iwMPN 2025 | Challenging and uncommon scenarios in MPNs

Claire Harrison:

Hello, my name is Claire Harrison from London in the UK and I’m delighted to be here at the 3rd iwMDS/MPN in Lisbon with three fantastic colleagues and we’re going to discuss rare and challenging scenarios in MPN and a session that we just had which was very lively and produced lots of practical advice and lots of bang up to date data. So I’m going to ask my colleagues to introduce themselves starting with you Andrea. 

Andreas Reiter:

Yeah my name is Andreas Reiter, I am a hematologist from Mannheim in Germany. 

Deepti Radia:

Hi my name is Deepti Radia, I’m a hematology consultant at Guy’s and Thomas’ Hospital in London. 

Nicola Polverelli:

My name is Nicola Polverelli, I’m a transplant physician at Fondazione IRCCS Policlinico San Matteo in Pavia, Italy. 

Claire Harrison:

So let’s start actually, let’s start with you Nicola because you’ve produced some really important data concerning some of the very rare and atypical variants of MPN and thinking about, you know, the definitive but risky treatment of transplantation and how to guide colleagues towards that. So summarizing that in 10 minutes is a challenge, but what would your messages be in less than 10 minutes for this panel discussion? 

Nicola Polverelli:

Yeah, as I said, during the discussion, the first aim of this presentation was to increase disease awareness because we are talking about very rare conditions and often we have a center with a limited experience managing such patients and therefore referring early such very rare and complicated cases to a transplant unit is fundamental to assure a smoother transplant journey for such a rare but aggressive condition. So during my presentation, I tried to manage all this stuff in just 10 minutes. It was quite complicated. But at the end, I hope that the audience enjoyed the session. 

Claire Harrison:

We definitely did. I mean, I think this is a big challenge, isn’t it? And your point about assembling a team for these rare entities, and especially also in a field which is really pretty fast moving and where there’s more and more data is so important. And that was really well exemplified by both Deepti and Andreas in the field of, you know, mastocytosis, eosinophilia, and understanding all of these molecular markers and how that plays into management. You really need to have a multidisciplinary team, but experts in all of these different fields, I think. 

Nicola Polverelli:

Yeah, the multidisciplinary team is key. I mean in current days we need to integrate each experience in order to ensure the right positioning of the transplant in every disease and this is particularly relevant for such rare conditions where a lot of different physicians coming to allergologists for instance are really important to manage the patient before the transplantation and even after. So, and we have a lot of therapeutic options also to deliver before, during and after transplantation. So we have to be flexible some way to discuss the patient with other specialist experts in the field. 

Claire Harrison:

Absolutely. And some of these entities can have a very, really quite benign and long course, and some can be very aggressive. And I’m just thinking about the presentation you did, Andreas, and all of your work in really defining some of these very rare fusion genes, outcomes with novel therapies and then you know the patients where you can treat with a novel therapy, we’re always tempted to do that, but when you should really be thinking about transplantation. Any key summaries from you? 

Andreas Reiter:

Well I would say I mean when you present all the data in 10 minutes I mean it all looks quite straightforward you know you do molecular testing you do this or do that and you have these or this recommendation. But I think one of the main problems is, number one, for example, for eosinophilia, I would say that the patient’s history of eosinophilia is probably a median of more than two years. I’ve seen many patients with a two to three, five years history of eosinophilia symptoms, and they are somehow lost in the network. So they are seeing the pneumologist, maybe the allergologist. So now that has really changed about 20 years ago with the first identification of this FIP1L1-PDGFRA fusion gene. And so now everybody is testing the patient for this fusion gene, but then it stops. And meanwhile, it has really become, as you could see, much more complicated. So we have other fusion genes and many of them, which I did not have the time to also present that, sometimes are very complicated to find. I mean, we really have to use different approaches of molecular genetics, I mean, up to whole genome sequencing sometimes, if you really think there’s a fusion gene. And then I also wanted to highlight the point mutations. I mean, this is something, you know, other disciplines are not doing at all, and we even find JAK2V617F mutations in some of the patients. And I mean, the most important mutation besides FIP1L1-PDGFRA is definitely KIT D816V. This is associated with systemic mastocytosis. And this is also, I think, a very nice link then to the presentation of Deepti. And I think my major point of my presentation is that, I mean, it’s sometimes difficult to detect a fusion gene. But the main message is that you should not miss, you know, a targetable molecular lesion. And then I always have to discuss with doctors, you know, should I do these extensive investigations? But I have to say, when we think about the expensive treatment, I mean, you know, we shouldn’t really talk about that. So, and I think in some of these patients, really, whole genome sequencing at the end is really necessary to find these molecular aberrations. 

