A four-part session with experts Naveen Pemmaraju, Ruben Mesa, and Claire Harrison, who discuss the latest updates in myeloproliferative neoplasms (MPNs) following the 2020 Texas MPN Workshop.

Welcome to The MPN Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Naveen Pemmaraju, Ruben Mesa, and Claire Harrison who debate key updates in MPNs.

The topics of discussion include learnings following COVID-19, mutations and molecular definitions of disease, therapeutic strategies, and takeaways from the 2020 Texas MPN Workshop.

 

Evaluating virtual meetings and learnings on COVID-19

I think with COVID-19, the pandemic itself, it’s created this situation where we cannot travel, but yet we must get our science to each other, we must exchange ideas, and we must debate and have controversial issues. And if we can still do that in some way, then I think we can reach the full potential of what it means to be a scientist.”

Naveen Pemmaraju

 

Pathobiology – inflammation, evolving understandings of mutations and molecularly defined disease

“Should we really be thinking about the disease in a molecularly defined way in terms of is it really JAK2 mutated early MPN versus CALR early mutated MPN or not?”

– Ruben Mesa

Treatment: interferon-based therapies, JAK inhibition & combination approaches

“I actually think what’s old is new again and interferon will be more important than ever in 2021 and beyond.”

Naveen Pemmaraju

“We all have patients who probably had two or three different JAK inhibitors as they progressed and go on clinical trials. But I think the patients ultimately, your thought is about transplantation. And boy, we have to learn to use that modality a bit better and our timing a bit better”

– Claire Harrison

 

Clinical trials and final takeaways from the meeting

“Yes, you can do clinical trials still in the era of COVID. They’re essential to continue. But you have to be creative with the correlatives, the labs, the consent, and do everything in a way that is still okay with your institution. “

Naveen Pemmaraju

“My takeaway is that, in many ways, the world has never felt smaller, which is wonderful. At a time where sadly there can be political leaders that really look to sow divisions between people on any number of reasons, as a medical community, along with our patients, we are one”

– Ruben Mesa

Full Transcript
Ruben Mesa:
Hello. My name is Ruben Mesa. I'm the director of the Mays Cancer Center at UT Health San Antonio MD Anderson. And I'm joined today for this wonderful discussion by my good friend and colleague Claire Harrison from Guy's and St Thomas's in the UK and my meeting co-chair for the first Texas MPN workshop, Naveen Pemmaraju.

Ruben Mesa:
We acknowledge our other co-chair Dr. Srdan Verstovsek, who is busy as we speak healing the sick in his very busy MPN clinic. So our hats off to Srdan.

Ruben Mesa:
But we wanted to get together to debrief a little bit, to think back on this first Texas MPN Workshop, what worked well, what we learned some of the sessions.

Ruben Mesa:
And perhaps I'll kick it off just by sharing some thoughts or discussion amongst us, really about the platform itself. So this had been initially designed by Naveen, Srdan, and I, and at that time Robin Sherber, with the idea of trying to pull together expert physicians and scientists in MPNs for more of a workshop sort of approach based here in Texas because of both my center and MD Anderson of course, having our MPN focus, but inviting many friends and colleagues from around the world for a meeting that likely would have 75 to 150 people max, with really, time to have some areas of focus, some longer discussions, ability to really delve into some deeper issues.

Ruben Mesa:
And then of course, like many meetings, COVID-19 and its overwhelming impact on this year hit. And we thought hard about this, and again felt strongly that, with the pace of changes in MPNs, it was important to still have this meeting and that the value in being able to connect hopefully would still be there. And indeed, we were really pleased to see that, in some ways, it expanded the reach. We had almost 1,400 people participate in over 30 countries.

Ruben Mesa:
So first, let throw it to yourself, Claire, who I know you've been on many virtual meetings, even today as you had mentioned. Share with me some thoughts both about this meeting, but some of the pluses and minuses you've seen with the virtual meetings. This, EHA, some of the larger congresses, but also some of the smaller ones.

Claire Harrison:
Well, I think ... So first of all, I have to congratulate the whole team and also the Brandcast team. It was really fantastic. I think your agenda was very fast paced. Having to do a talk in 10 minutes, that's quite a challenge, right? Because we always like to talk about stuff we're really passionate about.

Claire Harrison:
I think it's really important that we do continue to meet even virtually and that we do continue to dialogue. And we learn a lot. We miss the encounter things and personal discussion, but I think we're all quite practiced now at using these platforms and we're fortunate enough that this terrible pandemic has struck at a time when we are blessed with Zoom, Teams, you name it. We're all quite expert at it.

Claire Harrison:
But I think your meeting was very, very broad, very focused. You really had some true experts. And the flow worked very well. There were no technical glitches. I think it was fantastic that you attracted such a big audience. And I had people from across the UK WhatsApping and texting me and telling me about how wonderful the meeting was. So that's something you wouldn't have achieved if 75 of us had traveled to Texas. I'm feeling sorry that I couldn't be there, but we could still be there, we could still learn, we could still share, we could still think.

Claire Harrison:
I think that virtual meetings for me, they do maintain the contact. You do miss the informality, the chance meetings. But this is the way it has to be. I think EHA, I think, for me was a great meeting, but it went on quite a long time and some of the content that we had planned for EHA we couldn't have. But we did manage to do some of the things that ASH does as well. So the best of sessions, I think they were good, especially for a broad meeting.

Claire Harrison:
But I like the way it still keeps us connected. And for example, I know we'll discuss it later, but Tiziano, I know, was able to collect ... show you all the data we've managed to collect from across Europe about outcomes for MPN patients. So sharing something like that with a big audience is really important.

