In an interview with Targeted Oncology, Naveen Pemmaraju, MD, discussed recent advances for the treatment of patients with MPNs and shared his thoughts on recent hematologic meetings and the growing role of social media during the COVID-19 pandemic.
Virtual conferences have become an important platform for disseminating data and major advances in both oncology and hematology after the coronavirus disease 2019 (COVID-19) pandemic halted plans for most in-person meetings in 2020. Investigators persevere to bring forward new data that can change practice across a variety of cancer types, including rare blood cancers and myeloproliferative neoplasms (MPNs).
Virtual meetings are different than years prior where investigators, physicians, or fellows could meet and converse in person, whether to introduce themselves to experts, debate topics, or share ideas, but these individuals are now leaning on more virtual methods of communication to collaborate. In particular, social media has become an important part of these virtual conferences, as well as in specific cancer fields.
The MPNs treatment landscape has been enriched by 2 FDA approvals of JAK inhibitors for myelofibrosis (MF), but many other therapeutic agents and strategies are in development for the treatment of these patients. Naveen Pemmaraju, MD, helped to cofound the hashtag, #MPNsm, which stands for MPN Social Media. By searching this hashtag on Twitter, doctors in the field can see all the latest articles, reports, or even simply ideas from other colleagues in the field from anywhere in the world. In a rare disease such as MPNs, it is important to keep up with all the latest new treatments that are available in clinical trials.
Pemmaraju, Ruben Mesa, MD, and Srdan Verstovsek, MD, PhD, founded the Texas MPN Workshop to create another platform in which investigators could collaborate together on research for the treatment of patients with MPNs. The inaugural meeting was also held virtually, but much like what was observed with the virtual platforms for the 2020 American Association for Cancer Research (AACR) Annual Meeting and the Society of Hematologic Oncology (SOHO) Annual Meeting, attendance was high, demonstrating the importance of continued collaboration during the pandemic.
In an interview with Targeted Oncology, Pemmaraju, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed recent advances for the treatment of patients with MPNs, including both the JAK inhibitors and non-JAK-related therapies. He also shared his thoughts on recent hematologic meetings and the growing role of social media during the COVID-19 pandemic.
TARGETED ONCOLOGY: What is the current role of JAK inhibitors?
Pemmaraju: Looking at MPNs in 2020, heading into 2021, we still only have the 1 FDA-approved class of therapies, and that's the JAK inhibitors that most of our viewers are familiar with, in addition to the first in class ruxolitinib, there is now a second approved drug known as fedratinib. This drug has been approved for about essentially actually almost a year now and is broad label approval in intermediate- to high-risk myelofibrosis. These 2 drugs are notable in that they not only hit the JAK/STAT pathway, so you don't have to be JAK-mutated, just the JAK/STAT pathway, but they also each hit a number of other different pathways. These are 2 drugs, same class, JAK inhibitors, and then of course the field is urgently looking for therapies beyond JAK inhibitor therapy.
TARGETED ONCOLOGY: Where might pacritinib and momelotinib fit into this treatment landscape based on the data we've seen so far?
Pemmaraju: Beyond the 2 approved JAK inhibitors, ruxolitinib, and fedratinib, there are several JAK inhibitors in various stages of development, including in stages as late as phase 3. Two of those later stage agents are pacritinib and momelotinib for JAK inhibitor development.
Pacritinib is a very interesting molecule that's been tested for many years in both the phase 2 and phase 3 settings. It's currently being tested in the PACFICA phase 3 randomized trial. The interesting approach there will be to focus on patients with platelets lower than 50. Thrombocytopenia in myelofibrosis is an urgent unmet medical need, and because with most of the other JAK inhibitors, usually there's a platelet cut off. That's a very important subset to follow, and if that drug were to be approved 1 day, then that would give us another option in that setting.
Momelotinib is another important JAK inhibitor in late stages of development, such as the phase 3 MOMENTUM trial, which is another randomized study. Now the important signal with momelotinib, some of the other non-JAK pathways appear to be involving something called hepcidin, which effects anemia. The concept here is that it may serve to help patients with myelofibrosis and anemia. That’s also another urgent unmet medical need for our patients, so patients presenting with anemia or the development of anemia, that's significant and requiring transfusions, maybe other JAK inhibitors are exacerbating that. I think those 2 aspects, momelotinib in MF for anemia and pacritinib in MF for thrombocytopenia, represent 2 different areas from the other JAK inhibitors that are out there.
TARGETED ONCOLOGY: What are the toxicity concerns with each of these different JAK inhibitors?
Pemmaraju: As we develop these oral chemotherapies, we have to pay specific and particular attention to emerging and novel toxicities. For example, the tyrosine kinase inhibitors (TKIs) have been developed in a lot of other fields. Chronic myeloid leukemia now has several approved agents, chronic lymphocytic leukemia with the BTK inhibitors, acute myeloid leukemia (AML) with the FLT3 inhibitors, so I look at this in 2 different ways. One is a class effect, and the other is the individual drug as a class, JAK inhibitors. The most important thing to know is that they mostly don't hit just JAK1/2. They're going to hit other pathways, whether it's FLT3 or other pathways, so you have to pay attention to these other pathways.
