Loading summary
Transcript33 lines
- [00:02]
A
Welcome to this week's bonus episode of Blood Podcast, your source for innovative ideas and cutting edge information. In this episode, Associate Editor Dr. Jason Gottlieb discusses the How I Treat series on myeloproliferative neoplasms with contributing authors Drs. Claire Harrison, Aaron Gerdz and Andreas Reiter.
- [00:25]
B
My name is Jason Gottlieb and I'm an Associate Editor of Blood. I'm delighted to welcome listeners to this Blood podcast which introduces our new How I Treat series on myeloproliferic Neoplasms, or mpns, which comprises six review articles. This is an exciting time for MPNS with many bench to bedside collaborations that are driving therapeutic advances. The clinical and molecular heterogeneity of MPNS as well as the unique treatment goals of individuals often leads to a melding of data driven algorithms with personalized care approaches that are informed by shared decision making between patients and physicians. I'm excited to be joined by my three guests today who are well known to the field of MPNS and the challenges of managing patients with these diseases. I'd like to first introduce Professor Claire Harrison from Guy's and St Thomas Hospital in London. She and Professor Mary Frances McMullen have authored the article How I Treat Low Risk para patients who require cytoreduction. I'm also joined by Dr. Aaron Gerd from Cleveland Clinic. He and Dr. Akriti Jain have written the How I Treat piece on anemia and myelofibrosis. Lastly, Professor Andreas Reiter from the University Hospital Mannheim provides his insights on myeloid lymphoid neoplasms with tyrosine kinase gene fusions, which he authored with Georgia Metzgeroth and Nicholas Cross. Although not here today, this How I Treat series will also cover reviews from Drs. Lucia Masarova and Helen Chifidides who discuss how to individualize selection of JAK inhibitors for patients with myelofibrosis Professor Dipti Radia, who shares her expertise on diagnosing and treating systemic mastocytosis with an associated hemologic neoplasm and finally Professors Alexander Guy, Pierre Emmanuel Merange and Chloe James. They offer their approaches to the treatment of thrombotic complications in patients with MPNs. First, I'd like to thank all of you for joining me today. Claire, how about we start off with you? We have conventionally stratified PV patients into lower and high risk categories based on agent history of thrombosis. So for the patient with low risk pv, can you discuss what other factors you consider as a basis for using cyto reduction sure.
- [02:44]
C
And thanks, Jason and colleagues, for the opportunity to join you today. I'm really excited about this How I Treat series. I think our approach to polycythemia vera has traditionally been very binary and we've used very, very old fashioned, what I think are old fashioned criteria to think about risk. And risk has been really dominated by risk of thrombotic events. So we've been thinking really age 60 to 65, above and below, and then whether the patient's had a previous thrombosis and then something a bit woolly about platelets and something a bit woolly about spleen. The dawning realisation is that low risk PV is not no risk. These patients have a lifetime risk of thrombosis, which is significantly higher than the general population, which is age matched, even those with cardiovascular risk factors. And they also have a lifetime risk of other things, such as disease transformation. So now, as we discuss in the article, we are considering other factors, but what we have to learn is how do we integrate them and some of those other factors. Then, Jason, would be, does the patient have cardiovascular risk factors? Are they well managed? Do they have a leukocytosis over 11 to 15? Do they have a jack allele burden more than 50%? Do they have splenomegaly? How high should their platelet count be? So these are all things that we need to bring into play in routine practice and also intermerge with this is what are we actually targeting with treatment? So I think it's a very exciting time in the field at the moment and what we've tried to do in the article is pull all of that together and help the reader to try to integrate that into daily practice.
- [04:26]
B
Thank you very much, Claire, and perhaps I can segue to you, Aaron, and you talk again about the anemia of myelofibrosis. Can you talk about these causes of anemia at the time of diagnosis and dynamically during the course of treatment?
- [04:40]
A
Thank you, Dr. Gottlieb, and it's a pleasure to be with all of you. And in a direct polar opposite of polycythemia vera, you know, one of the key principles of treating myelofibrosis is raising the hemoglobin levels as opposed to lowering the red cell mass is what we do in pv. But I think one of the unique opportunities that we're seeing is we're targeting similar pathways in opposite ways to do both effects in opposite directions. So I think this is just such a cool story in the field right now. But the tricky part about anemia and Myelofibrosis, it's generally multifactorial. There are a lot of reasons. One given individual may have anemia. It may be anemia due to mutations within the marrow cells leading to dyserythropoiesis, kind of like an mds, if you will. Certainly we see inflammation driving anemia of inflammatory block via hepcidin and other markers as well. We see a treatment effect. So JAK inhibitors, while some may improve anemia in some patients, in general they can suppress red cell production and then, you know, there is increased red cell destruction, hemolysis or sequestration that can also occur in some patients. So you got to take a look at the individual and say, well, where are they with their diagnosis? What are the other factors going on and what are the tools available in order to select the best treatment for that individual at that time?