Ruben Mesa:
Wonderful. Wonderful. What about yourself, Naveen? And maybe afterwards, piggyback a bit off of Claire's introduction of that COVID session.

Naveen Pemmaraju:
I really found it, from an audience member standpoint, to be, as Claire said, to be really engaging, Ruben. And I know you and I and Srdan and others, we helped to put it on. But what Claire said was very important.

Naveen Pemmaraju:
David Steensma, our friend and colleague, wrote this really great editorial on ASH Clinical News about the so-called Zoombie Apocalypse, being online all day for 12, 14 hours and getting drained. I didn't feel that way at our conference, and I hope we can continue that.

Naveen Pemmaraju:
So I think engaging online is not as simple as back to back to back lectures. So I think prerecorded sessions, as Claire said, quick hitter, 10 minutes, broken up by live sessions, I have never seen anything like this before, maybe not even in our real life sessions, quite this way. So to that end, I believe this was an amazing experience.

Naveen Pemmaraju:
I think with COVID-19, the pandemic itself, it's created this situation where we cannot travel, but yet we must get our science to each other, we must exchange ideas, and we must debate and have controversial issues. And if we can still do that in some way, then I think we can reach the full potential of what it means to be a scientist.

Naveen Pemmaraju:
So having sessions on the standard of care, on combinations, on novel agents, old agents like interferon, COVID-19 in this session, it really brings together what's old and what's new again, I think, to be honest with you, in a very interactive way that I have not seen before in many other meetings.

Naveen Pemmaraju:
Ruben?

Ruben Mesa:
Yeah. No, no. I would agree entirely. It's interesting, even some of the things we learn, we had many of our sessions where we concurrently saw the presenter being taped while giving their talk as well as the slides themselves and really how much more engaging, compelling really to have that level of connection.

Ruben Mesa:
That, and I think the real-time live panels with people being able to put their questions in through chat was really quite interesting. It allows a little bit of a dynamic that we've seen in live meetings, where again it, in some ways, beats the process of everyone racing to get up to grab a microphone or things of that nature. It helps the moderators sort through for perhaps a little bit better distribution of questions, as well as questions that are more appropriate for the venue.

Ruben Mesa:
But why don't we kick it off first with that COVID session? I think that was particularly unique, where we had the chance to hear directly from many that have been in the hottest of hot spots, from Tiziano Barbui and Valerio De Stefano, that we all know that Bergamo in particular had a very, very rough go, both in terms of the volume of cases, but how overwhelmed the healthcare system became, from John Mascarenhas, where they got it about as bad as anyone here in the US.

Ruben Mesa:
Fortunately, I don't think it got to the resource constraint in the US to the degree that it did in some other parts, I think in part due to some of the warning. I think, Claire, maybe you could share. You guys felt somewhere in the middle, but I know that back remembering those texts, it was some pretty tense times.

Ruben Mesa:
But you surely went through this wave before us in the States. So what were some of your takeaway, Claire, or maybe some thoughts, both how that reflected the realities from March and April, but what do you think that might translate to now in the fall?

Claire Harrison:
So thanks. And I think actually I just wanted to add something to our discussion about the importance of these meetings. I think the other importance is the MPN field, we're all actually good friends. So there's something about the support of actually and the normality of meeting, albeit across the screen, is really, really important to ground you back into what is it you love about your job and what is it you're passionate about.

Claire Harrison:
And we're actually ... Most of us are passionate about patient care, bringing new therapies, learning more, trying to think about what's the next new step, what are they doing in San Antonio that's great, what are they doing in the MD Anderson, what do I want to do in my clinic in London. So I think that was really important.

Claire Harrison:
I think in terms of coronavirus, yeah, I think London, we peaked quite early really and we have been really out of our normal practice for quite a long time. So it has been helpful to listen to what other people were doing, listening to how they're structuring their service. We learned a lot from colleagues in Italy and we also got a lot of hope from them as well, to be honest.

Claire Harrison:
I think, as we've discussed, our hospital wasn't really overrun, but we did really ramp up our critical care activity and many of us stepped into different roles. So I was able to use my MPN research role into a research supporting role, including taking part in some studies myself at Guy's and St Thomas's. So that's been really important.

Claire Harrison:
Learning about the use of anticoagulation as we've worked together, all of us here actually just sat at the EHA and also the ASH guidelines. I think that's been really important and that's all facilitated by the virtual world.

Claire Harrison:
Thinking about how do we manage our patients, what do we do with therapies and the really important data that Tiziano presented about not stopping ruxolitinib in a patient that has the coronavirus, that's a really, really important message. But also equally important is the message that our young patients could perhaps adjust on hydroxycarbamide or no therapy or interferon, don't seem to be doing terribly badly. So that's also a really important message that I was able to take back immediately and share with some patients, because patients in UK have had a tough time. They've been shielded, they haven't been allowed out of the house, et cetera. So that was really important news for me.

Ruben Mesa:
And what about yourself, Naveen? Clearly, Houston has gone through a huge surge with this as well and you guys clearly interacted with many patients both locally, but from a distance with telemedicine. What were some of those takeaways from the session, or what are some of the things that you think will continue to be the key questions with COVID in MPN patients?

Naveen Pemmaraju:
Yeah, I really appreciate this discussion. I got a tremendous out of it. I think two major themes popped up for me. One is this concept of COVID as a hematologic, as a blood disease. So I think Dr. Laura from the US, our colleague, brought that up a lot. And I've now since seen that really talked about in both the media as well as in our scientific literature. So not just thinking about the viral infection as a respiratory illness, but more as an inflammatory or as a cytokine mediated entity.

