A session with experts Ruben Mesa, Claire Harrison, Srdan Verstovsek & Naveen Pemmaraju, who discuss the latest updates in myeloproliferative neoplasms (MPNs) following the 2020 ASH 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, Claire Harrison, Srdan Verstovsek & Naveen Pemmaraju, who debate key updates in the treatment and management of MPNs following the ASH 2020 virtual Annual Meeting.

In this insightful discussion, experts explore emerging updates on clonal evolution of MPNs as well as therapeutic strategies for polycythemia vera, myelofibrosis, essential thrombocytopenia, and rarer MPNs.

 

Clonal evolution of MPNs

“I think you have to factor in second, third, fourth hits, as we say, maybe the features such as environmental, things such as inflammation or tissue injury for our patients over time. We have this concept of CHIP, or clonal hematopoiesis of indeterminate potential, that we thought of generally for older adults, but you’re right, this paradigm shifts. Now we have to think about this in the younger setting. So factors such as inflammation, obesity, smoking, environmental factors, and the acquisition of other genetic mutations much younger than we thought possibly could play a role.”

– Naveen Pemmaraju

Therapies for polycythemia vera

“Hepcidin, as one of the key regulators of iron metabolism in a body, comes to the forefront with the application of PTG-300. PTG-30 is hepcidin-mimetic… With the hepcidin-mimetic, what happens is a redistribution of iron. It stays in the tissue of the body, in liver, in the spleen, and it’s less valuable for red blood cells and less of a growth of red blood cells. With the PTG-300, what we see immediately, in 18 patients that their outcome was presented in ASH, cessation of a need for phlebotomy.”

– Srdan Verstovsek

Therapies for myelofibrosis

 

“There is a very robust pipeline of myelofibrosis studies, particularly in suboptimal JAK inhibitor response, but even in naïve patients. Luspatercept, given it would be a third indication, I think has a high likelihood of being successfully indicated and a very nice addition in terms of anemia. I think momelotinib and pacritinib will become approved with successful Phase IIIs, and each kind of having their own unique niche”

– Ruben Mesa

Essential thrombocythemia, rarer MPNs and final takeaways

 

“Some of the agents we’ve been talking about, CPI-0610 and the Imago agent, bomedemstat or IMG-7289, both of them launching studies in ET, which I think is really exciting and important. We need some new drugs there, and we need to see the data from the ruxolitinib versus anagrelide study.”

– Claire Harrison

Full Transcript

Ruben Mesa:
Hello, my name is Ruben Mesa, and I’m the executive director of the Mays Cancer Center at UT Health San Antonio MD Anderson, and delighted to be joined by some wonderful friends and colleagues to give this VJHemOnc update on some of the highlights at ASH of the myeloproliferative neoplasms. I’m joined by my wonderful friend Dr. Claire Harrison, Professor at Guy’s and St Thomas’ in London. Welcome, Claire.

Claire Harrison:
Thank you.

Ruben Mesa:
Dr. Serge Verstovsek, fellow Texan colleague just down the road at MD Anderson, a spectacular leader of the MPN efforts at MD Anderson. Welcome, Serge.

Srdan Verstovsek:
Hello, Ruben.

Ruben Mesa:
And the always energetic, enigmatic, and social media star that is Naveen Pemmaraju, who is a deep expert in MPNs, also at MD Anderson; also a fellow Texan. Welcome, Naveen.

Naveen Pemmaraju:
Thank you, Ruben, for having us.

Ruben Mesa:
Fantastic. We’re going to cover, over the next 30 minutes or so, just an informal discussion regarding some of the exciting updates in MPNs, and I’m deeply excited. As I had shared with others on a discussion about ASH, I have been caring for MPN patients, it’ll now be 30 years next year, which is amazing. But the first 15 of those years, we didn’t have much. There was one MPN session, and at the MPN session, maybe we talked about interferon; maybe we talked about thalidomide. We tried to beg, borrow, or steal drugs from other indications, but not a lot was happening.

Ruben Mesa:
The discovery of the JAK2 mutation in 2005 really was a watershed moment, lot of investment from the pharmaceutical industry; a lot of expansion of our field in terms of investigators, global networks, patient engagement, and many drugs being developed. So, really, a very exciting time.

