it was seven tubes of blood—and that goes across the country into different labs and your lab, etc. So what are you going to learn from that that can help me and help others? 

Dr. Jamieson:      

Well, I think that patients now are getting to be extremely savvy and can consider themselves scientists by asking the question why. "Why did this happen? Did I inherit this? Can I pass it on?"

That's called a germline mutation, and that's really what we're looking for—because we didn't just get your blood, we got your spit. And so, when we get the saliva, we're really trying to understand, from the DNA in the saliva, what did you inherit. And then the DNA in your blood tells us what did you acquire as your disease evolved, and how can we stop it from progressing. And so the reason we're doing that—at a nano level if you want to use that term—is because, now, we're delving into the stem cells. So does every cell matter? If one cell gets a mutation but it only lives for seven days, who cares? But if your stem cell gets a mutation, it's going to last your life—your entire life span—if that's a robust stem cell.

So we're now digging into the stem cells and saying, "Are there mutations there?" And this is not unique to us—there are many groups doing this—it's called clonal hematopoiesis. So we can acquire mutations at the level of the stem cell, but what cancer does, especially as it progresses, is it can co-op stem cell pathways in cells that are slightly more mature. And they think they can behave like a stem cell.

So it's like a teenager like my daughter who's going to learn how to drive—she thinks she's going to be pretty good, and I'm not so sure about that. She may not know how to apply the brakes yet. And that's what happens with MPNs as they start to progress—the progenitors that are one step down from the stem cells don't know how to apply the brakes. They co-oped or hijacked these stem cell pathways and then they say, "Great. We're off to the races," but they can't shut them off. So a tangible example of why that matters is we started studying that in another MPN called chronic myeloid leukemia a few years ago, and we found activation of a stem cell pathway at the wrong stage of blood development, and that was called the "Hedgehog pathway." 

We found we could target Sonic the Hedgehog—and Sonic the Hedgehog is what is in mammalians—anyway, it seemed like a silly pathway to work on, but it ended up being extremely important. The positive results of the Phase II trial are being presented here in acute myeloid leukemia by Jorge Cortes where the hedgehog inhibitor was used in combination with low-dose chemotherapy for people with AML that had evolved from MDS, or myeloproliferative neoplasms. 

So, usually, people want to know how did they get this? Can they pass it on to their kids? And what's the likelihood that I'll progress to AML? And, if we do progress to AML, what do we do about it?" So the… 

Andrew Schorr:

…so you're on the trail?

Dr. Jamieson:      

We're on the trail for what we do about it. Things can go from bad to worse, but, even if they do, can we pull them back by taking away this bad stem cell behavior that allows these cells to clone themselves? And the answer is yes, we can, in part. So we can take you back to an earlier stage of disease, particularly if you incorporate this combination strategy.

Andrew Schorr:

Wow. Reset. So, John, so people know many of the medicines that are available for these conditions now, whether it's a JAK inhibitor—and we'll talk in a minute about where there'll be others—hydroxyurea (Hydrea) and other medicines that people take for some of these conditions, but she was talking about hedgehog inhibitor.

So I just want to ask a question—are there medicines that are developing for other cancers that may apply here because you're learning of some commonality or some other pathway—things like that?

Dr. Mascarenhas:               

Yeah, so the repurposing of therapies or agents that have shown success—or may not even have shown success—in other malignancies or even non-malignant conditions, in some cases, can sometimes be utilized in MPNs. And there's actually, if you sit back and look at all the abstracts that are being presented at ASH this year or last year—even in the last five years—you'll notice there's a lot of promiscuity.

There are a lot of agents that are being used in lots of different fields. And I'll give you one prime example, because it's something that I've been interested in for the last 5+ years, which is panobinostat (Farydak), which is a histone deacetylase inhibitor which, when we first started working on it, didn't have a name—it was just called LBH589. 

And it basically is an agent that inhibits or affects the protein scaffolding in which DNA is wrapped around and enables cells to produce or to transcript genes that would normally be silenced. So this was what's called an epigenetic-type therapy that was being looked at in a lot of different hemotologic malignancies and then saw positive signal, for example, in multiple myeloma. And, now, today, there's a drug, panobinostat, approved for myeloma. It's still struggling in myelofibrosis and other diseases—but I think it has activity—but it's an example of where there is the ability for multiple agents in multiple different related hematologic malignancies to have a promising effect.

