iwMPN 2025 | Novel therapeutic approaches in MPNs: targeting CALR, immune modulation, & JAKi specificity

David Steensma:

Hi, I’m David Steensma, I’m a hematologist oncologist focused on myeloid neoplasms and I’m currently working as chief medical officer at Ajax Therapeutics based in Cambridge, Massachusetts and New York City developing novel therapies for MPN. I am here at the International Workshop for myelodysplastic syndromes and myeloproliferative neoplasms in Lisbon, Portugal in June 2025. 

Shahram Kordasti:

Hi, I’m Shahram Kordasti, a hematologist and cancer immunologist from King’s College, London and Guy’s Hospital, London, United Kingdom. And I’m also the chair of EHA SWG for MDS. So, David, today we have this very interesting talk and presentation about CALR-mutated MPN and several treatments are now available, antibodies, potentially CAR T-cells. And so it seems like we can actually target CALR-mutated progenitors. But my question is, if we do that, some of these patients may have CHIP, may have other mutations, are we… do we need to be worried about what happens if we remove the CALR-mutated clones and do other ones take over or is it not really something that we should worry about? 

David Steensma:

Yeah, it’s a good question. This workshop, previously the first two editions were MDS only, but there’s so much going on right now in MPN that now it’s a combined workshop. And calreticulin has been one of the areas I think there’s been the most action, the most development. We just heard last week at the European Hematology Association meeting in Milan, a late-breaking abstract about the calreticulin monoclonal antibody in ET, John Mascarenhas presented, and there were some nice molecular drops with that and very rapid platelet normalization. In addition, at that same meeting, Beth Psaila talked about a novel bispecific antibody, and we had previously heard about a different bispecific antibody, as well as some CAR-T based approaches in London around calreticulin, and there are other approaches in development as well. So it’s an exciting time for calreticulin in particular. That said, calreticulin is about 30% of MPN overall and there are different types, type one, type two, that may be not equally targeted by different mutations. Sometimes you only have the calreticulin mutation and sometimes there’s a lot more clonal complexity and heterogeneity. In addition, you know, patients with CALR mutations do respond somewhat to the existing approved JAK inhibitors, and so there is some effectiveness there. I think we don’t know fully what the effects of reducing the calreticulin mutant clone would have on outgrowth of other clones, it’s an important thing that’ll have to be followed. 

Shahram Kordasti:

Yeah, and of course, some of these mutations present in the same clone of cells, and therefore we may actually remove both mutations at the same time. 

David Steensma:

Could be, and sometimes they’re parallel, where you’ve got a dominant calreticulin clone that’s actually a neoplastic process, and then you have a little CHIP clone on the side that may not matter that much, but maybe sometimes it does. 

Shahram Kordasti:

So we need to see and see what happens. 

David Steensma:

Great question. Yeah. So you spoke on immune remodeling and on, you know, understanding how the immune system responds to myeloid neoplasms, something you focused on for many years in MDS. And I would say, you know, in both MPN and MDS, we really haven’t had a lot of effectiveness with some of the immune checkpoint inhibitors or other therapies that have harnessed the power of the immune system. So where do you think things are going to go next in terms of immunologic approaches in myeloid neoplasms, timing, those sorts of questions? 

Shahram Kordasti:

Yeah. I think this is an important question. We weren’t very successful with checkpoint inhibitors. We were successful particularly with some of the anti-inflammatory therapies, if you like. And the question is, we should remember that inflammation is not just a switch that you switch off and everything goes back. Particularly non-physiological inflammation has consequences. And that was the question actually been asked that what’s the difference between infection and when you have this inflammation, why these two are so different? And this is not a physiological inflammation, so it has consequences. It’s a constant stimulation that changes the immune system. And once that happens, it doesn’t matter how much you inhibit the inflammation, the damage is done, and your immune system is completely remodeled, and switching back is very difficult. And there is a difference we should remember between solid tumors and liquid tumors, if you like. In solid tumors, all these things happen, but locally. Whereas here, you are talking about the whole body. And therefore, it’s not that easy to reverse that. You don’t have any reserve untouched immune system left, and therefore, that’s the problem. So what is now important, it becomes increasingly important, is the timing before this happens to intervene, and that, I think, needs some biomarkers, some more holistic approach to identify the best timing. And that’s what we discussed. 

David Steensma:

Along those lines, you know, we’ve learned a lot in recent years about the microbiome’s effect on the immune system and on its ability to respond to different types of signals. Do you think that there’s potential for microbiome targeting approaches and augmenting some of this host immune response? 

Shahram Kordasti:

Yeah, absolutely. To what extent it can control the non-physiological inflammation, it’s yet to be addressed. We don’t know. But for some patients, as you know, in MPN, one of the overwhelming issues with patients is fatigue, which is related to inflammation. Can this kind of intervention, at least for symptoms like fatigue, helps? Can it help with other part of physiological aspect as well? These are the questions we don’t know, but the good thing is we have tools to intervene. Again, when and in which patients is yet to be identified. And the other thing is it’s quite safe, that’s the good thing about it. All right. And then, David, you talk about JAK inhibition, and it’s now really being, I remember a few years ago, we just had ruxolitinib, and that’s it. And now we have an array of different JAK inhibitors, and more and more coming to market. You talked about the specificity of JAK inhibitors. How important it is and how specific we should really go? 

David Steensma:

It’s a great question, and you’re right. I mean, there are four FDA-approved JAK inhibitors for MPN, 3 in Europe. There are also a number of JAK inhibitors that target predominantly JAK1 or TIK2 that are approved for immunologic or dermatologic diseases. And so there’s been a lot of activity in this area. And there have been a number that have been in the clinic but have been discontinued for various reasons, either because of toxicity or because of just, you know, not clearly distinctive for business reasons, as they say. That said, I mean, I think, you know, there’s still a lot of interest in JAK inhibition and potentially additional mileage. I talked a little bit about what we’ve heard so far about JH2 targeting, targeting the pseudokinase domain, which is where the mutation actually is in JAK2V617F-mutant MPN, a Type 2 JAK2 inhibitor, which overcomes one of the mechanisms of persistence and the lack of sort of deep clonal reduction that occurs with the other agents. So a lot of interest in that. Your question about specificity is a good one because there can be some advantages for having, you know, say JAK1 inhibition. That’s why ruxolitinib probably is as effective as it is at GVHD and in some of the dermatologic conditions. There are also maybe disadvantages to inhibiting JAK1 specifically. We heard a presentation this morning about skin cancer risk and infection risk, and that is probably largely JAK1 related. Sometimes there can be benefit from hitting an off-target kinase as potential with some of the anemia benefit with some of the approved JAK inhibitors, but there can also be liabilities from that as well. So, you know, the more clonal selectivity that one has, that could be really beneficial in MPN, but then your trade-off is less effectiveness in a broader range of diseases. Yeah. 

Shahram Kordasti:

So, it’s good, but we need to be a bit more cautious, perhaps, to, yeah. 

David Steensma:

Everything has its pros and cons. Yeah, exactly. Thank you for listening. Thank you for watching.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.