Naveen Pemmaraju:
So as Claire mentioned, thrombosis, all of these things and how it relates through the blood and then directly into our both benign and malignant hem, I really didn't appreciate it until that session. So I thought that was dynamite actually.

Naveen Pemmaraju:
The second one, also brought up by both of you, is I really just was blown away, Ruben, by this American-European cross discussion in that exact session, so seeing what was going on in Italy juxtaposed with the States, talking about it across the world in this first of its kind meeting. We had 1,300 to 1,400 unique people who logged on and over 30 countries, I believe, represented, so all over the world. We know we had viewers from Algeria and other places, Australia as well.

Naveen Pemmaraju:
So this concept of best practices, as Claire was mentioning, what are folks doing in their region, their hospital, how can I apply it directly to my practice, again, this is the highest hopes of any meeting you attend. And often, I find it to be inverse with how large the meeting is. So the bigger the meeting, possibly the less direct practice-changing things I can bring.

Naveen Pemmaraju:
But these are some of the things that jumped out. And I also want to make a mention of this concept of giving people information in a moving landscape. So again, Laura was able to give some websites, "Here's what ASH is saying. Here's what these other websites are saying." And so because these slides will be widely available, people will be able to go back and reference them. That was a really nice part of it, Ruben.

Ruben Mesa:
Great. Great. Well, so that was really a wonderful session, I think, with key takeaways that we continue to study. One, some reassurance that perhaps ET and PV patients, it's not obvious that they clearly do worse than the general public. As I try to share with my patients, nobody wants this disease. And as we see even our ... As our general hospital beds have largely emptied out, but our ICU continues to be filled with people who have been on the ventilator for weeks or have succumbed, passed away on the ventilators.

Ruben Mesa:
This is a disease nobody wants. This is not like when I was growing up as a kid and if you got the chicken pox, it was just a rite of passage and they even had chicken pox parties so the kids could just get it over with. This is clearly something that nobody wants.

Ruben Mesa:
Two, with MPN patients, I think clearly not changing therapy and clearly not stopping ruxolitinib as being important, as well as all of the evolving issues of really how do we optimize thrombotic prophylaxis. When I have telemedicine visits, I have 10 today with patients, I tell them, "If you get COVID, contact me," because what we know is evolving. And if you get COVID and you're an outpatient, should we still start you on low molecular weight heparin? I don't think we know, but I think the answer's at least a good maybe, because we know if they're hospitalized, we would probably put you on low molecular weight heparin. So it's a very much of an evolving piece.

Ruben Mesa:
Now, we discussed a variety of key things at the meeting. And then maybe next let's pivot a bit toward a bit more of the pathobiology piece. There were sessions really dealing with inflammation, with issues of evolving understanding of mutations, as well as even the provocative sort of questions. Should we really be thinking about the disease in a molecularly defined way in terms of is it really JAK2 mutated early MPN versus CALR early mutated MPN or not?

Ruben Mesa:
Maybe let me throw that out to Claire. Some of your takeaways perhaps from that session, but as well, I know as well that's been an active discussion. It's an area where we have a range of opinions. Certainly, you were involved with the efforts with Tony Green and others that looked at those high impact papers in terms of that piece. What are your thoughts?

Claire Harrison:
You see, I think this is a really hot topic in the field actually. And I think that presentations are really good, but I think also the discussions. So I think one of the things I wanted to add ... One always thinks of something after one's served one piece, doesn't one?

Claire Harrison:
But the panel discussions were really very good. So unlike a normal meeting where you get questions after you've done your talk, the fact that you'd put the agenda together so that there was a panel discussion and you had a chair as a panel who was really thinking, yes, looking at questions and people are less inhibited at sending in questions, I think that's really important.

Claire Harrison:
So my takeaway from these sessions is this is really still a moving feast. And my strong sense is that we will probably redefine these diseases molecularly. And we've been thinking for a while now at tackling the beast of the national guidelines in the UK. I know you guys have made huge effort with NC and the guidelines, but ... NCCN guidelines.

Claire Harrison:
But I've been shying away from the guidelines on ET, but I'm really increasingly thinking now actually, and this is what the session made me think, really is CALR low-risk ET really the same as JAK2 low-risk ET? Are we really treating the same disease? And increasingly, I think we probably are not. And I think that's one of the key takeaways for me in that session.

Claire Harrison:
And then as we move on and think about some of the data that was presented, for example, at EHA, just to draw that meeting in as well, because there's a lot of science presented in that meeting, the data about interferon and how actually the diseases seem to respond a bit differently to interferon is also really, really interesting.

Claire Harrison:
I think it's a huge gap in our field at the moment as we look at all of the therapies, and I know we'll come to the therapy sessions later, but just really understanding which mutational analysis and maybe which ... what your immune system is like, it could really be dictating risk and response to therapy in the future. So I think that session was absolutely fantastic, very stimulating, very thought provoking, not really delivering tons of answers, but very thought provoking, I think.

Claire Harrison:
What do you think, Naveen?

Naveen Pemmaraju:
Yeah, Claire, I think this is really outstanding what you're putting forward here, because I thought the same thing. This concept of CHIP, clonal hematopoiesis of indeterminate potential, I think was long in the domain of the MDS and AML talks. And I think we nicely were able to bring that front and center here.

Naveen Pemmaraju:
So a pre-inflammation to inflammation to MPN disease model, this was the first conference I think that we have all really brought this out loud. So I think that's a big point, this pre-inflammatory/inflammatory context.