Ruben Mesa:
But first, let me throw this out here, perhaps have Claire comment first, as there was a very interesting, late-breaking abstract from Dr. Nangalia and the wonderful group there at Cambridge regarding issues of clonal evolution for individuals with an MPN, suggesting that the origins, genetically, may go all the way back even in utero, which raised questions about aging and the core of biology and hematopoiesis itself. So, Claire, what was your takeaway from that really interesting, late-breaking abstract?

Claire Harrison:
Well, thanks, Ruben. Well, first of all, to say, “boy, science has moved on,” because, five years ago, we were doing one PCR on a colony, and now we’re doing whole genome sequencing on a colony. I mean, Jyoti and the team at the Sanger, absolutely amazing work, fantastic mathematical modeling, showing that we cannot only have clonal expansion in utero, but also non-clonal expansion of stem cells, which is absolutely fascinating, and raises all sorts of questions about early treatment, whether some of our treatments can promote genomic stability and prevent further mutations from arising, but also public health issues, because many of these mutations may be associated with thrombosis as well. So, absolutely amazing; really inspirational; a great watch.

Ruben Mesa:
Naveen and Serge, it raised an interesting point in terms of the origin of that predisposition goes way back to, perhaps, infancy, but then, clearly there are pressures that lead to this turning on in some people, clonal evolution. Any thoughts regarding that? And if you’re a patient watching this, or even a physician, what might be some of the contributors to clonal evolution that turns on an MPN?

Naveen Pemmaraju:
Well, Ruben, thanks for having us. What an important question as we review Dr. Nangalia’s work. I think a lot of hypotheses here in this area with maybe not solutions. I think you have to factor in second, third, fourth hits, as we say, maybe the features such as environmental, things such as inflammation or tissue injury for our patients over time. We have this concept of CHIP, or clonal hematopoiesis of indeterminate potential, that we thought of generally for older adults, but you’re right, this paradigm shifts. Now we have to think about this in the younger setting. So factors such as inflammation, obesity, smoking, environmental factors, and the acquisition of other genetic mutations much younger than we thought possibly could play a role.

Naveen Pemmaraju:
But I’d turn it to Serge to see his thoughts as well. Serge?

Srdan Verstovsek:
Yeah, I think there are a number of factors that may contribute to one developing the disease later on in the course of their life, but this is exploratory field for us as of yet. However, obviously, this being a late-breaking abstract, many right away say, “What does this mean for everyday practice today?” And my patients come up, those that follow the chat rooms and news outlet that work on the MPN particularly, and they say, “Should I have my family members tested for …” and then they go on with the JAK mutation or any other mutations, and my answer is no.

Srdan Verstovsek:
There is no real knowledge who and whether they will ever develop any disease, as it has been discussed for, what Naveen alluded to, that we have known about older population of people. Some of them, particularly after 65 years of age, having a JAK mutation and never ever develop the disease. So the same type of discussion has to be extended to the earlier age, saying clearly that that is not something that is actionable at all right now, and no need for testing.

Srdan Verstovsek:
And I would like just quickly to see what your feeling is about the applicability or no applicability, or no action on this particular information … as of yet, because that’s what I’m asking my patients.

Ruben Mesa:
I would definitely agree with you, Serge. As I try to share with patients, it’s fascinating from a scientific standpoint, but if you’re the patient facing the disease, it’s clearly less fascinating and more terrifying watching the scientific sausage being made, that we’re gaining further insights into, really, some of the core issues of, “Why do you develop diseases like this?” but we don’t have the answers yet. Although they’re can be many speculations in terms of, “What is the driver that either turns it on or leads to progression?” it’s not quite ready for primetime. I would have folks be excited that all of this is going on but recognize, although it’s difficult, that patience is required, because, you’re right, we don’t know whether any of it is actionable in the near term for patients.

Ruben Mesa:
Claire, you had a comment?

Claire Harrison:
Yeah, a couple of things. No evidence of any impact of any treatment, so no evidence of benefit for interferon or hydroxycarbamide; small number of patients. But also, I think, in a way, it may be reassuring for patients because they probably have the disease very, very slowly evolving for a long time. Many patients would kind of tick off, “Well, I’ve had the disease for this long, and then I’ve only got another 10 years.” It’s just showing slow evolution, I think, for many patients, but also that we need the science of molecular genomics and modeling, and we really need to understand it. Thanks.

