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The State of MPN Treatments

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Published on June 5, 2020

Key Takeaways

  • Luspatercept (Reblozyl) was recently approved for treating myelofibrosis (MF). This is important, because it should reduce the number of red blood cell transfusions required for MF patients.
  • Patients living with PV or ET have two major choices for cytoreductive therapy—hydroxyurea (Hydrea) or interferon.
  • Communication with your doctor and/or nurse practitioner is essential when talking about and deciding on treatment options.

Treatments for myeloproliferative neoplasms (MPNs) can range from aspirin to transplants. What are the current treatment options, and how do you and your doctor decide which one is right for you?

In this segment from our recent town meeting, MPN experts give an overview on the current state of treatments, explain how doctors decide on treatment options, share what’s coming down the pipeline and more. This program features Dr. Catriona Jamieson and nurse practitioner Becky McAlpin from UC San Diego Moores Cancer Center, and Dr. Bart Scott from Seattle Cancer Care Alliance. Watch now to learn from MPN experts.

This program is sponsored by Bristol Myers Squibb. This organization has no editorial control. It is produced by Patient Power in partnership with Bag It, MPN Advocacy & Education International and MPN Research Foundation. Patient Power is solely responsible for program content. ​



MPN Advocacy & Education International

Transcript | The State of MPN Treatments

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:

Dr. Jamieson, treatments for the MPN range from aspirin in some cases, all the way to transplants.  How do you think about that?  How do you come up with recommendations for your patients?

Dr. Jamieson:

Some of us are more risk averse than others, and we won't want to consider a transplant. And other people will say, "You know what, I want to consider a transplant. I want this to be gone and I really want a curative option." MIPSS70 plus, which is mutation enhanced international prognostic scoring system for people under 70, where we also add the amount of scarring in the bone marrow turns out to be very, very helpful in terms of trying to predict who should see Dr. Scott for a transplant, as opposed to continue on a JAK2 inhibitor, or start on a JAK2 inhibitor.

So we've got two drugs approved in first line to really try and curtail the activity of one of the main drivers of this disease. And so that's a very important thing that we can do. And also in the NCCN national conference of cancer network panel that was originally started by Ruben Mesa, our friend, who focuses not just on quantity of life but quality of life, as you mentioned. We talked about a drug called Pegasys or pegylated interferon. So for people who don't respond to one of the JAK two inhibitors, we have that.

And then ultimately what we would really like people to do is participate in clinical trials, even if it's for a bio repository as it's called, so we can understand how these diseases came about and how they evolve. So as Becky and I have kind of been brainwashed, we try and get everybody on a clinical trial, even if it's for bio banking where we can do research to understand the disease

And really the big question now is when to use a combination strategy. When do we come in with a JAK2 inhibitor plus something else like a BET inhibitor, or a Bcl-2 Bcl-X antagonists like navitoclax. At what stage do we do that?  And that's really determined by person with the disease. People say, “Okay, I have time to consider a clinical trial, and I want to take that on as my job for the next couple of months.” And we have a discussion about that. Other people say, “I want to be matched and see if I could have transplant as an option.” And some of these are dictated by other health problems. Some people have more than one cancer, and it turns out that that is quite a common thing in myeloproliferative neoplasms, and so even though that sounds like bad news, the good news is the FDA is approving things so quickly. It's actually really kind of heartwarming.

What are the biggest advances in our field was the recent approval of a drug called luspatercept or Reblozyl.  One, because that should cut down on red blood cell transfusion requirements for quite a proportion of patients with myelofibrosis. So I'm thrilled about that. It's a TGF beta inhibitor, tumor growth factor beta inhibitor. And as you know, that has been implicated in driving scarring in the bone marrow together with JAK two. So this could be a twofer. So I'm really trying to get that into more of our patients. It's an injection under the skin every three weeks.

Andrew Schorr:

Wow. Well, so, Dr. Scott, I love hearing the science, and usually when I see Dr. Jamieson and Esther and I sit there, it's like science class. So, Dr. Scott, let me back up for a little bit. There are some people early on who may just need aspirin, right?

Dr. Scott:


Andrew Schorr:

Or there's a drug that's been around for a long time, hydroxyurea (Hydrea), that still seems to have a place. And then also we were talking about interventions, phlebotomy, or basically drawing off cells. People have been getting terrible migraines and all that. So does that still have a place, these sort of not super scientific therapies, older therapies?

Dr. Scott:

Yes, absolutely. So it's kind of interesting to follow the progress of all of this over time. But one of the very first trials that was conducted for myeloproliferative neoplasms was comparing phlebotomy to other agents that we don't use so much anymore. And the phlebotomy arm ends up providing the best leukemia-free survival, and I would say that phlebotomy, for some patients, is an adequate treatment. It's generally people with polycythemia vera, who have a hematocrit greater than 45, and you're trying to diminish their risk of thrombosis by iron depleting them.

