A session with experts Ruben Mesa & Naveen Pemmaraju, who discuss the latest updates in myeloproliferative neoplasms (MPNs) from the 2021 EHA Annual Meeting.

Welcome to The MPN Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Ruben Mesa & Naveen Pemmaraju, who debate key updates in the treatment and management of MPNs, including myelofibrosis, polycythemia vera and essential thrombocytopenia, following the virtual 26th Congress of the European Hematology Association (EHA) 2021.

In this insightful discussion, experts talk over the latest updates on JAK inhibitors, the evolving landscape of clinical trials, highlight novel therapies for rarer MPNs, and comment on the findings of ongoing Phase III trials in the MPN field.

JAK inhibitor updates: monotherapy and combinations

“I really sincerely believe that the era of combination therapy is arriving soon. The concept here is twofold. One is, can you add on or add back if you will, a second agent that synergizes or combines with the JAK inhibitor, and can you do it in a way that does not increase toxicity to the point of limiting one or both of these agents?”
– Naveen Pemmaraju

“I suspect as the JAK inhibitor field evolves, patients will be on likely a JAK inhibitor and you optimize JAK inhibition. Which agent? I suspect we’ll get more subtlety regarding which agent for which patient at which time.”
– Ruben Mesa

The evolving MPNs clinical trials landscape

“We now are experiencing a time where we have over a dozen or more Phase III randomized clinical trials, mainly in this space.”
– Naveen Pemmaraju

“I think if multiple of these agents are hopefully approved, we likely will learn that there are niches of specific patients that are more likely to benefit than others.”
– Ruben Mesa

Novel therapies for rarer MPNs: rusfertide, IMG-7289 & avapritinib

“A really interesting additional niche of drugs is starting to develop, and that’s drugs looking at the issue of simulating the anemia of chronic disease as a surrogate for phlebotomy.”
– Ruben Mesa

“You and I work in a space that’s considered a “rare disease area”, but many times as you and I have seen, the breakthroughs made in more narrow, smaller spaces are then extrapolated out into other areas. And to that point, some of the FDA approvals lately are tumor agnostic, meaning that it’s not an MPN drug or a breast cancer drug or a GIST drug, it’s a pathway drug.”
– Naveen Pemmaraju

Imetelstat, MDM2 inhibitors and the future of MPN therapy

“The imetelstat randomized Phase III will be, to my knowledge, Ruben, it will be the first trial in our field to make overall survival the primary end point.”
– Naveen Pemmaraju

“A tremendous amount of excitement: new therapies, new information on JAK inhibitors as single agents, their impact on survival, multiple new therapies alone or in combination in the frontline and second line, potentially, new options in PV, new options in ET, new options in mastocytosis, hypereosinophilic syndrome or others.”
– Ruben Mesa

Watch the full session
Full Transcript

Ruben Mesa:
Welcome, I’m Ruben Mesa. I’m the executive director of the Mays Cancer Center at UT Health San Antonio MD Anderson, a career focused MPN investigator and joined by my wonderful friend, colleague, and fellow devotee of the MPNs, Dr Naveen Pemmaraju. Welcome, Dr Pemm.

Naveen Pemmaraju:
Hi Ruben, thanks for having me here.

Ruben Mesa:
Wonderful. Well, many exciting things going on in MPNs. We’ve just had a couple of wonderful global virtual congresses, both ASCO and EHA. We’re all eager to get back in person, and hopefully can have a live event in December at ASH, and certainly we’ll put a plug in for our Texas MPN Workshop for folks to consider registering for, for August 20th and 21st. That’s a roundup on MPNs. That is a free registration supported by our partners. So, hope that you can join us for that. But a lot of exciting things going on in MPNs. Why don’t we break up our discussion into a few different sections? So first, let’s jump into a little bit regarding JAK inhibitors. A lot of exciting new things in JAK inhibitors. Naveen, well, why don’t you share one of your kind of key takeaways from, from the ASCO/EHA ark, as it relates to where we stand with JAK inhibition, now about 10 years out from the first approvals of JAK inhibitors?