Ruben Mesa:
We do. I’m grateful that we have field that really has a rich tapestry of people working together. On this call, clearly, most of us are really focused on therapy, therapy evaluation, the development of new pharmacologic therapies, but really grateful that we’re working in parallel with brilliant laboratory scientists, like Ross Levine, Ann Malali, Jyoti, Tony Green, Robert Kralovics, Radek Skoda, and may others whose phenomenal laboratories are really making some key insights.

Ruben Mesa:
Well, let’s pivot a bit toward therapy, and, again, some of these issues are relevant in that when we think about goals of therapy, avoidance of progression is one of those areas of interest. Certainly, at this year’s ASH meeting, there was an entire session on therapies for PV with a heavy focus on a whole slew of favorable data as related to interferons. You know, how early should we use them, a couple different formulations, long-term data from a couple centers regarding interferons.

Ruben Mesa:
Naveen, what was your takeaway from the PV interferon data?

Naveen Pemmaraju:
Ruben, great question. As is often in our field, what’s old can be new again. Our colleagues, Dr. Silver in particular in New York has been thinking and talking about interferon for decades now, and I was pleased to see sort of a resurgence of interest in this.

Naveen Pemmaraju:
Two things caught my eye at ASH. One is the ropegylated interferon, which we and others have been thinking and talking about for some time. Our colleagues, Dr. Gissinger and Jean-Jacques Kiladjian, showed this five-year, long-term follow-up data, and easier to give administration than the Pegasys interferon that many of us in the States are used to, possibly less side effects, and of course, long-term safety and tolerability data. That was encouraging to see. I think that, as that enters into the United States in clinical trial, hopefully, possibly, an approval at some point, it could change our landscape for our patients.

Naveen Pemmaraju:
I think a second factor was interferon-based therapies here in the States, as shown by Dr. Silver’s group. In terms of long-term, lots of patients treated and showing disease modification, safety, and raising the question if some patients can discontinue with interferon for our patients. So I thought there was a lot of great emphasis on it, and I think the future of the interferon field will be: Can we safely combine it with JAK inhibitor, as are several studies ongoing, the COMBI study and others, and can we continue to mitigate long-term side effects for our patients taking any interferon formulation? But I think these are some of the take-home points, Ruben.

Ruben Mesa:
Excellent. A couple other areas that I think were really of interest, have Serge comment on one and Claire on the other. But first, Serge, there was the pilot data presented from Ron Hoffman’s group at Mount Sinai with the hepcidin agonist from Protagonist. Had an interesting different mechanism of action. Maybe share with folks a little bit what does a hepcidin agonist … What role could it play in PV, and how do you think that might into our algorithm if it proves to mature and become an option…

Srdan Verstovsek:
Well, we are looking very carefully at the development of ropeginterferon, which is approved in Europe. It was approved a year ago, and application for its approval was placed here in United States in June of this year. Maybe it’s going to be approved for PV next year here in United States. We also look at other mechanism of action that potentially can benefit our patients.

Srdan Verstovsek:
Hepcidin, as one of the key regulators of iron metabolism in a body, comes to forefront with the application of PTG-300. PTG-30 is hepcidin-mimetic. What it does is keeps the iron … And iron is very important in PV, first to clarify. Iron … I simplify it always. It’s like a food for red blood cells. In polycythemia vera patients, there is iron deficiency because iron is utilized by red blood cells for growth. As we phlebotomize the patients, people become more and more iron deficient. There is less and less of iron for red blood cells and less of phlebotomy. But not everybody develops that favorable outcome, have side effects from phlebotomy; side effects from iron deficiency. So there are issues about it.

Srdan Verstovsek:
With hepcidin-mimetic, what happens is the redistribution of iron. It stays in the tissue of the body, in liver, in the spleen, and it’s less valuable for red blood cells and less of a growth of red blood cells. With the PTG-300, what we see immediately, in 18 patients that their outcome was presented in ASH, cessation of a need for phlebotomy.

Srdan Verstovsek:
At the same time, the measurements of other factors related to iron metabolism normalized in the patient’s body. The ferritin, for example, which is usually surrogate marker for measuring iron, normalizes; MCV, the size of red blood cells, normalizes. So it has some really favorable effect on the body itself by, at the same time, eliminating need for phlebotomy.

Srdan Verstovsek:
The question that you posed is really where we go from there. So highly effective; appears to be safe. With injectable under the skin once a week, it requires some months to find the dose that perhaps would be easy to deliver without monitoring blood cell count too often. We can utilize it in patients that are dependent on phlebotomies, have too many phlebotomies, or, because of iron deficiency, have side effects, or maybe as adjunct to cytotoxics, to hydroxyurea. Hydroxyurea is not optimal in managing the patients.

