MPN updates from iwMDS-iwMPN 2024 | Day 1 highlights: imetelstat in MF, challenges with MPN/MDS overlap syndromes & future outlooks

Naveen Pemmaraju:

Hi, everyone. I’m Naveen Pemmaraju, Professor of leukemia at MD Anderson Cancer Center in Houston, Texas. We really had a phenomenal day here at the iwMPN 2024 meeting, and I’m really excited to introduce, I’m joined by my distinguished colleagues, Professor John Mascarenhas from Mount Sinai in New York, Professor Claire Harrison, and also, Dr. Dan Wiseman, both from the UK. Really what I want to do is have a nice discussion at this conclusion of the first day with future ideas in the MPNs and, very importantly, in the MPN/MDS overlap syndromes. First, I’ll start with John. John, you gave a beautiful talk on a new agent that actually just got US FDA approved, that of imetelstat, thought to be the first ever telomerase inhibitor. And one great thing about it is that it has activity in MDS, as was just recently improved, and you’re also leading the trial in myelofibrosis. Can you tell us a little bit about imetelstat and what’s the latest on that?

John Mascarenhas:

Sure. So imetelstat is a drug, actually, it’s been in development for probably 20 years, across multiple different malignancies. It’s based on a concept that telomerase is a therapeutic target that’s overexpressed in malignant cells and not expressed in normal cells and only transiently in stem cells. And in myelofibrosis, we’ve been using it or evaluating it in patients with advanced myelofibrosis, who failed ruxolitinib, who have a poor survival and limited therapeutic options. And that’s really where the Phase III has been focusing on, the relapsed/refractory JAK inhibitor in treated patients, with a primary endpoint of overall survival, which you and I have talked about multiple times is unique. Because it sort of moves away from the normal spleen and symptom endpoints. And it’s really informed by the Phase II data that would suggest that there is an improvement in survival, progression-free survival, also symptom burden improvement, anemia improvement, and then, biomarkers of disease modification reduction in JAK2V617F, reduction in bone marrow fibrosis, both of which were correlated, in the analysis, with improved survival.

And with a propensity scored match analysis, imetelstat 9.4 milligrams per kilogram IV every three weeks, which is different dosing schedule than an MDS, does seem to be associated with improved survival. So I think it’s an intriguing agent. We discussed previously and at the meeting that I’m not sure we totally understand the mechanism of action of the drug. It’s a telomerase inhibitor, and hence, in theory, is affecting probably the cells that are most vulnerable. There’s those with the shortest telomeres, which are the malignant cells that are dividing and ultimately triggers both P53 dependent and independent pathways leading to apoptosis.

And there’s a lot going into these studies to try to understand whether there are clear pharmacodynamic markers of the drug and predictive biomarkers of the drug. But I think it’s really interesting to see the, and this was part of the, I thought, spirited discussion today, see the drug being developed in the relapsed/refractory MF space, but also come up with really great data, earlier on, in the lower-risk transfusion dependent space, with really phenomenal, I believe, phenomenal responses. I think we have to figure out where these drugs are going to fit in and balance the on target myelosuppression, which is reversible with this drug.

Naveen Pemmaraju:

Wonderful. And I love that you highlight, I want to make sure everyone out there caught that, and I praise you and the team, it’s probably, to our knowledge, the first ever large phase myelofibrosis study in which overall survival is the primary endpoint. So I really praise you for that. And John, I hope it can be a model for other studies to come in the future. So that’s wonderful. Dan, we’ll go to you. So we just talked about MPN and MDS as two separate entities, maybe some drugs working for both, but you covered something that’s emerging in our field, something very, very important, that had either long been forgotten or misunderstood. And that’s MPN/MDS overlap syndromes. I thought you gave a beautiful thought provoking discussion here. If you can, summarize for folks out there, what are we talking about? What’s encompassed there? And what do you hope for in the future for maybe pathology, diagnosis, and treatments?