Naveen Pemmaraju:
Right. Thanks Ruben. And there has been some nice movement in our field in this sort of primary category that we’ve come to know and love, that of JAK inhibition. So, after rux, and then the second approved agent fedratinib, there is some activity now. We saw data at ASCO and EHA with regards to several other JAK inhibitors. So, we know about pacritinib, for example, which is in the Phase III testing. You presented some very compelling data with momelotinib, specifically with the achieving of transfusion independence relating to long-term outcomes, potentially even overall survival, which I thought was quite compelling. And then there’s even new agents out there, jaktinib and others that we’re starting to hear data about. So, the concept in JAK inhibitors has been, what else does the molecule target? So, is that JAK1? Is it ACVR1? Is it bromodomain FLT3? And then what are the toxicities of each of these JAK inhibitors?

Naveen Pemmaraju:
So, I’ve been very impressed to see. Maybe some of them improve anemia, as is the case with momelotinib, as you brilliantly showed. Maybe some can be administered in the setting of low platelets, as we saw with pacritinib, and then so on and so forth. So, Ruben, for me, the excitement is for our patients. Is that maybe I can have a day where I have five or six of these in the clinic, and I can sequence them in various ways, personalized to each patient. Or maybe I’ll have a biomarker one day to select which one of these upfront I can give. But Ruben I’d love to hear your take, which is the concept that each JAK inhibitor is not the same and that they may be able to produce different outcomes and different toxicities.

Ruben Mesa:
I think you’re very right, you know there. JAK inhibitors are important for MPN patients and particularly in myelofibrosis as well as, you know, I think, for many likely in PV. I think one key takeaway is that JAK inhibitors, when they have a significant response, likely improve survival. And I do wonder whether this is a genuine class effect. I think it’s been demonstrated beyond question with ruxolitinib in multiple ways, both long-term data from the COMFORT studies. And now even at this year’s events. Further real-world evidence, multiple real-world studies that really suggest an improvement in survival.

Ruben Mesa:
Second, Claire presented on behalf of us and other investigators, data with fedratinib showing improvement in survival, in both the JAKARTA and JAKARTA-2 studies, the frontline and second-line studies. Again, people really achieving response. So, I think being on a JAK inhibitor has an impact, but I think the quality of the response that you have is also tied with that benefit, and there may be ties as it relates to are you on adequate dose, what response did you achieve?

Ruben Mesa:
I presented, as you had mentioned the very intriguing observation that, yes, there appears to be a survival advantage with momelotinib, but that it seems to be most strongly tied to those that achieve a transfusion independent response in terms of their anemia. Some correlation with splenomegaly and symptoms, no doubt, but the strongest signal was this tie in with transfusion independence. And is that solely because of an increase in red cells and oxygen carrying capacity, decreased debilitation, or is it a surrogate for a decrease in inflammation that helps further prolong survival? Momelotinib decreases at ACVR1, they’re an ACVR1 inhibitor. It can decrease hepcidin. Hepcidin is an inflammatory marker.

Ruben Mesa:
So, I think that’s really interesting and may have some implications regarding the benefits of achieving anemia response or individuals with other therapies that might impact anemia, such as luspatercept or as a secondary endpoint with things like the BET inhibitor from Constellation or others, pacritinib. Additionally, we continue to run more impact for cytopenic myelofibrosis patients, impact through other mechanistic aspects on the inflammasomes, it’s an IRAK inhibitor that may have other benefits.

Ruben Mesa:
So, I suspect as the JAK inhibitor field the evolves, patients will be on likely a JAK inhibitor and you optimize JAK inhibition. Which agent? I suspect we’ll get more subtlety regarding which agent for which patient at which time. Are we on the right doses at the right patient? Is there a marker to suggest a different JAK inhibitor, or when to switch? But then the next question will be, should you be on a JAK inhibitor alone? Or should you be on something in combination? So, why don’t you share with folks a little bit, and these studies are more, the large Phase III studies are more ongoing, so we don’t have data that is quite as a mature, but how do you think this view of additional drugs is evolving for folks watching?