Srdan Verstovsek:
This gives me, actually, opportunity to extend our discussion to two other presentations. They were not in oral session, but I find it very instructive. Analysis of the efficacy of hydroxyurea in community practice. It’s not very good. Only about 40% of patients appear to derive optimal benefits; majority don’t. We don’t have, really, such optimistic results on the use of hydroxyurea itself to say, “Yes, that’s the one. Forget about any other.” No, that’s not the case. There is room for improvement in hydroxyurea alone. There is room for adding PTG-300, alternative therapy with interferon, or even with ruxolitinib in second-line drug.

Ruben Mesa:
Wonderful. A final thing on PV, it was shown earlier this year at EHA an upcoming data regarding potentially even using interferons in early PV versus phlebotomy with perhaps kind of an event-free survival sort of endpoint. Our group presented a retrospective analysis of much of the symptom data that we had gathered that did help to validate that there are many patients that are on phlebs only or that are, quote, low-risk that do have significant symptoms, and surprisingly, at least a third or more are receiving cytoreduction. So I think it was very interesting to see those data coming forward from Professor Barbui in an Italian-led study.

Ruben Mesa:
Claire, any thoughts on interferons for earlier-risk PV? What do you think, particularly in the UK where you have very stringent standards … Things have to be approved by NICE. They not only have to be approved, they have to be paid for. What do you think makes the case for introducing therapy in low-risk PV?

Claire Harrison:
Well, actually, interferon isn’t … We kind of prescribe free of any NICE restrictions. But I think it’s important … I think there are a few issues. Actually, the British guidelines … We’re very fond of our guidelines. They reference treatment for PV patients for progressive symptoms, for progressive splenomegaly, and I think referencing that sometimes earlier treatment is indicated.

Claire Harrison:
I really want to see Tiziano’s data about progression-free events, because, whilst I’m kind of really impressed with the symptom data, it was open-label study. These are patients who are on an agent early on, filling in their symptom data. We did see, still, persistent fatigue, which is a very common problem for these patients.

Claire Harrison:
So I am interested. I’m also really interested in the hepcidin story for these patients too, because iron deficiency carries a lot of morbidity for those patients, and venesections is difficult. I think Jyoti’s data might play in here as well. How long is a low-risk PV patient really a low-risk PV patient? I think we need to do a lot more work here.

Claire Harrison:
What Tiziano’s data has made us think about a lot more though is, actually, really looking at symptoms and really looking at whether the patient might benefit from a trial of therapy early on to try to see what might help them. But I think we really lack an effective agency. Actually, in the UK, we’re interested in looking ruxolitinib early on in PV patients, and maybe even a combination, but that would be way too fanciful and costly for a UK practice, anyway. So we’re studying ruxolitinib versus interferon versus hydroxyurea upfront.

Ruben Mesa:
I think all of this has a lot of merit, and I think many patients with PV have a burden with the disease that’s inadequately addressed by phlebotomy and aspirin. I think we need to prove that case, and which therapy, and what are the endpoints, and what merits therapy, and how is it evaluated. I think there’s a lot of personalization of therapy that will happen as things evolve.

Ruben Mesa:
Well, let’s pivot in our final section to both myelofibrosis as well as some of the other more uncommon MPNs. But first, let’s start with myelofibrosis. As I’ve shared with many patients, there’s a very robust pipeline, and for many reasons, that pipeline starts with patients with MF. There’s a lot of unmet needs. A lot of therapies will be tested in MF patients first, and then potentially expanded to other areas.

Ruben Mesa:
Now, at this year’s meeting, there was several areas of discussion talking, really, about survival and improvement in survival, either retrospectively with very nice data that Serge’s group presented, as well as with momelotinib potentially, and even imetelstat. Serge, you were involved with many of these different analysis. What is survival as an endpoint? How is that evolving in MF? And just a high-level summary of what was seen with some of those abstracts as it relates to: are we improving survival in MF?

Srdan Verstovsek:
This is really important because that is the most important for the patient, and it should be the most important endpoint for our drugs in terms of what they do. We, so far, have focused, properly, on improvement on quality of life, improvement of the symptoms, decreasing the spleen, making people feel better, walking more, gaining weight, and also improving the bone marrow function; improving the anemia.