Dr Daniel Wiseman:

Of course. So for those out there, the MDS/MPN overlap syndromes are a completely separate chapter of the textbook. They’re separate and subservient really to MDS and MPN. It’s bigger brothers. And that’s always been a frustration to the few of us who have a particular interest in that field. It’s left those patients without as many trials, treatment options. And we went on a bit of a journey, I think. It was a nice opportunity, and that’s one of the great things that I found about today was it’s quite rare to have a platform in meetings like this. And bringing MDS and MPN together like this, I think it was, I think, a natural way to bridge the two parts of the meeting. So the point that I was trying to make really was that we’ve arrived at a classification system iteratively through the various WHO and now the ICC, that is rational in a way, but it isn’t how I would do it now, if we were doing it afresh.

And you’ve ended up with quite a hodgepodge of diseases that sort of misfits and don’t belong in any of the other categories. So not a big fan of where the boundaries between the overlaps in MDS and MPN are, but even within the overlap space, there’s a lot of inconsistent principles applied to what constitutes one disease versus another. We discussed some of the idiosyncratic combinations that you find in that melting pot, and I find it quite a satisfying area. Because it’s really very obvious, when you get the genotype/phenotype correlations coming through and you can explain it away by its underlying genetics and epigenetics. So highlighted, I’d certainly raised more questions than I answered, and I think that was the intention.

Certainly don’t claim to have the answers, but I think we should be thinking about this space and zooming out, I would argue, we should be thinking about myeloid malignancy in a slightly different way, rather than putting them into these separate buckets and everyone internally thinking about their disease focus. There are all of these, everywhere you look, there are overlaps and connections, and we can learn from each other. And I think there was a lot of that in particular in the final session. And I think that the imetelstat is a great example too, of that. So yes, it was a therapeutic exercise, because I’ve waited for the opportunity to give that talk for five years. And I may never be invited to give it again.

Naveen Pemmaraju:

That’s right, right. It was a one-time showing only, but what was great is there were the pathologists in the room, which you shouted out, and they were involved. And what I loved about your talk is you called for a sort of new classification, molecular morphology, maybe a little bit of the old, a little bit of the new. I want you to comment more on that. Yeah.

Dr Daniel Wiseman:

Yeah. So I just think that what we’ve seen is we wait five, six years and there’s another iteration and it’s better, it’s certainly better, in most cases. And you start to incorporate new information, but then, you do end up with this hybrid of a part pathological, part contextual, part molecular classification. I think MDS/MPN overlaps really highlights that. And one of my slides just, I think, trying to illustrate the problem was just that it’s not balanced in numbers. It’s not balanced in the sort of principles that go behind what separates one entity from another. You’ve got 72% of patients in this very heterogeneous CMML category, which I think is more than one disease. And we’ve spoken a few times today about one example of that, at the sort of lower monocyte level, with SRSF2, TET2, the 0.5 cutoff, hugely different from a patient with a white count of 200 and a huge spleen and a very different disease.

And so, you’ve got that, and then, you’ve got one molecular entity that’s beautifully defined molecularly. Because the ring sideroblasts and the thrombocytosis are very visible in your face, things that you can’t miss. And they’re both purely, obviously, driven by specific mutations, so that then gets its own molecular entity. Then you’ve got a purely morphological entity and atypical CML, if you’re an ICC person, or MDS/MPN, with neutrophilia, if you’re WHO, which is certainly in the UK, I find, is very poorly and inconsistently recognized and applied. And then, you’ve got this huge dumping ground of other stuff, and I just think there’s a problem if your second biggest disease grouping is the miscellaneous.

Naveen Pemmaraju:

Right, right. Well, brilliant. As I try to process this really exciting day together, I have to turn it to Claire. When Claire and I envisioned this day, I think I can speak for both of us, it exceeded our expectations. You summarize it nicely. MPN, MDS and then, MPN/MDS and the way you segued to end here to the MDS day, Claire, as I always usually do, I look to you, Ruben, Jean Jacques, now John and I and others, we try to process this. The spectrum was set forward today from CHIP to ET, PV, pre-fibrotic MF, MF, MDS/MPN overlap. And then, as we try to prevent these from going to AML, as you step back and think about this day we had, what are some of the take home points, with regards to the big picture, maybe coming out of the EHA meeting and here, combination therapies, new endpoints, what do you prescribe for us for the remainder of the year? What should we be looking out for?