For the second aspect, we have the unique side effects to each drug. We have had the longest experience with ruxolitinib, a fairly well-tolerated agent. I think the long-term studies are showing that we need to pay attention to such aspects as infections like viral and other opportunistic infections like herpes zoster, and in the long-term setting, I think that's an important point. I think with fedratinib, the obvious 1 is the Blackbox warning for the encephalopathy syndrome. That's something we're supposed to watch and so important that we should be checking the thymine levels before and during therapy. I think that's very important for prescribers to know about. For these newer agents, we'll wait and see as they are in the phase 2 and phase 3 clinical trials now. This is a very important question so when people are prescribing JAK inhibitors, pay attention to the class effect of all of these, what they do on the cytopenias, the blood counts, but also for the individual peculiar and particular side effects for each drug as they come out.
TARGETED ONCOLOGY: Outside of JAK inhibition, what other treatment options look most promising?
Pemmaraju: Now that I've come out of several important meetings, our own Texas MPN Workshop that was hosted by Reuben Mesa, MD, myself and Srdan Verstovsek, MD, and then the SOHO meeting, I have to say, I'm really excited to see in the last 2 years the emergence of 2 major categories of drug therapies for MF. One is the add-on approach, so that's where you keep the JAK inhibitor going, and then you add in the second agent, which usually should be a non-JAK inhibitor or something completely outside of that. The second category you have are the brand new novel agents which stand on their own. All of these are in various levels of testing, so phase 1 through 3.
In the add-on strategies, we have to be paying attention to the furthest along developed, so that is combining with hypomethylating agents such as azacitidine and decitabine. Then there are a host of new other drugs, so PI3K inhibitors, BET inhibitors, and Bcl-xL inhibitors. If you look at the publicly available information, from ASH to EHA and to some of these regional meetings that we've done, there's an explosion of studies in the novel agent category. My goodness, there's so many more drugs that there are too many to count in this interview.
I encourage folks to go to clinicaltrials.gov, which is regularly updated, publicly available, free website that any doctor, patient, or caregiver can follow, but you make a good point that there are so many drugs now that we have to have categories. It's very exciting for us and for our patients right now, whereas maybe 5 years ago, we didn't have so many drugs to talk about.
TARGETED ONCOLOGY: Are there any other agents that you would like to highlight right now?
Pemmaraju: I think of it more in terms of classes of drugs, especially for all these non-approved drugs. I think 1 we have to pay attention to is the concept of the tumor microenvironment, so that means not only the MPN itself but the surrounding areas and the surrounding signal. One of those is the so-called fibrosis, the scar tissue itself, so there's a number of different drugs, like PRM-151, among others, that have been developed to target the fibrosis. There are epigenetic pathways such as LSD1, and we mentioned BET and several other pathways there. Aurora kinase inhibitors are being developed. Our group is looking at the so-called SMAC mimetics or IEP antagonists with molecules in that space. For CD123 inhibition, I personally have led with an agent that can affect these patient groups.
I think the key in drug development has been focusing on intermediate- to high-risk patients with MF, most of whom have failed or are intolerant to JAK inhibitors. We should mention that allogeneic stem cell transplant remains the only curative approach in 2020 and beyond. We still send quite a few patients who qualified and who are appropriate for that, but alas, the vast majority of our patients are older, unfit, or have comorbidities. That's another question, how to optimize these JAK inhibitors and novel agents before, during, and after the process of stem cell transplant. This is an active research area for many of us around the world.
TARGETED ONCOLOGY: The theme at this year’s SOHO meeting was molecular classification and precision medicine, so could you discuss how this fits in with the MPN treatment landscape?
Pemmaraju: While we're excited about the explosion of research for some of these drug therapies, many of which we'll have to see in the coming years how they fair, there's been a simultaneous and parallel explosion in molecular diagnostics, prognostics, and so forth. I think 2 or 3 takeaways as we approach the new ASH meeting, from what we talked about it SOHO and at the Texas MPN workshop. Number one is the category beyond the big 3 driver mutations. The big 3 in MPNs are JAK2, CALR, and MPL. That makes up, in the majority of patients with MPNs, the recurring somatic mutations, but now we know as we and others here at MD Anderson and other places are checking extended gene panels on everybody who walks in the door that there are a number of different mutations that are important and serious. However, they're outside of that, so the ASX1 mutation, EZH2, SRSF2, IDH1, IDH2, so on and so forth. I think this is a big important factor, even though maybe those don't help with diagnosis as much. However, they can certainly help with prognosis and possibly with selectivity in targeting for therapies and clinical trials.
