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New Clinical Trials for MPNs in 2021 and Beyond

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Published on December 29, 2020

What Are Clinical Trials Like During COVID-19?

Participation in clinical trials has been a longstanding option for myeloproliferative neoplasm (MPN) patients, but it does bring about a variety of questions, especially in the time of COVID-19. In this final installment of our Answers Now: Facing MPNs series, experts answer important questions on clinical trials as we move into 2021, including: How will I be monitored? Will my care team change? How does COVID impact participation in clinical trials? And finally, will there be new clinical trials for MPNs in 2021? 

Follow along as host and patient advocate Ruth Fein speaks with Dr. Gabriela Hobbs, MD, active clinical researcher and leader of the MPN research program at Massachusetts General Hospital and Dr. Angela Fleischman, MD, Ph.D., assistant professor of Medicine at the Institute for Immunology at the University of California, Irvine. They will share information on what clinical trials look like in the age of combination therapies, how to find a clinical trial that may be right for you and more.

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

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Transcript | New Clinical Trials for MPNs in 2021 and Beyond

Ruth Fein: Hi, everyone. Welcome to this final installment of our series, Answers Now: Facing MPNs. I’m Ruth Fein. We're focused forward today. We're talking about clinical trials and particularly those that will be underway in 2021 and beyond. We have two extraordinary guests with us today, Dr. Angela Fleischman, who's Assistant Professor at UC Irvine Health and the Head of the Fleischman Lab at UCI and Dr. Gabriela Hobbs, who's Assistant Professor of Medicine at Harvard Medical School and Clinical Director of Leukemia Service at Mass General in Boston. Welcome to both of you.

Dr. Hobbs, I know you're the lead investigator on a number of studies. Let's start with you and tell us what you're really excited about, and what's hopeful for 2021 and beyond.

What Can You Tell Us About New Clinical Trials in 2021?

Dr. Hobbs: Thank you, Ruth. I'm excited about two main things. One is just more generally speaking I'm excited that there are so many phase three studies that are coming up in the MPN world and we'll have some open at MGH, and that means that there's more drugs that'll likely be approved for the treatment of MPN in the near future. And the other thing that I'm excited is for the first time ever at MGH, we're going to have a trial for patients with essential thrombocytosis and polycythemia vera trying ruxolitinib or Jakafi, and we haven't really had a trial that tests a new medication for this population at MGH. So, I'm really looking forward to that.

Ruth Fein: It's interesting — that’s ruxolitinib during and after transplant, right? Is that the study you're talking about?

Dr. Hobbs: Oh, so that's a clinical trial for patients with myelofibrosis, correct, where we will be giving, and we have been giving... This study has been open for a few years, ruxolitinib or Jakafi to patients with myelofibrosis before their transplant, but then we're also keeping the ruxolitinib or Jakafi after the transplant.

This other study that I'm mentioning is also with ruxolitinib, so a little bit confusing, but this is for patients on the other end of the spectrum. Patients with essential thrombocytosis or polycythemia vera that otherwise wouldn't be candidates for getting medications to lower their blood counts because they're considered low risk, but actually have a lot of symptoms like itching and fevers and fatigue, et cetera. And so, we are interested in studying giving ruxolitinib to this patient population just to control their symptoms, not so much to control their blood counts.

Ruth Fein: Dr. Fleischman, your focus is identifying the role of inflammation in MPNs, and as I understand it, particularly in the beginning of disease. Can you tell us about that and what you're most excited about for 2021?

What is the Role of Inflammation in Identifying and Treating MPNs?

Dr. Fleischman: So, what I'm most excited about is the acknowledgment that it's really important to treat disease very early on to try to do something to change disease trajectory, instead of simply watching and waiting. And then at the time when the disease progresses, then to start to intervene and as we learn more and more about the very, very early stages of disease and how it progresses, it opens up more and more opportunities for interventions.

Because from my standpoint, I really feel that intervening very early on is going to be much more impactful and honestly, probably a lot easier than after the disease has progressed to a more significant situation such as myelofibrosis.

Ruth Fein: I know there was a research study presented at ASH, the American Society of Hematology recently, and that was where they found that MPNs were recognizable and identifiable as early as in utero, not just earlier in life. Does that translate to you to real patient care?

Dr. Fleischman: What we're learning now is that people likely harbor the JAK cells or a very teeny amount of cells with a JAK2 mutations for decades before they have any clinical indication that anything is wrong. And in some patients can sort of date back the acquisition of a JAK2 mutation to even in utero or right after they were born.

However, what we don't know, and we actually do know the opposite is that the presence of teeny amounts of JAK2 mutant cells doesn't equal myeloproliferative neoplasm, and what I think is the most fascinating to me is what distinguishes when you have a very small number of JAK2 mutant cells, and then they grow versus a person who has a very small number of JAK2 mutant cells, and they just sit around and don't really then subsequently expand and turn into a myeloproliferative neoplasm.