- [05:58]
B
Great, thank you. Aaron and Andreas. Myeloid lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions are quite rare diseases. Can you talk about some of the clues you use to increase diagnostic ascertainment?
- [06:12]
D
Yes. First of all, many thanks for the kind invitation to be part of this podcast. As it is said in the name of this disease, it is eosinophilia. And eosinophilia is present, for example, in FIB1, L1PDGFRA in almost every patient. And the higher the eosinophils are, you may also find monocytosis. So this is really a very important combination. And then we check in the serum, for the serum tryptase and also for vitamin B12, which are usually elevated in the diseases. Then we do bone marrow biopsy. We may find a MPN or MPN MDS phenotype. So we should always check out for loosely scattered mast cells or for fibrosis. But then most importantly, there's something which is very strange at first spot that you may find in addition to this MPN or MDS mpn, a lymph node, enlarged lymph node or something. In addition, you perform a biopsy and then you may diagnose a lymphoma or a myelosarcoma and just this combination of MPN with or without eosinophilia and this lymphoma or myelosarcoma, which we call extramedullary disease. This is really a hallmark of these diseases. So the second scenario, this is quite frequent, in fact, our patients without eosinophilia. And this is quite tricky because then you may have to be suspicious of Fusion gene just in the combination of MP and MDS feature in the bone marrow. And if you find a lymphoma or a myelosarcoma as extramedullary disease.
- [07:56]
B
Andreas, can you also talk about the kind of the cytogenetics, FISH and molecular methods that you will apply to try to diagnose these diseases? Also in part because there's different availability of these multi gene panels or availability of particular types of fish and also some of these fusions that drive these disorders may be cryptic. Can you comment on that?
- [08:17]
D
This has become really a very complex issue with the increasing availability of all these new molecular methods. So the problem is that the most Frequent fusion gene FIB1L1PDGF4A, is only caused by a small deletion and this is actually cytogenetically invisible or cytogenetically cryptic. So you can only find this fusion gene by FISH or pcr. Meanwhile, we and also others have reported that even FISH is not as good as our tpcr. So you may have even to test cases which are negative for fish again without tpcr. Then for many of the other fusion genes they may be indicated by a balanced reciprocal translocation. I think the most famous one is the translocation H13 with ICETAMIM2FGF01 fusion gene or translocation H22 with a BC or FGF01 fusion genes. But even for all these other fusion genes, so basically we have the tyrosine kinases PDGFR alpha, PDGFR beta, FGFR1, CHEK2, FLT3 and ABL1. They can all be involved in these fusion genes. And meanwhile we have an increasing number of cytogenetically cryptic fusion genes similar to fib1l1pdgfr a. So how do I diagnose that the karyotype is normal? And of course what we do, we use a panel of FISH probes to check out for rearrangements. We use, as I just said, tyrosine fish probes for PDGF Alpha Beta for FGFR1, for JAK2, for FHG3 and also for ETV6 Area 1. And in the lab to which I'm associated with, they also use fish with etv6 probes because etv6 is such a common fusion partner to all the tyrosine kinases. But even that may be negative. So fish is not 100% sure. And then you have to go back to technologies like RNA sequencing, but also RNA sequencing, probably because we are dealing with RNA is neither 100% certain to find the fusion gene. And sometimes not even, even whole transcriptome sequencing. In the last months we have identified a couple of cases just by whole genome sequencing which identifies the break. And then of course, you have to create the primers for the RT PCR and you have to confirm the presence of the fusion gene by RT pcr. And this is something I clearly recommend to anybody who identifies, such as suspicious fusion gene by FISH or all these modern technologies. You always have to confirm the fusion gene by rtpcr, because meanwhile we also have a number of fusion genes which have no open reading frame. And for example, in patients with Translocation512 or Translocation412, you may think about, oh, this is a PDGFR alpha or PDGFR beta fusion gene. You treat the patient with imatinib and he has no response. Because the problem is that Translocation 512 creates a number of various fusion genes. So again, it's really the combination. You have to do cytogenetics, you have to do fish, you have to do pcr. I mean, it has really become very complex and you really need a very good lab to do all these various technologies.
- [12:00]
B
Thank you, Andreas, for walking through all the available methods that we can use to interrogate whether this group of diseases are present. Claire, let me get back to you about the issue about using subtle reduction in low risk patients. It seems like we never used to talk about this. How do you think that the introduction of peglated interferons and ruxolinum has changed the conversation?