And then aspirin has been studied in a randomized trial called the European Collaboration on Low-dose Aspirin Therapy in Polycythemia Vera, otherwise known as the ECLAP trial. So good that we have shortening of that one. But that was a randomized trial where patients received aspirin or placebo, and the use of the aspirin was shown to decrease cardiovascular events, thrombosis, and things along that nature.

So phlebotomy and aspirin is one of the mainstays of therapy for patients who have polycythemia vera, who haven't progressed to myelofibrosis, who are kind of in a lower risk category. Now whether you have ET or whether you have PV, we do look at risk factors for blood clots and blood clots, or thrombosis, is one of the major problems that people with ET and polycythemia vera can have. And if they fit into kind of a more higher intermediate or higher risk category for blood clots, whether they have ET or PV, then we would generally advocate for those patients to receive cytoreductive therapy. And there are two major up-front choices for cytoreductive therapy for patients with PV or ET, and those up-front choices would be either hydroxyurea or interferon.

And the choice between those two, I think is a little bit controversial. But I'll summarize the data that we know as follows; there have been two randomized trials comparing an interferon like therapy to hydroxyurea. The first one was the MRC 112 trial, and it randomized patients to either receive pegylated interferon or hydroxyurea, and there didn't appear to be a big difference between the pegylated interferon group and the hydroxyurea group.

And, unfortunately, I think we're going to be somewhat limited to follow those patients long-term to know which would be better.

What I do for my patients is I talk to them about the data that we know, and I've talked to them about the side effects of both interferon and Hydrea, and we discuss which would be the best for them. In general, I would favor using the interferon compounds in younger patients, and I would favor using the Hydrea compounds in older patients, and that has to do with my own thoughts about tolerability and the potential benefits of obtaining a molecular remission.

So, Dr. Jamieson, does that ring true for you? I know—and Dr. Scott was saying there's debate about some of this, I know you talked to some of the European doctors, they are big fans of interferon.

Dr. Jamieson:

It's funny because Dr. Scott and I were the big proponents for interferon, but we had the last NCCN panel in-person. It was kind of surprising, because I've been involved in the JAK2 inhibitor development, and Dr. Scott has been involved in the allogeneic transplant field, and yet we both said, "Interferon is a pretty good choice." It's harder for some people to get, it's actually pretty expensive with a high co-pay, because they approval for Pegasys, pegylated interferon, not ropeginterferon, but the standard pegylated interferon was not for myelofibrosis. But one point I wanted to add to what Dr. Scott said so eloquently there is pregnancy.

We don't want people on hydroxyurea if they're planning to become pregnant or if the risk of becoming pregnant, because it can be teratogenic, so in other words, cause problems for the fetus, the developing fetus. But also for men who are partners of people who want to become pregnant, I say, "You know what? We should switch you to pegylated interferon or Pegasys.  And for women who are pregnant, Pegasys seems to be entirely safe. So that's a very good choice, not only if you're planning to become pregnant but also if you are pregnant. So we've carried people through pregnancy with Pegasys, and we certainly wouldn't do that with hydroxyurea or even with a JAK2 inhibitor.

And the one thing that I was just kind of surprised me with a few of my patients is depression, which is a known side effect of interferon and not in people that didn't have depression before. Everybody I've seen with that did have a past history of depression, but that kind of sneaks up on people in a surprising way. And with hydroxyurea, what I worry about are skin cancers. So I see more people maybe just here, because it's Southern California who have skin cancers that seem to proliferate a little bit more on hydroxyurea. And there were some patients who had transformation to acute leukemia on hydroxyurea. We're not as much as with fly embryo cell or with P-32 as we saw with the other previous studies. But nonetheless, even though it's not statistically significant, it may be clinically significant.

So yes, Andrew, the Europeans like it because of what Dr. Scott was alluding to in that said, it looks not only do some people get molecular remissions and clear their JAK2 mutation or calreticulin or MPL mutation, they may actually reduce the scarring in their bone marrow, and they're in very early stages of disease.

Andrew Schorr:

So, Becky, she mentioned possible depression, we talked about other things if you are pregnant? So these are all conversations that you're asking people questions all the time. How are you doing? Are you feeling this, feeling that? You're monitoring when somebody goes on any of these medicines including the JAK inhibitors, and we're going to talk about those more in a second. So that dialogue with you about how you're doing on a certain therapy or what's going on with your illness and how are you feeling? That's got to be a two-way street, right?