Naveen Pemmaraju:
Right, Ruben, it’s a perfect segue. So, as we expand the JAK inhibitor monotherapy, which has been truly the gold standard for our patients with intermediate and advanced myelofibrosis, I really sincerely believe that the era of combination therapy is arriving soon. The concept here is twofold. One is, can you add on or add back if you will, a second agent that synergizes or combines with the JAK inhibitor, and can you do it in a way that does not increase toxicity to the point of limiting one or both of these agents? A couple of these areas are starting to be developed, but as you said, I think still early on, and again, we have to emphasize safety.

Naveen Pemmaraju:
So, from the lab, a couple of signals have come out from some of the older agents. Our group showed several years ago that potentially combination with hypomethylator can be something that can be used with JAK inhibitor, and Dr Odenike from UChicago and others have done this clinically as well, particularly in the accelerated phase patients after Ron Paul and others, particularly as it goes into the blast phase to AML. Interferons have been combined with JAK inhibitor, particularly with our European colleagues, and even the IMiD drugs such as thalidomide and lenalidomide. Some toxicities were encountered there, and some lessons were learned, including keeping the JAK inhibitor on for what you would consider a peak or optimal, something like around three months.

Naveen Pemmaraju:
Now in this next generation, those lessons have been learned. And so now what we’re doing is keeping patients on the JAK inhibitor three months or longer, suboptimal or failing response, and then we’re adding in these new agents. Some of them include targeting Bcl-xL. So, a lot of folks know about Bcl-2 with venetoclax, but in our MF MPN, it appears that upregulation of the Bcl-xL appears to be an important pathway to target, and so that’s a molecule, an oral drug called navitoclax that you and I and others are involved in developing. And so, we showed an update of those Phase II data encouraging longer term outcomes, starting to show a signal for some overall survival benefit, and then the toxicity of low platelets or thrombocytopenia, which was expected, is not resulting in major bleeding.

Naveen Pemmaraju:
A second very important strategy is combining with bromodomain inhibitor. This is the Constellation drug that you mentioned earlier. Very important as this is also going into Phase III. And this drug has shown to be not only well-tolerated, but also some improvement with regards to the anemia transfusion dependency. So, I’m very excited to see the development of that agent and still others, PI3 kinase inhibitors being combined.

Naveen Pemmaraju:
Remarkably, Ruben, and I’d love to get your take on this. We now are experiencing a time where we have over a dozen or more Phase III randomized clinical trials, mainly in this space. And so, my question to you would be, what do you think about this? We are going to have some final results potentially in the next two to three years, what do you make of all this in terms of Phase III clinical trials when before we never had these?

Ruben Mesa:
Well, it’s really an extraordinary sign of progress. I have been involved with this field for a while now. You know, when I started in the field, MPNs were really a very niche area of focus, you know. At a meeting like ASH, there will be one oral session.

Naveen Pemmaraju:
Oh, wow.

Ruben Mesa:
There was only one, you know. Everything from biology to treatment was, you know, one oral session, you know, and then half the oral talks included either word Hydrea or interferon. And that was the field. And the drugs we were able to try, largely, we were able to kind of beg, borrow or steal from other indications. You know, we used things like anti-helminthic agents that it might have an impact in TGF-beta. We had agents being developed for pulmonary fibrosis, like pirfenidone, that was almost inert in myelofibrosis. And then we would have agents being developed for other reasons, like thalidomide, where companies like Celgene were intrigued, but it was not an area of focus. They were really being developed for myeloma and other things. So, to have, you know, dozen in myelofibrosis specifically developed therapies, is really extraordinary, you know.

Ruben Mesa:
Folks are listening, I would really share a couple things. One, if you’re having patients that really are having a suboptimal response, or even now newly diagnosed patients, there likely are trials that might be an important consideration for them and would really encourage you to consider referring patients to your appropriate MPN center for trial participation. It’s a key moment in that, you know, getting these trials both accrued, learning their benefit, you know, learning from that data so that we can, again, help best guide therapy. I think if multiple of these agents are hopefully approved, we likely will learn that there are niches of specific patients that are more likely to benefit than others. I don’t view it that there’s going to be 12 drugs all trying to do the exact same thing. I think that it will be more subtle than that. There will be specific niches.