Andrew Schorr:

Okay. And then let's get to the nitty-gritty of where we are now. So we have ruxolitinib (Jakafi) that's been approved for a few years now. I've been on it. It doesn't work for everybody. We have other JAK inhibitors that have been in trials. Is there any news about that?

Will we have others? And then we'll continue our discussion about other kinds of drugs, but let's just talk about JAK for a minute. 

Dr. Mascarenhas:

Sure. So I think the abstract that many of us are waiting and interested to be presented will be a late-breaking abstract on Tuesday morning, which will be the result from the PERSIST-2 Study with pacritinib—one of the other JAK inhibitors. And this is a drug that has gone through a couple twists and turns, but amongst the notable features are that this drug seems to cause less effect on the platelet count. And so, perhaps, would have a specific role for many are aware, the drug has been on hold by the FDA due to safety concerns, but the results that will be presented on Tuesday are updated results from the PERSIST-2 Study. So we'll see what they have to say in terms of both safety and efficacy. 

In the best-case scenario, if this drug were to be shown to be efficacious and safe, then, ultimately, again, it could have a potential role—particularly for those patients that have low platelet counts.

Andrew Schorr:

Okay. And momelotinib is another one and there was some data I saw, if I understood it right, that said it has effectiveness but didn't seem to be as exciting as they thought. 

Dr. Mascarenhas:               

Yes, so momelotinib, again, another JAK inhibitor. Perhaps one distinction with that—and compared to ruxolitinib pacritinib is that, in the early phase study, there was a significant proportion of patients who had improvement in anemia. And that is, of course, a major issue in patients with myelofibrosis and something that does not typically improve on treatment with ruxolitinib. And, as you alluded to, just before this meeting, there were topline results released from two Phase III studies with momelotinib and myelofibrosis. 

And, if I recall correctly and to simplify, one study which was randomizing patients to receive either momelotinib or ruxolitinib, they conducted what's called a "noninferiority analysis" basically saying, "Is this drug not inferior?" and that was found to be true in terms of spleen response. However, they did not meet the secondary endpoint of symptom response. It's a mixed bag there.

The other part, I think, that's unsatisfying at this point is we don't have detailed information about anemia response in that study because of the way that, I think, the statistical analysis was designed—they did not conduct that. There happens to be a separate study that's ongoing that we are participating on which is focused specifically on this anemia question. So it's enrolling patients who have transfusion-dependent anemia, and all of those patients will be treated with momelotinib.

So that's a smaller study, but, hopefully, we'll gain some clarity as to the potential benefit of momelotinib for anemia.

Andrew Schorr:

So, Catriona, we hear this drumbeat of pipeline drugs—not yet approved—and we want these drugs to come to market so they're available to us or, maybe before that, available in a trial with the hope that it will improve things. So when there are FDA holds and you're talking about noninferiority, it's not really exciting. Maybe you could put this in perspective, because it dampens the enthusiasm, if you will.

Dr. Jamieson:      

Well, it certainly does for us, as well. We've all been in this field for a little while, so it's not a great ASH for us, because it's a wake-up call. Maybe monotherapy is really not sufficient. In a disease like myelofibrosis, it's fairly complex—either because the drugs that we give as single-agents long term can have long-term side effects or just not sufficiently effective over the long term to eradicate the malignant clone or clones plural.

So I think that what we're looking at is some drugs that have very specific effects—whether it's momelotinib actually not inducing as much anemia or NS018 which is made by NS Pharma—very selective JAK-2 inhibitor, not quite as potent but doesn't cause the low platelet counts—pacritinib, same thing, JAK2617F inhibitor—very good as a drug, doesn't cause low platelet count. But maybe bleeding in some patients so, maybe, if we lower the dose—Imetelstat's another one, a telomerase inhibitor.