Ruth Fein: So much of what we're hearing about in clinical trials is about combination drug therapies for MPNs. So, if that's the primary area that we should expect to see more continued research, would you explain why is this the direction that therapies are headed?

What Should Patients Know About Combination Therapies for MPNs in 2021?

Dr. Hobbs: Part of the reason why we're in that direction is because Jakafi or ruxolitinib was FDA approved in 2011 to treat myelofibrosis. And since then, we have had one more drug that's been approved, fedratinib (Inrebic), which is another JAK inhibitor. And both of those drugs are really important for patients with myelofibrosis, but we know that it doesn't cure myelofibrosis, but they've become the standard.

And so just based on logistics about how clinical trials work, if you have a standard first-line drug, it's difficult to change that standard with a new drug and say, "We are going to either give you drug X, which is new or Jakafi," because that's not exactly ethical necessarily. So, it's difficult to move drugs into the first-line setting without first trying them in the second line setting, and what I mean by lines as you know, how many drugs you've gotten. So, if Jakafi is the first drug you're getting, that's your first line.

And the other thing that's kind of interesting about myelofibrosis compared to other diseases is that some patients may be on Jakafi or ruxolitinib and may not be responding as well as an investigator doctor would want, and what I mean by that is they still have a large spleen or they still have symptoms but having patients stop taking the ruxolitinib or Jakafi is really difficult, actually. So, some patients, you think they're not responding, and you think they're not having your response, and you're like, "Okay, let's forget about this drug." And then you try to stop it, and then patients are like, "Oh my God, I feel awful."

So, it really was doing something. And so then, because of those things, it's been logical or easier to say, why don't we keep the patients that are on Jakafi already on their dose. So, if you notice many of the studies require that patients are on a stable dose of Jakafi for a certain period of time, without a complete response, meaning their spleen is still big, they still have symptoms, et cetera, and then we add on another drug. So that's really the reason why we're seeing all of these combinations come up.

Ruth Fein: I'd like to move on to immunotherapy. What's happening in the clinic?

Immunotherapy for Myeloproliferative Neoplasms

Dr. Fleischman: So, immunotherapy is a very hot and exciting topic for cancers, in general, these days. And in particular with myeloproliferative neoplasms in particular with the calreticulin mutation, it's sort of a really nice target for immunotherapies. However, with myeloproliferative neoplasms, it's also an inflammatory disease, and interestingly the treatments that we have at the present time available to us, meaning JAK inhibitors actually suppress the immune system, so sort of do the opposite, and a lot of the symptoms that are associated with myeloproliferative neoplasms in particular myelofibrosis are due to high inflammation.

So, in some aspects, maybe enhancing inflammation or enhancing the immune response one could think of possibly that, that may have some negative effects in terms of enhancing the inflammation or enhancing symptoms, which is what we really do try to target in myeloproliferative neoplasms. I'm not trying to be negative about immunotherapy in any way, shape or form. I just wanted to sort of play the devil's advocate here in that a lot of our treatments are actually trying to dampen down the immune response.

Another issue that may be encountered in myeloproliferative neoplasms with regard to immunotherapy is if we do know that MPN patients, they do have their JAK2 mutation or their calreticulin or their MPL mutation, their driver mutation, but we know they can have a lot of other mutations as well, and those other mutations may be in a different cell than their JAK2 or their calreticulin. So, it's important to note that even if you got rid of your JAK2 mutant clone, some MPN patients may have other mutant clones that are totally distinct from their JAK2 mutant clone. So, it may not solve the entire problem. If we just get rid of the JAK2 clone, you might have some other bad clones hanging around still.

Ruth Fein: With so much recent discussion of high inflammation within the MPN patients, are there anti-inflammation drugs we should consider? Are there any new anti-inflammation drugs being looked at specifically for MPN patients?

Are There New Anti-Inflammation Drugs for MPN Patients?

Dr. Fleischman: Very interestingly JAK inhibitors are anti-inflammatory agents, ruxolitinib itself or Jakafi is also approved for graft versus host disease, which is an inflammatory disease post-transplant, as well as other JAK inhibitors, are also used for other auto-immune diseases. So, one of Jakafi or ruxolitinib's main benefits may be for dampening inflammation. Also, aspirin, almost all MPN patients are on aspirin. That's also an anti-inflammatory agent. So, it's funny or curious that a lot of the treatments that MPN patients are already taking are anti-inflammatory agents.

In the future, hopefully in the near future, at my institution trying to develop an investigator-initiated clinical trial with an antioxidant called N-acetylcysteine, which also has some anti-inflammatory properties in patients with myeloproliferative neoplasms. That's not open yet but will be hopefully in the near future. Other things that my lab is interested in is non-pharmacological approaches to reducing inflammation such as through a healthy diet, which everybody should be doing anyway, no matter whether you have an MPN or not, it's important to have a healthy diet. But trying to leverage very low-risk things like a healthy diet to try to reduce people's inflammation as much as possible.