Naveen Pemmaraju:
Number two, outside of the big three driver mutations, JAK2, CALR, MPL, that we've all long known and studied, now the emergence of the so-called non-driver mutations, ASXL1, SF3B1, IDH1 and 2, and the concept that some of these mutations are not just prognostic, but also maybe predictive, that now we have IDH1 and 2 inhibitor data in our own field, not just extrapolating from leukemia, FLT3 if there's a small percentage et cetera. And then out of the non-driver, non-targetable ASX1 others, as you said brilliantly, not only this will help us to understand the disease and prognosticate it, but maybe even categorize all of these entities as their own. So that really blows me away.

Naveen Pemmaraju:
A final thing I would put into this discussion as well is this concept of triple negative MF, which is actually becoming more and more extinct, if you will, if we say NGS negative, I remember Dr. Steve Oh and our colleagues talking about that. So it may be only 10 to 15% of our patients are triple negative, but maybe 0% are negative if we sequence deep enough 100, 200, 400-gene panels. So I found that to be very provocative, the concept of NGS negative versus positive MPN.

Naveen Pemmaraju:
So I like this idea that you're putting forward that we will be able to further, ideally specifically, distinctively categorize our diseases beyond morphology. Ruben?

Ruben Mesa:
Yeah. No, I think, again, it's a period of time where we're learning a lot and we still have some missing pieces how it all ties together.

Ruben Mesa:
But like yourselves, I see clearly a spectrum of chronic myeloid patients. And again, you see really how much overlap both in terms of phenotype, MPN not otherwise specified, MPN/MDS overlap, CMML, on and on. There's this kind of continuum where, again, we're getting a granularity, particularly with these other somatic mutations. What are really some of the drivers? If you have that P53 mutation, if you have the ASXL1, if you have IDH1 and 2, or even some more less prevalent mutations. You have ET, but you've got JAK2 and you got something else, is it a bigger problem? So there's just a lot going on there.

Ruben Mesa:
I think we're going to continue to really evolve in terms of that molecular phenotype and, again, are really probably dealing with a continuum of disease. But molecular characterization, I think, is going to become increasingly critical, as well as clearly as we end up developing some therapies. So if we ... It's long been recognized that CALR on the cell surface might be amenable to some sort of immune-based therapy or vaccine or others. We're not there yet, but I know that much of that is on the near horizon. So clearly, that will be a very CALR-specific approach.

Ruben Mesa:
Another session for us to perhaps ... to tackle was really the discussion of interferon. And I do think interferon is really having a moment in 2020, both with the increasingly positive data from ropegylated interferon studies. It's long been recognized that pegylated interferon alpha 2A has been very beneficial. Even though there's not been a big push from the makers at Roche and Genentech to necessarily get a license in MPN, its utilization has been significant.

Ruben Mesa:
The provocative data from Tiziano's study at EHA, looking at low-risk PV, pegylated interferon versus phlebotomy, and obviously, the wonderful sessions we had at the meeting, Claire, what were some of your takeaways? And weave in the discussions at EHA. Again, I think the thing we lack at the virtual part is the lack of people really being in the room to talk about, if that study is it, is that enough to change practice for low risk PV with pegylated interferon?

Claire Harrison:
Well, I think you had a tweet poll on that. Did you not?

Ruben Mesa:
I did. I did. I did a Twitter poll, which was like 60-something to 30-something.

Claire Harrison:
Yes. I think I might have been in the 30-something on that one. I think ... It's interesting, actually. So what we didn't discuss when we were talking about molecular was we didn't discuss molecular monitoring in terms of achieving reduction of allele burden and the benefit that might bring to the patients.

Claire Harrison:
And of course, the attraction of interferon is that it potentially can do that. How it does it, we don't really know. And that's something that disturbs me a bit about interferon. I think Tiziano's data ... Well, he's amazing, isn't he? He's really, truly one of the pillars of our own field. So his data is really interesting.

Claire Harrison:
But I think, for me, I'm not surprised that treatment with interferon reduces your need for phlebotomy. It should do, right? But the interesting piece for me was the symptom piece. But the message for me from that data was actually a bit mixed, because clearly some symptoms, the microvascular symptoms maybe were improving, but there were other symptoms that were a bit worse for patients. So I would really like to see more mature data.

Claire Harrison:
And the thing that I find quite difficult with interferon is that some people think it is absolutely the drug and I have to have interferon. And actually, it is a drug that is difficult to take. I know we've discussed this many times. And I just don't think that the benefits are really worth sacrificing one's quality of life for. And I know that many clinicians remember using interferon for CML, very big dosages, for example will be concerned about that.

Claire Harrison:
But I think it certainly has a very strong role to play, particularly, I think anyway, in terms of the JAK2-driven disease and especially in PV patients. I think this link between molecular response may be a disease outcome, as we showed in the MAJIC-PV disease a while back, is a really important one to try to gather going forward.

Claire Harrison:
I'm looking forward to seeing the five-year data from the CONTI-PV study and your data. I think you're doing an ET study with the Ropeg, aren't you?

Ruben Mesa:
Correct. Correct. Yeah.

Claire Harrison:
And how we use interferon is myelofibrosis, if we use it, I think it's quite a big challenge. It has to be used early probably. Interested in the combination.

Claire Harrison:
But what really worries me in the setting of ET is how much ... sorry, the setting of interferon. It's a bit late here in London. The setting of interferon is how much interferon we're actually going to have and where we're going to be able to use it and the tolerability aspect for patients.

Ruben Mesa:
Good. Good. Correct. And certainly, having worked with you in terms of discussions for national payers, NICE, things of this nature, I can imagine they, at a minimum, are going to want a much more robust data set in terms of that group. I think low risk patients are a mix. I have no doubt there are low risk patients who would clearly benefit from being on pegylated interferon, but it may not be everyone. Or in some, it may be overkill.