Claire Harrison:

Well, that’s a massive question at the end of a really easy day. I suppose I could be an optimist, a pessimist, and a realist… I think we should be optimistic, because we have some brilliant minds, really passionate people and we have great industry and also patient engagement, say the patient voice was in the room today, perhaps not enough MPN patient voice in the room today, but that’s really, really important. We also have fantastic science. You illustrated that beautifully today, Dan, pulling together 3000 patient data and showing how the patients separate out and then, thinking about time as well and reflecting AI and maybe AI in morphology. And I think we’re at a kind of point where we’ve got all of this, plus we’ve got all of these medications. So it’s a ton of huge opportunity, but it’s also a time of a bit threat.

And I kind of feel like there’s a bit of a runaway train as well here. So what we also covered today was we’ve got two trials you and I speak about, where we’ve got our endpoints rock, saying there’s a pressure to do better. That’s definitely well established. How will we do better when our endpoints are not great? And I want to go back to the beginning of the day and think about Kristen’s talk. So we deliberately gave her that topic that was about which patients should be treated and which ones not. So I think there are some patients probably in our entities where we do more harm by treating them. I definitely think triple negative ET probably falls into that category, although they probably need a bit molecular work. Triple negative MF, I think it’s probably something a bit different, but in using maybe some AI base morphology to really make out [inaudible] and what’s not, then I think moving through PV, treating those patients early, I definitely think we’re getting there.

I loved Jan Bewersdorf’s presentation. I’m going to quote it from his beautiful article in Blood. But I think the problem in myelofibrosis is really understanding who we should be treating, what with, and how we measure success. And then, when it comes to your MDS/MPN overlaps, what are we treating and how should we be targeting that? And I wonder if mutation is the whole story, whether we should be looking also a bit more at pathways and what we can use to talk and maybe applying AI also to morphological features, because not everyone has access to an expert.

Dr. Daniel Wiseman:

I couldn’t agree more. I spoke a lot about trying to reshift the boundaries within MDS/MDN overlaps, but actually, the boundaries with MDS and MDN at either end are just as important. Because I think that they’re probably in the wrong place at the moment for that reason. I think there are definitely patients who are currently CMML, for example, who should, in the future somehow, I don’t have the answers in terms of trial design right now, but they should really be being treated in the same trials with the same drugs as some of your MF patients, specifically the CMML with fibrosis, huge spleen and the JAK2 mutation. It’s a joke in our institute, if they get referred to Tim Somervaille, my colleague, they get called MF with monocytosis. If they get to me, they’re called CMML with fibrosis. And it’s better for the patient if they get to Tim, there’s a bit more treatments. So yeah, I agree completely.

Naveen Pemmaraju:

Yeah. You two brought up something, and John, we’ll close with you. You brought up two important things, stakeholders in the room and standardization. There’s a bit too much subjectivity in our rare disease space. And John, this is something you and I are passionate about, as we think about the combination data, frontline combination trials, we’re getting them all the way to Phase III, maybe not all the endpoints hitting the way we had envisioned. I think one other stakeholder, besides the patient voice, which is essential, pathologist, essential, AI, new technology, is that we feel passionately that we want to have an open invitation to regulators, the regulatory agency. So we invite FDA colleagues, EMA colleagues, and other regulatory bodies to start joining in these very discussions. And John, I know you’re passionate, I wanted to give you the last word on that before we close. What do you envision?

John Mascarenhas:

I think it’s going to be essential. So I think we have to also appreciate, are we moving drugs forward to move drugs forward for the interests of others? Are we moving drugs forward because they actually provide a substantial benefit, a meaningful benefit to our patients? So I’m not interested in just moving drugs forward, but I am interested in moving the right drugs forward so that we have options for our patients. And I think that is going to definitely require a close collaboration with our regulatory colleagues that may be sitting there sort of assessing what we’re doing from a different perspective and not maybe fully appreciating the value that some of these agents may bring, even if there’s some risk or some vagueness to what we’re accomplishing. I think having more options is important, but obviously, we’re not going to be able to do this, unless we have their buy-in too. So I think their participation at the table is going to be essential.

Naveen Pemmaraju:

Well, that’s fantastic. Colleagues, I can’t tell you how lovely this day has been. So much new information in this workshop. We’re entering a new era of mutant specific, mutant selective, combination and novel drugs, which I think, by definition, as my colleague said, will require new sets of lenses for response criteria, pathological diagnosis, and regulatory considerations. So with that, thank you all very much, and we hope to see you next time.