We may be able to get away with combination strategies so that we'll be able to have what I like to think of as the future of care, which is a treatment-free remission. Now, that's a very ambitious strategy, but we've done that with chronic myeloid leukemia where, now, that's part of the lexicon. "Of course, you come off therapy." Who would even have thought that that would be the case? But the way to do that is to determine, in individual groups of patients—and I don't mean in individual patients but groups of patients—what have they activated in terms of other pathways?

Will they be able to respond to an epigenetic modifier as you were alluding to, or do we have to come in with these other, more interesting agents that we have to develop with one of them being a splicing modulator? So there's a lot of great science going on, and this is happening because the MPN support groups that are so strong. So we saw this with HIV—completely changed everything. So my husband works on HIV—has done research in that area for a long time—now, he has to work on preemptive treatment of HIV. Those are called the prep studies. So I think what we're doing with MPNs is we're dialing back the clock and saying, "When is the earliest time we should direct and treat these disorders? When can we redirect them safely to not allow this abnormal scarring in the bone marrow?"

So that's really the issue that we've been talking about in our NCCN panel meetings—how soon is too early to start treatment? And that's when clinic visits become quite long. I have the JAK2 mutation, I have the TET2 mutation, I have scarring, but I don't have a big spleen, and I don't have symptoms. So those are great discussions to have, because we'll understand how to move forward in terms of tailoring therapy.

Andrew Schorr:

So, John, there are many patients that tell us, "I maybe went with PV or even—I went years and nobody even told me. Either the doctor didn't recognize it or didn't tell me." And now she's talking about preemptive strategies, so what dialogue should we be having with our doctor, or where will this go?

Dr. Mascarenhas:               

Yeah. No, I think it's unfortunate when you meet patients who've had a related MPN that progresses to myelofibrosis, and they weren't even aware of it. It's not infrequent that I meet patients that are not aware that their diagnosis is considered by the World Health Organization, and the NCI, and the NCCN as a hematologic malignancy.

And they use the word "cancer" or "leukemia," and they fall on the floor. They've never been told that before, and I always find that sad, in a sense, because it robs them from what they really have, which is a serious illness. It's not necessarily meant to scare them but to put things into perspective, and these diseases do have complications that can be serious, including thrombosis and bleeding. And they have a tendency, over time—particularly if they're diagnosed earlier in life—to progress to myelofibrosis or even acute leukemia. So discussion's important, and it needs to be had in a compassionate way but an informative way. And the benefit, I think, of all the mutational molecular understanding that's taking place today is we're able, now, to better re-stratify patients, and that's an important part of the clinical discussion.

So it's not just sending a 40-gene panel Genoptics or to another company and then saying, "Oh, you have three mutations, and this mutation appears in 20 percent of your cells and this in 30 percent of your circulating cells." And, like Catriona said, that probably doesn't give you a full picture of what's happening at the level of the hematopoietic stem cell in which the disease originates, but we're able to use some of these markers now to categorize patients into risk groups. And the whole approach to treating patients—whether it's ET, PV or MF, now, is a risk-adapted approach.

The risk-adapted approaches have classically been based on clinical features and, now, they're really evolving and incorporating these molecular features. So the discussion today is what the disease is and what may happen down the line, and how we can restratify you today to better prognosticate you and, perhaps, tailor therapy appropriately to you.

Andrew Schorr:

Okay, so Stephen mentioned this panel of genetic testing. So it sounds like we patients should have that. Is that the way you feel? Is that what you do at Mount Sinai?

Dr. Mascarenhas:               

I do. I think that molecular profiling is important today in the care of patients with the caveat that I think the science is further along than the clinical applications, so I'm always cautious to warn patients that it's like a fishing expedition. Sometimes you throw the bait out there, and you get bites, but you're not always sure what to do with that. And it's happened to—I'm sure it's happened to you—where you get a readout from a panel, and it can cause alarm and fear in the patient. But, in reality, sometimes, we don't know what that actually means clinically for the patient. So you have to temper the pace of science and technology as somewhat ahead of what we can do clinically.