Ruben Mesa:
So I think there is a spectrum of molecular phenotype, there's a spectrum of disease burden, there's a spectrum of symptomatic piece, there's even a symptom ... really a spectrum in terms of, let's say phlebotomy burden that people experience.

Ruben Mesa:
What do you think, Naveen? Have you started taking pegasys yourself or ropeg on a prophylactic basis?

Naveen Pemmaraju:
I'm a big fan of interferon, and so for me, watching our first meeting was really cool to see Dr. Silver to be able to be such an active part of the meeting, particularly with his and Jerry's New York meeting not happening this year due to the pandemic and to have jean-Jacques to give his perspective with the ropeg interferon.

Naveen Pemmaraju:
Look, I really appreciate this discussion. I think that it is such an interesting concept in clinic, particularly in the States, where some patients have researched pegylated interferon and, "This is absolutely what I'm walking away with here. Don't talk to me about hydroxyurea or anything else." So that's pretty interesting.

Naveen Pemmaraju:
And then some of our non-MPN colleagues really hesitant to understand and give the drug. So I think we work with patients, right? So dose reductions, dose interruptions, watching for the immune side effects, counseling about the psychiatric and/or neurological side effects, watching the LFTs. I've had a lot of good success with pegylated interferon.

Naveen Pemmaraju:
I think that the ropeg interferon could be a game changer for us in the States when you're talking about a drug that's so effective. Let's prove it here again. But effective drug, easier to give, possibly less side effects, Ruben, this is something that a lot of my patients are already seeing online from meetings like ours, but their own research with the approval in Europe.

Naveen Pemmaraju:
So I myself am a big fan of this, but I'd like to see how it works in ET, as you said, as we're looking to do, and then can we confirm these results in PV, particularly the early res?

Naveen Pemmaraju:
One other comment I'd like to say in the model fibrosis, as Claire was mentioning, Dr. Silver did show his provocative data set and it looks like we'll hear more about possibly overall survival benefit over this long term. Boy, I can't wait to see that full flushed data set and that paper, with the suggestion being that earlier can possibly overcome the inflammatory burden earlier than later.

Naveen Pemmaraju:
So I think that this is a really important area. And finally, the combi peg, right, so the combination of interferon with JAK inhibitor, we know we have the two European studies that have already shown safety. I'd like to see continued long-term followup, particularly with regards to toxicity. So I actually think what's old is new again and interferon will be more important than ever in 2021 and beyond. Ruben?

Claire Harrison:
I think I agree. I'm just going to ... I just ... In one of my other virtual travels, I was having an interferon discussion with Jean-Jacques and it was really interesting. And I think another thing to explore is actually how we all dose with this drug, because Heinz Gisslinger was there, Jean-Jacques was there ... I was discussing. There was another colleague as well. And we were all dosing with interferon differently.

Ruben Mesa:
Right. Right.

Claire Harrison:
So there's got to be something there as well about how we are stimulating the immune system in a completely different way with interferon to what's done with JAK inhibitors, for example.

Ruben Mesa:
Right on, Claire.

Claire Harrison:
That's something else we should really be discussing and learning from each other. So sorry to interrupt, but I was just suddenly struck by that.

Ruben Mesa:
No, wonderful. Wonderful. Well, let's pivot to JAK inhibition because clearly one of our goals have been for that to be one key area of discussion where we can really dissect a bit into where we stand with rux now is clearly the backbone of JAK inhibition, where the addition of fedratinib really fits into the equation, where momelotinib and pacritinib potentially will fit in the equation.

Ruben Mesa:
And back before, we discussed both combinations in novel therapies. I thought that was really a great discussion, and in many ways, I think a real positive in that we now have had the fedratinib approved in the US since September. And again, it was a real chance to delve into some of the newer analysis that you and I have done, Claire, and others regarding fedratinib in patients with moderate thrombocytopenia, the more longer term stringent reanalysis of JAKARTA-2, showing a solid 30 plus response rate from the splenomegaly and symptom control in the second line setting. So I think it really helped to frame that fedratinib piece as well as have that you know mature discussion.

Ruben Mesa:
Ruxolitinib has been our base for a long time, and deservedly so. I think it has aged well. The COMFORT studies are almost historic in terms of timeframe, but it's aged well. It's still a very good drug. It still helps folks. It still can help folks across a spectrum of issues, and now potentially with momelotinib and pacritinib coming up on the scene.

Ruben Mesa:
Where do you envision ... In the UK, we know that the ability to both prescribe as well as your experience, Claire, each country's quite distinct in terms of how difficult or strained it is for drugs to be able to be used. How do you envision the interplay between let's say for JAK inhibitors if they're all approved?

Claire Harrison:
I think we already learned from the CML field, don't we, that we clearly need more than one TKI for myelofibrosis. Each are evolving with a different signature. Let's try to leave aside the issue of reimbursement, which is actually an issue across Europe.

Claire Harrison:
But fortunately, these studies were designed with the correct tools so that we do have the data that we would need for a NICE assessment or equivalent in France or Germany, for example. I think ultimately it's all about the patient that you have in front of you and what their disease looks like, what their tolerability might be. So Inrebic, fedratinib, clearly has some GI toxicity. It clearly causes probably a little bit more anemia than ruxolitinib.

Claire Harrison:
And so I think probably people will not feel comforted to use it first line until they had it in their hands and seeing a few patients, see how they do with it. We don't have survival data for any of the other TKIs for myelofibrosis in the same way that we do have for ruxolitinib. So that's really important, getting it right the first time for your patient.