Srdan Verstovsek:
But ultimately, we want, through those, control of the symptoms and signs to also make people live longer. So we are finally in the area here where we are actually talking about devising studies with a ultimately goal, or a first goal, actually, to make people live longer. So where would that play the most? And that would be in the second-line setting where people, after treatment with JAK inhibitor, most of the time, ruxolitinib, have retrospectively, looking at survival, have a short survival with a bad quality of life with big spleen, with anemia, and not much one can do.

Srdan Verstovsek:
The evidence from imetelstat, this is one of the medications that you have mentioned, in a re-analysis of a prior study where the imetelstat, which is telomerase inhibitor given on the IV every three weeks as a infusion, was tested for improvement in the spleen and quality of life, eventually suggested strongly that this drug actually makes people live longer, possibly.

Srdan Verstovsek:
So now we have a number of reports at ASH on addition of imetelstat, trying to understand, “Why would people live longer?” So there was improvements in the bone marrow fibrosis, in some genetic abnormalities, analysis of chromosomes. Some people felt better; some people had a smaller spleen. There is a concoction of these benefits that apparently, and that’s a subject to the next study, make people live longer in the situation where the life is bad and it’s short. So we are looking forward, actually, based on all of this knowledge about what imetelstat can possibly do to conduct altogether the survival study — that’s how I say it — for imetelstat in a second-line setting after JAK inhibitor to compare to best available therapy and see whether this drug really prolongs life.

Srdan Verstovsek:
Now, I’d like to add information that you alluded to in our own efforts to analyze what is actually the survival of the patients in modern era. We are very cognizant of the prognostic scoring systems that were developed on past experience, like International Prognostic Scoring System, and now we have molecularly inspired prognostic scoring systems. But I always say there are developed based on the past, 10, 20, 30 years in the past, and we are looking to project the future for patients that are here with us in the clinic now.

Srdan Verstovsek:
So we looked at our own experience in 1,500 myelofibrosis patients, and we clearly documented and presented that the life expectancy is improving every five years as we separate patients in groups. It’s getting better and better through better care; through earlier intervention; through everything that we do for our patients. Even though we don’t have too many new medications approved as of yet, the life is better and it’s longer just through our care. So very satisfying.

Ruben Mesa:
Wonderful. Wonderful. Well, I think it continues to validate that I think therapies, as we’ve all reported together as investigators on the comfort studies, that ruxolitinib has had an impact in survival. Any of us that care for a lot of MF patients don’t doubt the validity of that for one moment. Patients are living longer there is no question. In the latter 15 years of my career versus the first 15, it’s pretty significant. The very severe MF patient, massive spleen, ascites, I see lots of this, and I think JAK inhibition and effective therapies have really made an impact.

Ruben Mesa:
Now, there was a variety of themes, and perhaps would try to summarize them at a high level, both in terms of the potential of combinations, either at the time of for JAK inhibitor-naïve patients. So it’s a rux + the BET inhibitor, CPI-0610, or adding another drug to rux in some optimal responders, both 610 as well as navitoclax.

Ruben Mesa:
Claire, you were on both of those. Any thoughts … Just at a high level, what do you think the combinations bring to the table? Do you think we’ll evolve to a place where everyone gets a combo, or that we use them in subsets?

Claire Harrison:
Well, thanks, Ruben. I think super exciting data and, boy, a really crowded field, actually, second-line for myelofibrosis. The first thing is the definition of the second-line patient, probably very heterogeneous. Quite difficult to compare across studies. Probably the most developed story the CPI story with the sequential monotherapy add to rux, and then their JAK inhibitor-naïve randomized study. Interesting. 67% response in naïve patients; probably slightly less in the second-line add-on. But importantly, anemia responses, which I think is … Anemia is a big unmet need for these patients. Well-tolerated drug; very little in the way of additional side effects; seems to be beneficial. A number of different agents showing data for bone marrow fibrosis regression this year. That seemed to be quite a common theme and an unvalidated endpoint, really. But it’s nice to see that data being collected, and also the allele burden changes that were collected by both.

Claire Harrison:
So navitoclax, clearly different agent; very different target; slightly smaller number of patients, but really exciting data as well, adding onto rux. Clearly, additional benefit. Fibrosis reduction again, and quite a difficult group of patients, high molecular risk, mutations, but slightly more challenging because of thrombocytopenia. I think, probably, there will be different patients who are best suited to different agents.