Andrew Schorr:

Okay. So, Stephen, we've talked about the analysis, and I think you're all doing it now. And you're all in your labs, looking further which gives us a lot of hope. But you're detectives, but you don't know all the answers yet, so let's go back to the medicines we have.

So we talked about the medicines even in development for the JAK. Now, she mentioned telomerase—where does that come in?

Dr. Oh:

Yeah, imetelstat's a telomerase inhibitor. There was a lot of excitement a couple of years ago with the initial results reported from Mayo Clinic from their relatively small study and actually seeing some patients with myelofibrosis have a complete remission on treatment, which is almost unheard of for anything other than stem cell transplant for this disease. So, as we need to do, we followed it up with a larger study, and that study is now ongoing at multiple sites.

But also, have received some disappointing news recently about that study in which there have been two dose levels and, on the initial analysis, the lower dose level did not appear to have any efficacy, and so that arm has been closed. The higher dose level, I guess the best way to say this is there is, perhaps, some hint of activity but it requires longer follow-up and further analysis.

So that study is currently suspended in terms of further enrollments until there is more follow-up and more analysis.

Andrew Schorr:

Okay. And there's also been study of a drug—I know at least one—to try to reduce the scarring.

Dr. Oh:

Yes. 

Andrew Schorr:

Where does that stand?

Dr. Oh:

So PRM-151 is, I think, the drug you're talking about and that's, I think, very promising. I don't think there's any results being presented at this year's ASH, but there have been earlier results presented in years past, and it does appear that some patients have had improvement in their fibrosis treatment with this medication. And it's being looked at in combination with ruxolitinib, as well. So I think there's certainly optimism with that. In comparison, I participated in a study with a different anti-fibrotic agent, simtuzumab, a LOXL2 monoclonal antibody, and that study was negative. So this one, PRM-151, is looking promising. We'll need to see what the next update shows.

Andrew Schorr:

Okay. So, Catriona, let's back up. So John alluded to it—talking about people living a long time, diagnosed early with, say, ET, and they say, "We've been talking a lot about these drugs for myelofibrosis." They're going to say, "Is that me? Is that where I'm headed? Or, are you going to be, with genetic panels, able to tell me that's where I'm headed? And, if so, what do we do about it?" In other words, "Should I worry? Am I on a freight train going toward myelofibrosis?"

Dr. Jamieson:      

Yeah, we worry about that freight train and I think that, again, if the cells are really mature—they're not going to last long in the system—we have to forget about those cells and look a little bit earlier in the hematopoietic or blood-forming system or look at the stem cells and their immediate daughter cells called progenitors to try and prognosticate for the future what's likely to happen with that clone —that long-lived clone. So, in essential thrombocythemia, what we're really looking for is do those stem cells have a survival advantage or don't they?

Are they CALR-mutated or are they JAK2-mutated or do they have BCLXL overexpression? And, if they do, think of drugs like Navitoclax which is a BCLXL inhibitor. It's a BX3 pneumatic but it inhibits BCLXL so that could be a great opportunity. So I think we have to look, as John was saying, at drugs that may have failed in other indications but may be extremely useful earlier on in some of these other diseases where we're just saying, "Well, we know we have to stop clotting or thrombosis, in other words, but we don't know how to stop that freight train."

Well, it can become a freight train so I think we have to look at how many markers does it take to be a freight train? Or, if you've bot JAK2617F, or you've got CALR mutation or MPL and then you add to that, BCLXL up regulation, maybe we should be looking at that. Not just in terms of treating with a JAK2 inhibitor or even interferon, but maybe we should be coming in with Navitoclax.

So the reason I keep talking about combination strategies is this is a way the rest of the cancer field has gone. If you think about diffused-lodge B cell lymphoma, for example, or a lot of different types of lymphoma, we give combination therapy. Why would be ever give a single agent? That seems a little facile. So, other than CML, chronic myeloid leukemia—where, clearly the driver is BCL-enabled and, as long as you can treat early, you can stop it—I think, for other diseases, we're kidding ourselves and we just need to say maybe they're a little bit more complex so it's going to be a little harder but that doesn't mean it's impossible.

And, in fact, if we start earlier, we can start these therapies and then may

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Page last updated on February 13, 2017