Claire Harrison:
And then trying to decide, do I jump between JAK inhibitors, do I jump to a combination? And if you're talking about reimbursement, boy, combination is going to be tough. We know we're looking at fedratinib plus luspatercept. I know we're going to start talking about combinations shortly.

Claire Harrison:
I think there's plenty of scope for other agents. I think they're all novel enough. We know that patients start to lose their response to ruxolitinib, unfortunately. We still have a few of our COMFORT study patients on the drug, but most of them have needed something else.

Claire Harrison:
And I think the clear signal with pacritinib probably being easier to give in patients who are thrombocytopenic, with consistent story with anemia and momelotinib under the strong message from the JAKARTA-2 study, which I remember, Ruben, we designed on the back of an envelope, I think.

Claire Harrison:
These are all important messages. All these drugs are slightly different. I think it's the more, the better really, to be honest. What do you think, Naveen?

Naveen Pemmaraju:
I totally wholeheartedly agree, and I think some new areas are going to emerge for us in 2021 that I never envisioned. One will be, Claire, this concept of sequential JAK inhibitor therapy. So whatever sequence, but a patient may get pacritinib if and when it's available followed by fedratinib, ruxolitinib, et cetera, momelotinib followed by another JAK inhibitor, et cetera. So we have not yet studied this in any way, either pre-clinically or clinically. So I'm actually very eager and curious to see how that goes.

Naveen Pemmaraju:
And in particular, we've never had a point mutation of JAK2, for example, like we see in FLT3 and some of these others. So do we start to see the emergence of resistance mutations and other sequelae of sequential JAK inhibitor therapy?

Naveen Pemmaraju:
A second topic will be the concept of re-challenge of the JAK inhibitor. You're on a JAK inhibitor, you go off to the next one, now you go back. Some of our colleagues, Aaron Gerds and others, have shown some preliminary data that that's feasible and possible in a real world setting. I'm eager to see how that goes, particularly, as you mentioned, beautifully in CML we see that actually happening all the time.

Naveen Pemmaraju:
And then still, a third issue will be in and around stem cell transplant, Ruben and Claire. We have some data now that took a while to get with ruxo, and now actually ruxo, in an interesting twist, approved, I guess, in the acute GVHD setting. So what about pacritinib, momelotinib, fedratinib pre and post transplant? And how does that play into JAK inhibitor withdrawal syndrome, Claire, and some of these other things that you and Ruben and others have mentioned?

Naveen Pemmaraju:
And in particular, the tox profiles, you both did this amazing reanalysis for the Wernicke's encephalopathy signal in fedratinib. So how do these newer side effects play pre and post transplant? Claire, I'd love to get your thoughts on that with these new agents.

Claire Harrison:
Yeah. So I think we have taken a few patient fedratinib to transplant. I don't think that's too different. I can't see fedratinib being used in a big rush for GVHD, though, because I think the gastrointestinal toxicity would be very tricky, especially in somebody with gut GVHD.

Claire Harrison:
I do think, though, there is something that's been really important for clinical practice. I'm super happy that you brought up transplant because we shouldn't be blindly cycling patients. Let's be honest. We all have patients who probably had two or three different JAK inhibitors as they progressed and go on clinical trials. But I think the patients ultimately, your thought is about transplantation. And boy, we have to learn to use that modality a bit better and our timing a bit better.

Claire Harrison:
But I think it's not in the patient's interest to cycle them through multiple lines of therapy. So if you're losing a response to one JAK inhibitor, it probably is the time to talk about transplant, unless that transplant is really, really high risk.

Claire Harrison:
But that segue is going to be important. And I think there are going to be patients whose mutational patterns means that they will respond better to one JAK inhibitor in the run up to a transplant or as a combative longer term therapy.

Claire Harrison:
I don't know, Ruben. What are your thoughts?

Ruben Mesa:
Well, I think it's very interesting as things are evolving, because I think we're pivoting as a field, particularly as it relates to myelofibrosis, from an era where we basically had two options, rux or transplant or some kind of combination therein. And now, we're going to have many more options.

Ruben Mesa:
And again, mindful that none of this is occurring in a vacuum. While we've been taping this, there have been three more drugs approved for AML and two for myeloma. So there's almost this whole cascade of new available agents. And as it relates to myelofibrosis, I see that there's really fundamentally a couple, two different philosophical approaches in terms of the trial designs.

Ruben Mesa:
One is completely new novel therapy in somebody that's completely off of ruxolitinib, imetelstat, IMG-7289, on and on. Or you take a suboptimal responder and you add a drug on top with it, luspatercept if it's anemia, CPIO610, navitoclax from AbbVie. And they've all been somewhat positive.

Ruben Mesa:
So we've got two different approaches, completely off or something else in addition. And I think what probably is going to evolve is the prior approach of you give someone something for years and, even if they're a suboptimal responder, they stay on it.

Ruben Mesa:
So I think there's going to be you start on something, you've had a great response. And we've all had those people who've had just magical responses. Messing with them further probably doesn't make sense. But then you've got this whole other group.

Ruben Mesa:
So Naveen, maybe let me ask you. This approach of ... With all these other therapies, and maybe make a comment or two about them, we've all been involved with their trials and many of them are very exciting. But do you think we really need to go to the approach of you're completely off JAK inhibition and then we're starting the other drug, or is that really a bit more artificial in terms of the drug approval process?

Ruben Mesa:
I know drugs are trying to get approved as a standalone drug, and that's more of a drug development question. But in terms of patients, do they really need to jettison JAK inhibition to benefit from a drug hitting a different mechanism of action.

Naveen Pemmaraju:
Right, Ruben. You hit on a very unique and important topic, I think primarily to our field in MPN. And so the answer is no. You're exactly right. There is a middle category. I call it the add back or add on strategy. I'm quite pleased to see this taking off now in the last one or two years.