Claire Harrison:
It was interesting to look at the imetelstat data and see that they could clearly see that responses were better in patients that had higher TERT levels or shorter telomeres at baseline. And indeed, we presented some data with tamoxifen showing that we thought we could identity responders upfront with RNA-seq.

Claire Harrison:
I think, to come back to your question, and your challenging one, actually, “Will all patients end up with a combo?” I doubt it at the moment, certainly in the short term, because I think ruxolitinib is good for many patients as a single agent. It’s nice to test other things in combination upfront. At first, many patients, probably ruxolitinib alone is good enough until they start to lose response or if we find a way to identity them as a patient that’s high-risk of progressing. So I think lots of excitement. You picked two drugs, but there are others, like LSD1, also showing exciting data. So I think busy, exciting.

Ruben Mesa:
You know, I strongly agree with you. What I’m really excited, just the depth of the platform. There’s the MBM2 inhibitors. I’m involved with the studies from Imago with the IMG-7289, both in MF as well as a PV study, and clearly active. These other drugs that are being looked at as single-agent, we’ve not looked at them in combination, but is it going to be a similar story? Expanded benefit if you use in JAK inhibitor-naïve with a JAK inhibitor, or do you add it on after three months or as a second line?

Ruben Mesa:
I do think, in terms of clinical management, we probably will evolve to starting with a JAK inhibitor, maybe have a subset that we have identified from Phase III studies have a higher likelihood of response to a combination, but probably not in everyone, and then we’ll probably more rigorous in terms of what’s an optimal response at three months or six months, and add something else on. The issue of a single agent for years and then adding another drug is probably more of a reflection of a bit where we have been than where we may be going.

Srdan Verstovsek:
Not to forget about the luspatercept, which is in development for anemia. Anemia is a major problem, major unmet need, where we struggle. I mean, anemia leads to underperformance of JAK inhibitors, under-dosing and early discontinuation. So luspatercept, which is approved for some patients with myelodysplastic syndrome is being tested as add-on approach to JAK inhibitor for people who are anemic. If that makes it at the end … I hope all of these drug eventually makes it, but this one has opportunity to, in a simple and effective way, cover the third, as-of-yet-uncovered problem, so spleen symptoms by JAK inhibitor; anemia with luspatercept.

Claire Harrison:
Yeah, and I think, also, the interesting thing with that data is it seems to be very effective in patients already on ruxolitinib. Maybe small numbers, but maybe more so, which is also intriguing but good, because it may help us in managing ruxolitinib or other JAK inhibitors. But I think, you know, Serge, you presented the data with momelotinib, which is also an interesting JAK inhibitor. We didn’t see so much with pacritinib this year, but there’s the PACIFICA study ongoing. But your momelotinib data with the long-term efficacy, long-term durability of responses for transfusion independence and spleen were really very interesting.

Srdan Verstovsek:
Yeah, we talk about combinations to enhance the benefits and add additional benefits, but in momelotinib, I’m really, actually, very pleased what we have shown by a reanalysis of the past phase III studies, SIMPLIFY 1 and SIMPLIFY 2. It is really effective to great deal in improving the spleen, and symptoms, and anemia, and for a long period of time, and possibly extending life, which is not surprise. We know, as we said before, that’s the fact with ruxolitinib. So here we have a drug easy to give. It’s being developed as a second-line choice for control of the symptoms and anemia, and it can do good on the spleen, and possibly make people live longer. So I encourage everybody to enjoy that drug on a clinical study if it’s available to you.

Ruben Mesa:
I think that definitely should be a strong takeaway for everyone watching this. There is a very robust pipeline of myelofibrosis studies, particularly in suboptimal JAK inhibitor responds, but even in naïve patients. Thank you, Serge. I had forgotten to mention luspatercept, that I think, given it would be a third indication, I think has a high likelihood of being successfully indicated and a very nice addition in terms of anemia. I think momelotinib and pacritinib will become approved with successful Phase IIIs, and each kind of having their own unique niche. But for folks who have MF patients out there, know there is a robust pipeline of Phase III studies as well as institutional Phase II studies. If you have someone who’s really not having an optimal response, think about that piece.

Ruben Mesa:
We’ve mentioned PV; we’ve mentioned MF. We’re nearing the end of our time, but wanted just to tackle a couple other quick things. First, Claire, we haven’t mentioned too much about ET. We’ve got some exciting things coming up. There is a global study with ropeg that Serge and I are leading. Put a plug in for that for a second line for ET. But other key ET updates from ASH?