Becky McAlpin:

Absolutely. I feel like a lot of patients are more open with advanced practice providers than with the doctor, and so we can get into a lot of things. I try to ask questions in two or three different ways, making sure that I've gotten the correct answer and just letting them know, there is nothing they can say that would be against them. I think a lot of times patients feel  like they want to hide some things, because we're not going to like it. Like if they haven't taken a certain medicine, everything is important and when we keep telling them, communicate, communicate, communicate, and their psychological state is huge beyond medications. We see a lot of younger patients, and they are frightened, and they don't know what the future holds for them, and we just need to hold their hand and take the burden off of them.

Andrew Schorr:

Now let's move on a little bit. So, Dr. Scott, people hear about, they wonder about what's next, and we want to talk to Becky more about this as well. So people here, we've got some heavy-duty science patients who are in this community. They ask about CRISPR in gene editing and all these kinds of things.

 So we'll start with the CAR T-cell therapy, because that's on everyone's mind, and it is a novel therapeutic intervention for patients. But essentially, what is done is you modify the patient's own immune system. Their T cells, and T cells are a part of our immunity, and we modify the T cells so that they recognize the cancer cell as being foreign and elicit an immunologic attack against them. And when we modify them, we do so by changing their receptor expression, which is how the cells came to be known as CAR, which stands for chimeric antigen receptor. So we modify the patient's own T cells so that the T cells now recognize their specific cancer. There are a lot of issues with that therapy. One of them is that it takes time to modify the T cells. So it's not as if a patient can come in with Dr. Jamieson and her Federation studies and start the medication that day.

So there is generally a lag from anywhere you know from about three to five days to a week, where we have to modify those T cells to recognize the cancer as being foreign. Another issue is the modification process itself. We really need something on the cancer cell that the T cells can specifically recognize that's not on the other normal cells. And that is a very difficult scientific process  

Another issue is that when you give the CAR-T cells, it activates the immune system and it kind of gets back to what we were talking about earlier, but people get the cytokine storm and they develop an overall profound inflammatory response and in some ways it's very similar to what some of these patients get when they have COVID-19 infection. There's actually an agent called tocilizumab (Actemra) that we use for that process. It's also being explored to prevent the profound inflammatory response with COVID-19 but patients can get this profound inflammatory response with a lot of side effects. But I will just say that the CAR-T cells is a very exciting type of therapeutic intervention. It harnesses the patient's own immune system, and it's been proven in principle to work for certain cancers, but there are barriers that need to be overcome.

And like Dr. Jamieson said earlier, we should encourage patients to enroll into clinical trials and to participate in these studies so that we can learn more about these disease processes.

Just one thing, this whole gene editing. So when I got my first computer, what was so cool is I could edit words, you know, and we've heard about this for a long time now, CRISPR in the idea of editing a gene. So we talked about these genes gone wild oncogenes. So, Dr. Jamieson, will we be able to edit genes? So instead of doing bad things or not turning off, we can kind of clip something out of them and make them behave.

Dr. Jamieson:

Yeah. So I remember a few years ago when Jennifer Doudenal and Emanuel Sharpens CA, talked about CRISPR-Cas9 editing a very specific genes and they discovered this in bacteria, is the way they protect themselves from invading viruses called bacterial phage. And I presented it in our stem cell course and people said, "Hey, that has nothing to do with stem cells. It has nothing to do with any cancers that I was doing the cancer stem cell lecture." I said, "But it might in the future, because it may be a tool like the scissors for the DNA to be able to cut out that mutation." And my background is in microbiology and immunology. So I thought, "Well maybe this will work." And, of course, it wasn't the only one. A lot of people really grasped onto these molecular scissors. So we may be able to cut out stretches of bad DNA and replace it with good DNA.

I think that the problem with that is it really depends on proper repair of that cut. And that depends on our system doing that properly. The double strand break repair and if we think an MPN is that may be defective, it may not work that well, not because of the JAK2 mutation, but because of other mutations. The doctor's got and I see in people that have sort of higher risk MPN, so they have an ATM mutation or other DNA repair mutations that may not make that work that well. But the good news is that CRISPR field has exploded. So now what it is, is base editing, and so you take these special enzymes that we have in our bodies, they don't come from bacteria, they're our own editors.

It's not the whole word was wrong, it's that one letter was wrong. And being able to say in the future, can we base edit that one letter, and can we do it efficiently enough without off target effects that, that will last for quite a period of time. And that's where we would base edit, the stem cells and then give them back after trying to clear the bone marrow of the bad stem cells.