Naveen Pemmaraju:
I think it's unique and important for our patients because they derive so much pleiotropic clinical benefits from the JAK inhibitor. And by that, I mean quality of life benefit, as you yourself have pioneered and shown us, making the subjective objective through this MPN symptom burden and other aspects of disease control that just don't show up in some other metrics.

Naveen Pemmaraju:
And so you keep the JAK inhibitor on for a defined duration. We're still trying to argue and decide what that is. And then add in the second agent, presumably and preferably something that does not have an exact overlapping toxicity profile, but possibly can have some of the same. And then now you do it.

Naveen Pemmaraju:
We're all involved in all of these, as you said. So the two furthest along are the Bcl-xL inhibition with navitoclax. You, me, Claire and others have pioneered. This has been a remarkably encouraging story early on thus far, a longer follow-up, of course, needed.

Naveen Pemmaraju:
But exactly as you said, in this situation, you have two oral drugs, the ruxolitinib, and then you add in the second agent. Another program with the bromodomain inhibition, as you were mentioning, also a pleasantly surprising, nice story early on thus far, suggesting that, yes, you can keep the JAK inhibitor, add in the second agent, and then derive further benefit in either a synergistic and additive way. That's really cool. We have not yet formally been able to do that with two targeted novel agents.

Naveen Pemmaraju:
And then finally, there is a group of drugs with IV drugs, believe it or not, that can also be possibly combined as well. So my take home point is, yes, not only is it feasible, but there are phase two, even leading into phase three studies with this exact approach. Ruben and Claire?

Ruben Mesa:
Now, Claire, I know that this is a particularly complicated issue for you in the UK and many other countries, because I'll be transparent. In the US, it sometimes is easier to get coverage for combination therapy than it might be in the UK, that the level of evidence in terms of qualities and other that they're going to have to present to NICE to have them pay for these things is a high bar.

Ruben Mesa:
What are your thoughts in terms of those sorts of strategies that both show us efficacy, but also show us sufficient benefit to make that case to those that might be more skeptical about the expense?

Claire Harrison:
I think if there's evidence enough to make the case, then there's evidence enough to make the case. I think one thing, as I was just remembering, it's probably 10 years since we put our last patient on COMFORT-II, and the trips I made to NICE to discuss. I think we've learned a lot more about the disease since we started together. And so actually, symptoms are really important and spleen size is really important.

Claire Harrison:
And the health economists at NICE, the academic health economists are still looking at you like you're completely crazy. But let's be honest. When we've taken ruxolitinib to NICE and said, "Actually, here, we've got a disease treatment that makes patients with this awful disease feel better and live longer," your metrics are there. If your metrics are there, that's fine. The issue is what is the metric. And this is something that I would really challenge you guys to put in a NICE session, or maybe we'll do it at one of the European meetings. What are the best surrogate endpoints for survival for patients? What is that going to be? Is that going to be more durable spleen response? Is that going to be a deeper spleen response? Are we really actually going to start looking at molecular monitoring of disease? Are we looking at fibrosis reduction, et cetera?

Claire Harrison:
I think that will be the question from the payer. But it's a good question. Would they understand that achieving a major molecular response in CML is important? They understand spleen response in MF now. We just need to understand what it is we're trying to deliver. If we're not delivering on anemia, that's fine. That's clearly a major issue. And as we all have colleagues across the globe, we see that management of anemia is a huge challenge.

Claire Harrison:
So I think these things are fine. It's just how we do the studies and how we don't keep having a bunch of patients on a control arm. So that's a big challenge, this is a rare disease. We're trying to do randomized trials, and some really unfortunate patients will end up on a control arm. So in order to demonstrate benefit is a big challenge.

Ruben Mesa:
No, I think that's very key. I think all of you, like myself, really chatting with patients and discussing drugs with them, it's very difficult to ... The patient's willingness to be on a control group is wisely very limited. Nobody wants to be in the control group. As I relate it for folks now, it's a bit like the COVID vaccine. And I know you participated in the Oxford study. But again, nobody wants to be in the control group. If the vaccine's effective, you want it, so it'll protect you against COVID.

Ruben Mesa:
And similarly, if you have life threatening disease like myelofibrosis, you don't want to be an arm that from the beginning of the study we're hypothesizing is a worse arm. Now, fairly, that's not always the case. We remember your very famous PT1 study where the control arm did better than what was thought to be the arm that...

Claire Harrison:
Exactly. And it wasn't a non-inferiority study. We mustn't do non-inferiority studies. Yeah.

Ruben Mesa:
Right. I think without question.

Naveen Pemmaraju:
Yeah.

Ruben Mesa:
It still highlights the importance in this era, that clinical trials are crucial. That's really the only way we learn. Again, in our country, there's discussion now of people trying to ... Should we shortcut the clinical trial process to rapidly approve vaccines before we know they're safe or effective? And as tempting as that is, it leads to all kinds of problems in terms of relying on something to be effective if it's not, or you're introducing toxicity to healthy individuals that otherwise would be doing well.

Ruben Mesa:
But clinical trials in this COVID era are as relevant as any. But there are some real challenges. I chatted with a patient two hours ago who clearly benefited from one of the trials we have, but she's five hours away my car. She's widowed. And I may as well be on the moon as in San Antonio for her to be able to drive here for weekly visits for a trial. So it's tough.

Ruben Mesa:
And Naveen, clearly, yours is a center of tremendous excellence for trials. What are some of the lessons learned during drug trials and COVID?