Claire Harrison:
Yeah, great. I think not so much from ASH, but wanting to just call out that, yes, your ropeg study, and we’d like to join that in Europe. Would be fab. But that some of the agents we’ve been talking about, CPI-0610 and the Imago agent, bomedemstat or IMG-7289, both of them launching studies in ET, which I think is really exciting and important. We need some new drugs there, and we need to see the data from the ruxolitinib versus anagrelide study. Be good.

Ruben Mesa:
Fabulous. Now, a couple less common diseases, perhaps we’ll close out just to show you the breadth of everything’s that’s going on. First, some real progress with systematic mastocytosis. As someone who has spent part of his career really focusing on disease burden and symptoms, patients with systematic mastocytosis really can have some of the most difficult times with their disease, and there have really been some excited, targeted therapies. Serge, any high-level summaries of what folk should be thinking are coming over the horizon for systematic mastocytosis?

Srdan Verstovsek:
There is a lot of excitement, and hopefully, next year we’re going to have a new drug approved for systematic mastocytosis. Just to remind everybody, there are a large two groups of mastocytosis patients. So this is the chronic disease of mast cells, type of white cells that may be in bone marrow and other organs. We divide patients based simply whether they have organ damage from the disease or not.

Srdan Verstovsek:
Normal organ function that is indolent or benign systematic mastocytosis, bad quality of life, but normal organ functions and normal life expectancy. Most of the people are treated by allergists. The goal, obviously, is to improve the quality of life. But advanced mastocytosis or aggressive comes with organ malfunction and life is short, three, five, seven years. Here we need to be more aggressive. That’s the bread and butter of what hematologists/oncologists do.

Srdan Verstovsek:
In that setting, in particular, we have avapritinib as the new drug that has been developed through several years now as a very effective therapy. It’s showing high level of elimination of the disease or partial elimination of the disease in the patients that suffer a lot from symptoms, inability to produce red blood cells, having big spleen, losing weight. Similar clinical picture to advanced myelofibrosis.

Srdan Verstovsek:
It’s all about targeting underlying biological problem, which is mutations in KIT gene, KIT-D816V, which drives the disease process. In that sense, this targeted agent, and very effective, and the correlations that were presented at American Society of Hematology says that pathological elimination of the disease, to different degrees, correlates very nicely with clinical outcome and possible survival benefit of these patients. So a lot of enthusiasm to not only, again, like in myelofibrosis, focus on immediate control of the symptoms, but moving on to the elimination of the disease in mastocytosis, and prolonging life. The drug is also being tested in indolent disease patients at much smaller disease, which should be safe and effective for control of symptoms. So we closely follow this developmental path for this drug called avapritinib.

Ruben Mesa:
Wonderful. And finally, not a common disease but one where there’s been a tremendous impact, and Dr. Pemmaraju has really been at the forefront that evolving story, BPDCN. Naveen, want to give folks just the elevator speech, if you would, of the disease, the burden, but how the new therapy is impacting them.

Naveen Pemmaraju:
Yeah, thanks, Ruben and team, for highlighting these ultra-rare blood cancers, which I think are now finding a home in a lot of the research and patient care, because when you’re a patient with a rare disease, it’s not rare to you. It’s a disease that you and your family are facing. Blastic plasmacytoid dendritic cell neoplasm, or BPDCN, really is kind of its own myeloid neoplasm entity now, and it basically effects 500 to 1,000 Americans a year. It has features of lymphoma, skin disease, and leukemia as it effects the skin, bone marrow, and lymph nodes. Really, overall survival has been short, Ruben, 8 to 14 months with standard cytotoxic chemotherapy.

Naveen Pemmaraju:
The breakthrough in our field was the discovery that CD123, or IL-3Rα, is over-expressed in 100% of these patients, and there have been no targeted approaches until recently. I was able to lead our group to study the first one, tagraxofusp, or SL-401, which gained FDA approval for ages two and older in BPDCN. That was two years ago now. Now, at ASH, I presented data on a second generation, if you will, of CD123 targeting agents with IMGN632, which is showing promising, encouraging data, which I presented in the ASH oral presentation.

Naveen Pemmaraju:
So the take-home point is, in rare diseases, rare blood cancers, try to find a personalized, precision, targeted way to treat, minimize toxicity, and improve research understanding and outcomes through this sort of focused approach, and then try to extrapolate it to other diseases.