Ruben Mesa:
I think as well, as was discussed in CML, but I think we’ll be a bit broader, therapies that impact myelofibrosis likely will have other uses in human health and disease. We’ve seen that with ruxolitinib on multiple levels, from GBH inflammatory disorders. So, I think even if there are 12 drugs for myelofibrosis, I think their impact on human health and disease likely will probably be quite a bit broader than only that piece. So, a very exciting time, please consider referring appropriate patients.

Ruben Mesa:
Now, a really interesting additional niche of drugs is starting to develop, and that’s drugs looking at the issue of simulating the anemia of chronic disease as a surrogate for phlebotomy, both hepcidin agonists, and I know there’s other drugs a little earlier in development as well. And for me, a fascinating kind of flip side, as we try to inhibit hepcidin with, with momelotinib to improve anemia. But why don’t you walk folks through a little bit of what the hepcidin agonist data presented from our colleagues at Mount Sinai, what are the implications of that interesting drug?

Naveen Pemmaraju:
Right. Well, thank you, Ruben, yes. And this drug you’re mentioning is quite exciting, this molecule known as PTG-300 is its code name, and actually, it has a name now, rusfertide. So, the PTG-300 story is a very lovely bench to bedside story. And it centers around exactly what you said, which is the observation in P-vera, polycythemia vera, an elevated cell state has a dysregulation or an imbalance in iron homeostasis. So, that’s the key. So, it turns out, in even the healthy state, our body has some complex mechanisms to tell iron where it should be distributed, stored, how much in the blood, how much in the liver, et cetera. And in P-vera, that balance is deregulated. This is a lovely drug. It’s an injectable drug, it’s weekly. I should also let people know I am a co-author on this abstract.

Naveen Pemmaraju:
Ruben, I think the key with this drug is that it can lead folks in the early stages of investigation here to become phlebotomy-free. We oftentimes, as physicians underestimate, I believe, in our patients, the degree to which the phlebotomy process is uncomfortable for our patients. Waiting to get the blood drawn, the actual blood draw event, the needle, the frequency, the anticipation. Sometimes people have vasovagal events at these phlebotomies. They’re not benign procedures. And so, the PTG-300 aims to restore that iron homeostasis to allow patients to become phlebotomy-free. The trial itself is pretty ingenious. It’s basically three trials in one, which also includes a phase where patients will be randomized to staying on the drug or coming off for a short while and then crossing back over if and when needed.

Naveen Pemmaraju:
So, the early stages were showing encouraging safety profile and this signal for phlebotomy-free. And so, now, as the drug continues on into later stages, let’s see what the durability of this phlebotomy-free, you know, how long can this be maintained? Is this a standalone drug approach, Ruben, or is it an adjunct or combined with hydroxyurea or other agents? And then finally, will it also continue to show as the early signal that there might be an improvement in the quality of life, disease modification, all of these other measures. So, in summary, I think this is an agent I think to keep watching. Let’s get more data, more patients as it continues to go into Phase II and later stages of development.

Ruben Mesa:
Wonderful. Now, progress is occurring, not only in MF in PV, but there’s also a movement in ET. There’s the LSD1 inhibitor IMG-7289 that is having an impact on MPNs. There is increasingly mature data from a large Phase II in its use in myelofibrosis. And there are now ET studies. There’s an ongoing ET study, investigator initiated, at my institution that Robyn Scherber and I started. And then there’s a company sponsored one with data being presented at EHA as an e-poster. So, an interesting drug, it’s having activity. The ET data is certainly maturing. And exciting to see both that and then a global Phase III study that Serge and I are leading that, again, would put the word out there for people to consider referring patients for enrollment, second-line study ro-pegylated interferon, a control arm of anagrelide for individuals with problematic ET. So, important options that are evolving.

Ruben Mesa:
Now, we also saw some updated data regarding some of the rare MPN types, including updated data as it relates to the just announced approved avapritinib. Why don’t you just share with folks a little bit, what do they need to know about avapritinib?

Naveen Pemmaraju:
Well, the quick update on avapritinib is seismic in the rare disease field space. So, the supposition here is that systemic mastocytosis, really kind of its own MPN entity now, is largely driven by something different than our JAK-STAT pathway, and that’s the KIT, K-I-T pathway. And we’ve known that for quite some time at a biology level, but targeting KIT, specifically, has gone through some iterations. In this space, you do already have the oral drug midostaurin, which was approved several years ago, but the avapritinib is a really nice development. It’s a very KIT-selective or specific drug. And these trials were done in a very lovely way in order to collect quite a bit of translational or corelative knowledge. So, I think a lot of disease biology has come out of there.