Ruth Fein: Rather than just looking for cures, I know you're looking at what can help symptoms. What's happening there that we can look toward 2021 for that might be either new or just ongoing?

How Can We Improve the Symptoms and Side Effects of MPNs?

Dr. Hobbs: Yeah, sure. So, I think one of the things about all MPN clinical trials is that they really all ask about these questions. They all ask about quality-of-life and every MPN patient should be getting asked questions related to their symptoms because we know symptoms are such a big part of living with MPNs, and so most of the endpoints of the clinical trials include an improvement in quality-of-life by improving symptoms. The study that I mentioned before, where we're trying to use ruxolitinib in patients with ET and PV will have a very large component of what's called a PRO or a patient-reported outcomes where patients will be asked pretty frequently how they're feeling, and really the main impetus for this study was that I see patients in my clinic that are young, that have to work, that have kids and just are so debilitated by the chronic inflammation and the symptoms that are associated with having these diseases.

And that's why we decided to use ruxolitinib in this earlier setting to see if we can lower the level of their inflammatory markers or these cytokines that are floating around in the blood of patients with MPNs, even when it's early MPNs to see if that can help improve their quality of life. But like I said, there's several clinical trials that are in development that are now in the phase three studies that all ask the similar questions, "Are these combinations improving quality of life by helping people live with less symptoms and helping them be more comfortable with their large spleens if they have myelofibrosis?"

Ruth Fein: To participate in a trial, do I have to be near a major hospital or near a specialist? Let’s answer that.

How Do I Find a Clinical Trial That is Right for Me?

Dr. Hobbs: Let me add something to that. I think one of the huge limitations about our healthcare system and just the way that research is done as generally the answer is yes, you have to be close to a major hospital. Now there's one good thing when it comes to clinical trials that's come out of the pandemic, and that is that I think it's easier for patients to participate in clinical trials even when they don't live immediately next to a large cancer center, and the reason I say that is because pharmaceutical companies have actually been pretty understanding about the fact that traveling and staying overnight and those kinds of things, it's just not realistic during a pandemic.

And so many of the visits that are required for participating in the clinical trial have now been either postponed or they allow us to do them like this on Zoom. And so, for many patients, it's actually now more practical to participate in a clinical trial. And one of the nice things about MPN related clinical trials is that many of those trials are with medications that are pills. And so, if you have your pills at home and somebody can call you and ask you how you're feeling, and you can get your blood work checked locally, then maybe you can participate in the clinical trial, even if Moffitt is four hours away.

So, I wouldn't rule that out. I would say if you have the opportunity to go to Moffitt or to another cancer center and talk to one of the doctors to see if you're eligible for a trial, you may be pleasantly surprised that you can participate in a study even if you live far. So, don't rule that out.

Ruth Fein: Why in other countries, particularly Scandinavia and France, for decades, they've been using interferon as frontline therapy. And why is that and why aren't we doing it here?

Dr. Fleischman: That's a good question.

Dr. Hobbs: So much of medicine is cultural and if you train in a place that does hydroxyurea (Hydrea), that's what you learn how to do, and if you train in a place that does interferon, that's what you learn how to do. And I think Europe has been always on the interferon side and the United States with the exception of many, there's several centers that do interferon, you learn. We do hydroxyurea more frequently here, but I think that's changing.

I don't know Dr. Fleischman if you have an opinion about that, but we haven't had a definitive clinical trial that says hydroxyurea is definitely worse or definitely better at the following things, controlling blood counts, preventing progression and helping people live longer. And so, there's many hints about things related to interferon, but I wouldn't say it's like interferon cures every single patient and hydroxyurea doesn't. And so, it's not that obvious or not that straightforward. But I think we're trying to investigate that as a field.

Ruth Fein: This is my closing question and it's perfectly timed. The question is, "I'm 85 years old and I'll be starting hydrea this week. Is it advisable for me to get a COVID-19 vaccine?" And God bless her. Who would like to answer that?

Should MPN Patients Receive a COVID-19 Vaccine?

Dr. Hobbs: Before COVID, I was studying how patients with MPN responded to the flu, but as the COVID vaccines are rolled out, we are going to be investigating how MPN and leukemia patients, in general, respond to the COVID vaccine. So hopefully we'll have some information about that in the future. So, I would say, "Yes, you should get vaccinated," and there's also an American Society of Hematology, large registry actually, where physicians from all over the country are participating and giving information about their patients that have been sick with COVID. So, I think there's a lot that we're going to learn, but I think in the short term if you have the opportunity to get a COVID vaccine, I would recommend that you do that. 


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