So I think you'll see more about that next year, Andrew. And that's why I really liked Dr. Scott's approach to curative therapies. And it's certainly something we thought was too grandiose before science kind of just took over and the MPN Research Foundation, The Leukemia & Lymphoma Society, MPN Advocacy Group, NCI sort of ganged up on this set of diseases and said, “Let's do something.” And not to mention the FDA, we have friends at the FDA who really do take what you and others say into account, Andrew. When you go there, they're listening, they're compassionate and to have an approval that will really help people with this disease for symptoms at a time when everybody was distracted by other things, they've kept their eyes on the prize, that to me is very uplifting.

So I just want to sum up sort of our clinical discussion for a minute. Dr. Scott, when we've talked about the whole range of things, are you hopeful for MPN patients? So somebody new comes to you and maybe they have ET and they say, "But gee, over time I may progress to these others, "Are you hopeful for me that first I can be treated effectively and B, that I can live well?"

Dr. Scott:

Well, absolutely, and we have the data to prove that, as I mentioned we do a lot of epidemiological research in these myeloproliferative neoplasms. And we know that if you compare outcomes by decade, we have improved over time with the care of the patients and we have gotten better. And there are a lot of new and exciting drugs that are in development beyond just the JAK inhibitors. Cellular therapy is also improving. So if you look at our transplant outcomes each year, each decade they've improved and gotten better. So there's a lot of hope for the future and a lot of hope for positive outcomes.

And there's hope for curative therapy that doesn't involve allogeneic transplantation, which would be good, because we fully acknowledge that allogeneic transplant is not without its risks.

Andrew Schorr:

Dr. Jamieson, excuse me, one thing from you. So I think you'd have a hopeful message as well, and we'll hear from you later in the program as well. People worry about progression, and we didn't cover this, but I just want to take a second. Somebody with ET, will they necessarily run the table like Ruth who we're going to meet? Or what do we know about progression? Are these therapies changing that?

Dr. Jamieson:

Dr. Scott and Becky and I have seen people who have ET for a long time with no evidence of progression. And so we're not really sure why some people progress and other people don't. And by progression we mean to myelofibrosis, which is scarring of the bone marrow and ultimately some people move on to get acute myeloid leukemia or AML. So what we're really trying to understand is what are the instigators of progression? We've done it with quite a large study now on people who have evidence of progression to try and find the drivers. And what we're seeing is a viral activation signal. Where we think that it may be exposures to those very viruses that we're now having to grapple with as an entire community that may potentiate progression. And if we can stay clear of those viruses, treat them early as Becky was saying, and treat them sustainably, it may help our immune system from getting riled up and starting to enhance proliferative mechanisms at the stem cell level.

So, we all have exposures based on our occupation but also based on travel. So I think what's really important about understanding this viral pandemic is we really start to realize, wait a minute, we're getting exposed too much when we travel to either viruses or other toxic exposures in the environment. And so I think we're all just going to be a little bit more careful. And handwash, it may not sound very scientific, but it really works. I think what we're learning is early detection, early intervention and prevention.

Andrew Schorr:

 Well, okay. So, Becky, you're going to be my friend as we sum all this up. Okay. Because, Dr. Scott and Dr. Jamieson, besides seeing patients are scientists and I'm sure as you said, people will say to you, Becky, after they visit with a doctor and their head is spinning, and we've talked about genes and stuff like that. Okay. It sounds to me where they're headed and hopefully with curative strategies in the range of things they have two JAK inhibitors.

We're talking about combinations, smarter use of interferon if it comes in. You mentioned another drug in development along the way, Dr. Jamieson, DaVita clocks, does that come into play? You talked to me about it personally. People being able to change from one JAK to another for people to have phlebotomy as appropriate for people to have hydroxyurea to be monitored or even aspirin. It sounds like there's a lot to talk about and people should have some confidence that we can be well-managed. Did I, did I get it right, Becky? What do you think?

Becky McAlpin:

Absolutely. I think we have to encourage the patients really to be open. When the doctors talked about CAR-T cell, the side effects that come with that can be frightening. I heard a doctor who actually had a CAR-T cell give a lecture and his physician told his wife, "No matter what happens, don't give up." And after they had 911 come for the third time, she almost gave up. But she remembered that. So we really have to prepare the patients with as much education as we can, but let them know we don't know everything. Anything that comes up, tell us about. Now with the CAR-T cells, everybody else would be telling them but symptoms, symptoms, symptoms, tell us anything that happens. I had a patient who quit taking an antiviral because it upset her stomach. She didn't tell me. Unfortunately, she died from a viral disease. So you can't overcommunicate, talk, talk, talk, talk, talk to us.

Andrew Schorr:

Exactly.  Talk, talk, talk.  Communicate, communicate, communicate. Thank you to our panel, great information.  I’m Andrew Schorr. Remember, knowledge can be the best medicine of all.

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.

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