Ruben Mesa:
Wonderful. Well, this has been a phenomenal discussion. Maybe we’ll have just one last comment from each of our panelists on something they’re really excited about as it relates to MPN progress in 2021. Claire, why don’t you start us off?

Claire Harrison:
Well, I’m just continually excited by the way we work colaboratively and we use science to drive the way forward. But I was just struck by Naveen’s comments, and wanted to shout out the pemigatinib story in FGFR-mutated diseases too, another really rare, probably fewer than 500 to 1,000 Americans. We only managed to recruit two patients in the UK, but that’s a game-change drug. So think about that if you’ve got a patient with 8p11-mutated myeloid or lymphoid disease. Thanks, all.

Ruben Mesa:
Fantastic. Serge, how about yourself? What excites you with MPNs in ’21?

Srdan Verstovsek:
At the last count, I think we had about 10 different Phase III studies in development or underway. Phase III studies are those that compare new to old and make us approve new drugs. Imagine that we have 10 new drugs in next 10 years or five years. It’ll be incredible. So I’m excited about the potential. I would like to encourage everybody, the doctors, the patients in particular, to join the effort together. Only as a team, we will succeed, and imagine where we are in three year’s time, in three year’s success on all these fronts.

Ruben Mesa:
Fantastic. Naveen?

Naveen Pemmaraju:
My last take-home point, Ruben, would be for looking at these combinations, doublets and maybe even triplet regimens in our MPNs, particularly in the accelerated phase, blast phase, and post-MPN AML. This has been a very difficult of research, but a lot of new companies and older companies are working in combination with JAK inhibitors and brand new, novel agents. So I’d like to keep an eye on that as we move forward over time.

Ruben Mesa:
Wonderful. And I would share what I’m excited about, one, the unprecedented degree of both activity and collaboration, but, two, we’re clearly seeing we’re not talking about three diseases. We’re talking about a lot of nuances at a molecular level, at a phenotype level, at a symptomatic level that we need all these therapies to be developed because the path for each individual patient might be different. We’ve learned about a myelodepletive phenotype that may benefit with pacritinib. We’ve learned subtlety of who might respond to tamoxifen, or to IMG-7289, or to momelotinib. So I think much more for us to learn, much more individualized therapy, and the advances that occur in MPNs, I think, will have benefits well beyond that: the issues of aging, CHIP, MBS, secondary AML, on and on. Everything is linked, and I’m excited by the progress.

Ruben Mesa:
So, with that, let me thank the wonderful co-panelists as well as the kind invitation from VJHemOnc for us to be able to share with you some of these exciting updates from ASH 2020. Everyone keep well, and we look forward to hopefully seeing people in person in 2021 sometime soon. Thank you.

Srdan Verstovsek:
Thank you, everybody.

Claire Harrison:
Take care. Bye.

Naveen Pemmaraju:
Bye. Thank you.

Srdan Verstovsek:
Bye.

Disclosures

Srdan Verstovsek – Research support for conduct of clinical studies: Incyte, Roche, NS Pharma, Celgene, Gilead, Promedior, CTI BioPharma, Abbvie, Blueprint Medicines Corp., Novartis, Sierra Oncology, PharmaEssentia, Constellation, Ital Pharma, Protagonist, Kartos

Naveen Pemmaraju – Committee: ASH Communications Committee, ASCO Leukemia Advisory Panel. Consultant: Pacylex Pharmaceuticals, ImmunoGen, Bristol Myers Squibb, Blueprint Medicines. Grants: Affymetrix, SagerStrong Foundation. Honoraria: Incyte, Novartis, LFB Biotechnologies, Stemline Therapeutics, Celgene, AbbVie, MustangBio, Roche Diagnostics, Blueprint Medicines, DAVA Oncology. Research support: Novartis, Stemline Therapeutics, Samus Therapeutics, AbbVie, Cellectis, Affymetrix, Daiichi Sankyo, Plexxikon. Travel: Stemline Therapeutics, Celgene, MustangBio, DAVA Oncology, AbbVie. Volunteer/uncompensated: Dan’s House of Hope, HemOnc, Times/Oncology, Times

Ruben Mesa – Consultant: Novartis, Sierra, Abbvie, BMS, Genentech, Roche, Blueprint. Research: CTI, Incyte, Sierra, Blueprint, Imago

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