Naveen Pemmaraju:
Yeah, several, guys. So a very important topic to me. In the beginning, we had to slow down, cut down, but we have ramped up again. I think I have three takeaways. One is, to our surprise, we've been able to conduct quite a bit of the paperwork and the behind-the-scenes aspect of the clinical trials with folks working at home. We never envisioned that because there was never a platform for that. There was never an infrastructure.

Naveen Pemmaraju:
But as Claire mentioned earlier, the necessity of our time with these Zooms, Skype, and all these meetings have allowed that. So I'm amazed. So 80% of the workforce is still at home here in the Houston area. So the ability to do that quickly and to turn around documents, that's the key. You have to have that first.

Naveen Pemmaraju:
Number two, the consenting process. Very, very onerous and difficult already to begin with. How do you consent people from a remote way? How do you get that approved with your IRB and your governing boards and your sponsors?

Naveen Pemmaraju:
And then I think the final aspect is the travel and logistics, as Ruben brought up. If someone's not going to fly, which typically would have been an hour and a half flight, but now it's an eight-hour drive, what's the feasibility of that if they're driving alone, if they don't have a caregiver, if they don't have quite the funds that they would have had normally before the pandemic? Or if you are on a special drug or a special program that, due to the pandemic or hurricane, as we almost had here, as some of our colleagues had recently, then that disrupts supply chain.

Naveen Pemmaraju:
So these are issues that we have never been able to envision. But I will say, I want to commend particularly my center here in Houston at the Anderson. We are up and running again. And as you both mentioned, the importance of clinical trials are actually now apparent more than ever before.

Naveen Pemmaraju:
So for those that are able to travel and are able to come to the center, we have clinical trials for everything. And this both in COVID and out of COVID, but everything is directly and indirectly affected.

Naveen Pemmaraju:
So I think those are the takeaways that, yes, you can do clinical trials still in the era of COVID. They're essential to continue. But you have to be creative with the correlatives, the labs, the consent, and do everything in a way that is still okay with your institution. Claire?

Claire Harrison:
Yeah. Actually, I completely agree. We were actually ... we had to stop our clinical trials almost completely. That was a national mandate. And we have still got a huge COVID trials workforce. We vaccinated 500 staff in two weeks. Huge credit to the trials team.

Claire Harrison:
I think, if I was a patient thinking right now about clinical trial or a clinician talking to a patient, it would really be what is the benefit for this patient. Clearly, that we all need our patients to ... Patients progressing on ruxolitinib, that's nearly a medical emergency, isn't it? That's bad news.

Claire Harrison:
But would I stop ruxolitinib now to a patient on a clinical trial? Well, that would really depend what the local prevalence was and how flexible the trial rating we've been. Some of our sponsors, as well as the staff, and the same as you, we've had to start working remotely et cetera. And we've been doing remote consenting, too.

Claire Harrison:
But some of the sponsors have been amazing, querying drugs to patients. Our distance is not quite the same as yours, but we do have patients who would travel six, seven hours into the center. And the sponsors have been very flexible. And I think that's been really important.

Claire Harrison:
And yes, it's really important to carry on doing clinical trials, but it's super important to really think about what you're doing as a patient and a clinician. And I think that's a really important point.

Ruben Mesa:
Well, it's really been a wonderful discussion. Maybe we'll have each of us just give one takeaway point from the meeting or platform. And Claire, why don't you start us off?

Claire Harrison:
Anything's possible if you plan it and you've got the right team, I think. And staying connected is so important, that professionalism as a team and the presenters as well as the audience. I think it was a fantastic meeting, very inspiring. Please do it again.

Naveen Pemmaraju:
Guys, for me, I think as we spend our lives and careers working in rare and ultra rare diseases, I think my lesson from our successful meeting together is, if you are a patient or a loved one facing a rare disease, it's not rare to you. It's a disease. It's a cancer. It's what you have. And I think it's heartwarming to see the messages I've recieved from people all over the world to say thank you for having a meeting in such a "rare" area. For us, this is our life and our livelihood.

Naveen Pemmaraju:
But to show people that there's hope and progress not being extrapolated from other areas, but that we and others are dedicated to an historically rare area and making breakthroughs. So I think that's my takeaway and a successful meeting. Ruben?

Ruben Mesa:
My takeaway is that, in many ways, the world has never felt smaller, which is wonderful. At a time where sadly there can be political leaders that really look to sow divisions between people on any number of reasons, as a medical community, along with our patients, we are one.

Ruben Mesa:
Mindful really as the whole COVID pandemic evolved, how much collaboration there has been around the world, whether it's connecting with our colleagues in Wuhan or in China as this evolved or Italy or South America or India or in North America. We are one community. We share a mission and love how we have been a resource for each other in these times, both personally and professionally.

Ruben Mesa:
So really glad that this meeting really provided a venue really for us to be able to engage and interact. I think many of us are learning how we better can continue to engage in future and how do we preserve some of the best aspects of live face-to-face meetings and still have some of those, maybe not quite as many as we before. But how do we help those things to still be inclusive so that we really have broad based discussions and really act as a global community?

Ruben Mesa:
So really been ... The meeting was wonderful and this has really been a wonderful discussion. As Claire said, one of the things I find the most rewarding about being in this field is I love the patients that I have the chance to meet, treat, and interact with their family members. And I really love the people in this field. I think of this as a very collegial, collaborative, positive, and genuinely engaged community. And that is a special thing, I think something that we should celebrate. And I know together we will solve MPNs.

Ruben Mesa:
And with that, we'll close it out. You guys take care. A special thanks to Claire for doing this late at night. An honor that VJHemOnc has included us with some of these discussions. Thank you.

Claire Harrison:
Take care. Bye.

Ruben Mesa:
Bye bye.

 

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