Naveen Pemmaraju:
So, that’s right. So, during the EHA, or just after EHA was completed, we found out that avapritinib was approved in this advanced mastocytosis space. It’s also a drug that can be used in solid tumors, such as GIST. And Ruben, this is a great point you made, I really want to emphasize it for our viewers out there, what you said is so important. You and I work in a space that’s considered a, quote, rare disease area, but many times as you and I have seen, the breakthroughs made in more narrow, smaller spaces are then extrapolated out into other areas. And to that point, some of the FDA approvals lately are tumor agnostic, meaning that it’s not an MPN drug or a breast cancer drug or a GIST drug, it’s a pathway drug. So, I just want to emphasize that.

Naveen Pemmaraju:
So avapritinib, FDA approved in the U.S. And so, I think the last part of this will be to monitor for toxicity and safety. I think overall it’s shown to be a well-managed drug. There was a signal, as we all know early on that there was some, there were some bleedings, head bleeds early on. There were no deaths from this. So, these were mainly in patients with lower platelets and there were some quick and easy modifications the investigators made to ensure this is a safe drug. And importantly, this drug will now move into the indolent space. Indolent systemic mastocytosis for clinical trials. And so, again, safety and outcomes there will be important in that earlier group.

Ruben Mesa:
Wonderful, well, a lot of exciting things that are evolving, both in the more common MPNs and even in the less common ones. Interesting seeing the data from, even in hypereosinophilic syndrome. Again, diseases where we typically have not had many options. Further update on mepolizumab, which is an anti-interleukin-5 monoclonal antibody for patients with difficult to control disease. Now they were presenting data at EHA in over a hundred patients that have been treated with this disease with, with efficacy. So, very exciting to see. And again, many of these things may have potential links or interactions with other conditions, both malignant as well as benign.

Ruben Mesa:
Now, there’s a couple of key drugs in Phase III, that due their timing don’t necessarily have an update at this year’s meeting but are probably important for us to mention. You had mentioned one earlier, which is imetelstat. It’s a telomerase inhibitor. There’s a suggestion of a survival benefit. That survival benefit, a bit like I had mentioned with momelotinib, may not be solely tied to the degree of benefit in spleen or symptoms, but may have other mechanisms. Is that decreasing inflammation? Is that decrease in additional mutation, pressure, or progression-free survival? I don’t think we know yet, but a very interesting signal that’s being tested in important second-line Phase III studies. Also, some interesting stuff with MDM2 inhibition. Naveen any comments on the status for the MDM2 inhibitors?

Naveen Pemmaraju:
Yeah, and you know, two things to say. Gosh, you’re just bringing up so many important points. I just want to make sure people are capturing what you’re saying. This imetelstat story is exactly what you were mentioning earlier, which is, we’ve moved away, I think, appropriately and smartly to just focusing on spleen and looking at these other outcomes. Quality of life, symptom burden, something you personally pioneered for our field – overall survival. And to your point, the imetelstat randomized Phase III will be, to my knowledge, Ruben, it will be the first trial in our field to make overall survival the primary end point. So, kudos to all the folks there.

Naveen Pemmaraju:
With regards to these other pathways, as you said, so MDM2 inhibitor, you asked me about. Fascinating science, really pioneered by many of our colleagues, Dr Ron Hoffman in New York and others. I think this is a good example of what we were talking about earlier. So, as we move beyond JAK inhibitor or combining, we must balance the patient toxicity safety profile with the science. I’m still very optimistic about this field of MDM2 inhibition, both in earlier MPN states, such as P-vera and in myelofibrosis. But I think the early studies have shown us that we have to mitigate toxicity. So, GI toxicity and others, I think we will do that as a field over the coming years. And dosing schedule, all of these things will need to be worked out, but definitely several companies involved there at all stages of MPN, right, so PV to chronic MF to even accelerated blast phase combining with hypomethylator. So, simply an exciting field, but again, we have to think about toxicity and how we pair these drugs as we move forward.