Second is the identification of these targets for new drug development, testing, and clinical trials. We've seen some of our colleagues present, and even if it only affects less than 5% of patients, if a patient has an identified targetable mutation, whether it's FLT3, IDH1/2, so on and so forth, can we reuse or repurpose the existing drugs for AML or myelodysplastic syndrome and use them into our MPN space, particularly in patients with accelerated blast phase. Those clinical trials are just now being started, and so we'll look forward to seeing those.
A third concept in this precision medicine/biomarker space is what's called cytokines. We've been talking about that a lot over the past few years, so can we identify those patients outside of mutations and pathways that have abnormal and high amounts of cytokine that lead to high symptom burden and constitutional symptoms? Can we predict who the patients are who may transform to higher states, such as blast phase AML? Can we predict which patients may be able to be even targeted by a new drug that hasn’t yet been invented for that space?
I think these are the main takeaway points that we've discussed in these meetings.
TARGETED ONCOLOGY: What were your thoughts on the new virtual format for the SOHO meeting?
Pemmaraju: It’s revolutionary. I think it's surprising how just a year ago, we would not have even thought about it. I didn't hesitate to get on a plane and fly wherever. You know, you want me in France? Okay, I'll be there tomorrow. The COVID-19 pandemic era, which will unfortunately stretch into 2021, has made us rethink everything on the fly emergently. I've got some takeaways from these virtual meetings. One is that the good thing is they allow, somehow during a tough time for a lot of us, the open and serious exchange of ideas, of scientific breakthroughs, debates, and discussions in a much needed way as something that you can't just communicate by reading a journal or emailing. There needs to be some back and forth, so that's been great.
A second aspect is I've been reaching out to colleagues through social media, on Twitter and through these conferences in Algeria, Australia, all throughout Asia and Europe, South America. It’s incredible. The engagement is actually higher than it was in years past. With some of the meetings that have already happened virtually, such as AACR, reports show a double or even triple amount in their viewership. For the Texas MPN Workshop that I cofounded, we had over 1300 individual participating from 30 countries. The Soho meeting had something like 2500 participants. Most of these folks are reporting that they got more out of the meeting than if they had attended in person, so I think it’s been great to reach our colleagues across the world. Now we're in a pandemic, so you just can't travel and may not be able to travel for some time.
I will say to be realistic, the downside of this is I personally am a people person. I mean, anyone who knows me knows I love people. I love the side meetings, the ideas, the brainstorming, the networking, just the social part of meeting, so we're going to miss that for quite some time. I think for a young investigator, which I was years ago, you miss out on the opportunity to catch someone like Mesa or Verstovsek and say hey, I'd like to talk to you and meet, so you miss that, what I would call sort of on the ground level learning and networking. If you are an investigator, established or aspiring, and then if you are a community provider or somebody who really wants to engage and meet people, you're going to miss out on that.
Then of course, 1 of my colleagues, David Steensma, MD, wrote about this kind of “Zoombie Apocalypse”. There's this fatigued aspect of doing online things all day, particularly in an online meeting all day, so I think we have to think about, as we go into 2021, how to keep the virtual part but how to engage people more. My biggest tip is to make sure you schedule breaks. Have some recorded sessions, have some live sessions, and panel discussions, but make sure that you break so people can check their email and to break up the day so that it's not just sitting in front of the computer all day and getting drained.
TARGETED ONCOLOGY: What message would you like to share with colleagues regarding advancements in the MPN space?
Pemmaraju: A key aspect that's emerging for us in the MPNs, and in all the rare blood cancers in particular, which I've spent my life dedicated to, is the rise of social media. This is really interesting. I myself got on social media about 6 years ago in 2014 on Twitter, and I've noticed that both with MPNs and rare diseases, patients, caregivers, and even us as investigators have really connected on Twitter in particular. I think this is because the medium allows fast back and forth dissemination of information, it's archived, easy to use, but certainly the other social media outlets are useful as well. It's given all of us a chance to connect, and I tell you, it's been more highlighted to me now more than ever during the pandemic.
At the end of the day, you can look at your Twitter feed, and you can know what's going on in a particular area. I cofounded a hashtag, as you know, called #MPNsm, and this has been a great resource, even for me personally now 6 years later. That's something I look at every day. It has a very low spam rate. It's just users like me and other people who post articles or interesting thoughts about the MPNs, so it's a grassroots movement that we started 6 years ago that's really caught on. I think it's another way to get information straight from experts. If you want to know what I'm thinking, or Mesa, Jean Jacques Kiladjian, MD, PhD, from France, or Claire Harrison, MD, from Europe, we're all on Twitter. We're all ready to engage. We have to maintain privacy and respect on the medium, so no personal patient-based kind of questions should be asked that should be done in the clinic and medical space, but this is [great] for general exchange of information. It's a pretty powerful way to communicate, particularly during these rough times of 2020.