Claire Harrison:

And as I’m thinking about the field, just coming to you now, Deepti, and thinking about finding these point mutations, you mentioned JAK2 and there’ll be a lot of discussion about JAK2V617F, although it’s more than 20 years old now, in this meeting, but the CKIT mutations the mastocytosis, aggressive, indolent, but also those patients with overlaps. I mean, that’s where we’ve really seen huge impact. 

Deepti Radia:

I think it’s been revolutionary for the patients within the SM arena and also spilling over into what we do with transplantation moving forward for those with very advanced disease. And I think we’ve been lucky in this field to find for the indolent patients a drug and a targetable mutation that makes a difference. Again, talking about how many of those patients really need to have this is the next bit of work to be done in terms of quality of life and in the advanced arena, I think if they have that, they’ve got a better outcome. Talking about transplanting and a better remission like we did with the CNLs, the better they are from an SM point of view in these advanced diseases, the better their transplant and a possible potential cure might be as a result of that point mutation.

Andreas Reiter:

If you see a patient, let me say with 2000 eosinophils, I mean the problem is really at the end of all we are doing in diagnostic procedures, it can end up with watch and wait, you know, but it can also end up with a very strong referral for allogeneic stem cell transplantation. So we have the whole, really we have the whole gap of treatment decisions so and we have to work very hard to get to this point to make really the right decision for the patient. 

Claire Harrison:

And I think more and more it leads to, you know, really finding your expert and assembling your team and understand what you’re dealing with. But I just wanted to come back to mastocytosis and ask a question about avapritinib. I mean, your group, Andreas, presented that beautiful data with revised prognostic scores and showing that avopritinib, you know, patients do better, but the patients who are really struggling are those with also an additional hematological malignancy. Do you think the next step is to do avopritinib plus targeting those other things? I’m just asking both of you, actually. 

Andreas Reiter:

No, I mean, this has now really become the hot topic, and this is just the next step. So we first had to find and to use a new drug. And I think, you know, in my experience in for many of these diseases, really the use and the efficacy of drugs has then shown that it is even more complicated. And now we have found this issue that avopritinib can really produce or patients can achieve very durable remissions on the mast cell compartment. But this AHN, it may be driven by KIT D816V, but it may be driven also by additional mutations. It may be driven by additional mutations alone. So now we have a completely new field again on molecular genetics, maybe even with something like single-cell sequencing when it becomes, so that you really have to decide what is going on in the AHN. And then, you know, it’s getting more complicated, but then again to make the right decision. Is this a patient for avopritinib alone or for avopritinib plus something else, which still needs to be defined, probably a drug like azacitidine, I always say please do not forget cladribine it’s also an effective drug, so it could also be, and then at the end you know to make the decision on whether and when I perform the allogeneic stem cell transplantation. Because this is another really hot topic now, should I perform the transplant, I mean at least in my view, at time of best remission, or should I wait very long for the efficacy, should I wait you know for signs of relapse and then to go for transplant. So again so there’s still a lot to do. 

Deepti Radia:

I think we’ve got this seesaw haven’t we with the mutational landscape and we’re learning a lot more about it and at some point I think possibly combination therapy to balance out that seesaw depending on where they are to move to transplant which might be the only curative option. And the only reason we’ve got here is we’ve had a drug that produces complete remissions in up to 30% of patients, allowing us to look at the rest of the mutational landscape. So the more we’ve done, the more we’ve unearthed, but combination treatment with transplant for those that are eligible is the only cure, really. 

Nicola Polverelli:

Yeah, the patient journey is becoming even more complicated, thanks to the diagnostic, to the therapeutics and I would say not at the end to consider transplantation but at the very beginning discuss with, we discuss with our team to investigate the role of transplant for that specific patient, and even if the patient has another substantial indication for transplant, at that time, we strictly follow the patient during the follow-up to detect the time point, the right time point for transplant indication. That’s the way I think we should manage such patients. 

Claire Harrison:

Absolutely fantastic. Well, thank you all very much. Thank you for your contributions to the meeting. Absolutely excellent discussion, so much more to learn, but good to have your team assembled. 

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