Ruben Mesa:
Well, wonderful. Well to summarize for folks, a tremendous amount of excitement, new therapies, new information on JAK inhibitors as single agents, their impact on survival, multiple new therapies alone or in combination in the frontline and second line, potentially, new options in PV, new options in ET, new options in mastocytosis, hypereosinophilic syndrome or others. So, a lot of exciting things going on. Again, we’ll plug our upcoming Texas MPN Workshop, August 20 and 21st. And Naveen, final thoughts, exciting things for the future of MPN, for people to keep an eye on?

Naveen Pemmaraju:
Two exciting thoughts, Ruben, as we head into thinking about our own workshop and into ASH, one is I want folks to pay attention to the explosion of translational research that’s coming out a lot of times out of the clinical trials themselves or on separate studies. Our colleague, Dr Nangalia presented really ground-breaking research at ASH that the JAK mutation or driver MPN mutations can be acquired as early as in utero, so, just after birth, not genetic, as somatically acquired mutations. And so, the implication is that these MPN HITs can occur at the earliest stages of life. I think that may have some implications, Ruben, in the next 10 years on our thinking about CHIP, chemo prevention, early detection, you and I have talked about this for hours. So, I want people to focus on that.

Naveen Pemmaraju:
And then two is the excitement in terms of having multiple drugs in the clinic and figuring out, doctors and patients together, how to best sequence cost of care, insurance, availability, and then monitoring of toxicities, both short and long-term. I think these are exciting topics because we didn’t have these to talk about five years ago. There wasn’t this much research going on. And so, it shows you that even in rare disease fields, there are many people out there, many people who are excited and interested. And I believe in my heart that online and social media communities have brought many of these stakeholders together. Patients, advocates, caregivers, non-profit organizations, pharma investigators. And so, I would urge folks to be active in your communities online, social media. If you have a question, if you have an idea, if you want to meet someone, get out there and reach out because no matter how rare a disease is, it’s a disease that you or your family member, your loved one have, and there’s likely someone out there who’s working on that field. Ruben?

Ruben Mesa:
I would agree entirely. A lot of exciting things. And, again, an aggregate, this is a very significant group of individuals. There’s a lot of ties with even, as we learn about MPNs that ties in with the issues of clonal hematopoiesis, issues of predisposition to thrombosis, the issues of aging. The more we unravel the story behind some of these aspects. One never knows the implications in terms of broader populations in terms of health and disease. But exciting times. We’ll leave folks at that and look forward to our meeting coming up this summer. A lot of exciting things to delve into regarding the future of MPNs.

Naveen Pemmaraju:
Wonderful.

Ruben Mesa:
Bye-bye and thank you, my friend.

Naveen Pemmaraju:
Bye, everyone.

Disclosures

Ruben Mesa, MD, has participated in a consultancy role with Novartis, Sierra Onc, La Jolla, Pharma and Constellation; and has received research support from Celgene, Incyte, AbbVie, Samus Therapeutics, Genotech, Promedior, CTI and Constellation.

Naveen Pemmaraju, MD, is a member of the ASH Communications Committee and the ASCO Leukemia Advisory panel; has participated in consultancy work for Pacylex Pharmaceuticals, ImmunoGen, Bristol Myers Squibb, Blueprint Medicines, Clearview Healthcare Partners, Astellas Pharma US Inc., Triptych Health Partners and CTI Biopharma; has received grants from Affymetrix and SagerStrong Foundation; has received honoraria from Incyte, Novartis, LFB Biotechnologies, Stemline Therapeutics, Celgene, AbbVie, MustangBio, Roche Diagnostics, Blueprint Medicines, DAVA Oncology, Springer Science + Business Media LLC, Aptitude Health, NeoPharm Israel and CareDx, Inc., has received research support from Novartis, Stemline Therapeutics, Samus Therapeutics, AbbVie, Cellectis, Affymetrix, Daiichi Sankyo and Plexxikon; and has received travel reimbursement from Stemline Therapeutics, Celgene, MustangBio, DAVA Oncology and AbbVie.

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