- [12:21]
C
I think a number of things have changed the conversation. That's a really pertinent point, Jason. So one is to reiterate that in the past, I think we did think that these low risk patients didn't really have major impact on their life from disease. And the second thing is then we've got these newer agents that are better tolerated. So we know that pegylated interferon, on the whole there are problems with it, but it is much better tolerated than the more conventional interferons that we all grew up with treating CML patients with. And also ruxolitinib, although generally that's only used in the second line setting. Certainly in England and France, we're currently testing it in the frontline setting and there's been a study in Germany testing it in the frontline setting. So as we know, these agents are better tolerated, probably don't increase the risk, for example of leukemia and for younger patients, don't impact, for example, probably fertility. We're more confident in using them. But there are also other aspects that I just wanted to bring into the discussion here and that is that increasingly we've also recognised catching up perhaps finally with our peers in other myeloid diseases. We realise that impacting the clone size, which can be done with both of these agents, may impact the longer term outcome for disease. So we've recently seen, for example across a couple of prospective studies that a relatively modest 50% reduction in JAK2.5 which can be achieved with both of those therapies, can impact event free and indeed overall survival. So it's about impact of the therapy and safety and tolerability.
- [14:02]
B
Let me ask you to continue this thread. It seems that physicians and patients alike are enamored by the idea of reducing the eject mutation variant allele frequency or burden. How do you approach that conversation with patients in terms of what do you tell them about how does or what data we have regarding whether reduces JAK 2 may change the or modify the natural history of the disease because that's what they want to know and they always ask for reducing JAK2. Can this drug do that? Particularly for the younger patient? How do you frame that conversation?
- [14:35]
C
It's always a pleasure to have a conversation with a patient that's well informed and asking this type of question, but I would rewind a bit to make sure they really understand what we mean by ferro frequency and then I would frame the conversation in the context of we are really beginning to understand this and we need more robust data. We need to understand if your test, for example, is done in one lab and then a repeat test is done in a different lab, how reliable that actually is. What I am particularly I'm interested in it and for myself, yes, I would agree generally to do this on roughly an annual basis for my patients, but very rarely would I change therapy on the basis of that. So I would talk to them about that and then I would reframe the conversation in the context of yes, I believe it's important, maybe equally important, is that you do stop smoking, you do lose weight, we do address your cardiovascular risk and if we are going to treat you actually the data from those two prospective studies so proud and continuation PV in the front line and the magic PV setting in the second line actually suggested that achieving complete control of the blood count was maybe as important. So I frame it as it's of interest. We're not totally sure how to use that. I'm interested in what my colleagues on the call think, but I Still think it's useful to collect. It's one of those things you can't ever go back and get again. And just to broaden the conversation, I think we really don't know anything similar with regard to the CALR mutation, which of course we wouldn't be seeing in pv, but this is a conversation that's playing out across all of the common Philadelphia negative mpn.
- [16:27]
A
Claire, I think you put it in such a nice way and really framed the conversation very well that you have with your patients. And you know, I have a very similar approach when I do talk to patients about allele burden. As you said, they're a lot of the patients are very well informed, they go online, they read about these things, they've heard of the Magic PV trial, they've heard of the ROPEG studies showing allele burden reduction and want that added benefit. And I do, to check JAK2 allele burdens on my PV patients and fully acknowledge that I'm not entirely sure what to do with it. You know, we celebrate the wins and we kind of scratch our heads when it doesn't change and say, well, it doesn't change what we really are doing today. But and I think it's really important though that we do this because it's going to take a long time to generate that hard data that prospective gathered, data that is correlated with hard outcomes. So I think in the meantime, the best we can do is clinical experience, right? We gather that experience, we kind of see and get a feel for what's happening in the clinic every day and that could somehow inform our everyday practice right now as well as maybe lead us to better questions that we can ask in prospective trials in the future.
- [17:32]
C
Maybe I can jump back in and say I totally agree with you. I just wanted to raise one scenario though. So having said the interferon is well tolerated, etc. Occasionally there are patients who don't have the best disease control with that drug and who are experiencing a lot of sense side effects, but they're really wedded to, they want to be on interferon because they believe it's modifying their disease. And occasionally if the JAK2vaf hasn't changed, and just to remind colleagues that it can actually take three or four years to see a substantive change, we're not talking about a three month check with a TKI for CML here, but occasionally in that scenario it can be helpful to frame that conversation about these patients who are struggling with interferon and then maybe to think about segueing to A drug like Roxolitin, if that's the only time when I've really used it in clinical practice, no.
- [18:27]
B
Andreas, would you like to add to that conversation?
- [18:30]
D
Yes, I would also like to do a little burden testing and I think it's a good signal. If it goes significantly down, it's something good to report to the patient. And if it remains stable, we do not know yet what happens, but at least it does not increase. And I think we should also talk about the increase of TAK2B6 and ethylene burden, whether that may in the future change something. I mean, we have a lot of problems to define progressive disease on check inhibitors. We have, is it splenomegaly or is it the symptoms? And so the Increase of the CHEK2 VIS examiner Nilburton may be important. And I just want to add another point, that if we do it, and if we know about other somatic mutations, we should probably also have a look at the allele burden of the other additional somatic mutations, because it may easily happen in the future. Like we already know from other diseases that, for example, with the decline of JAK2V 6NF, we may see an increase of the other somatic mutations. And this is also a bit of a danger, at least in a minority of the patients.
- [19:39]
B
This goes to the point how in the early days when we're looking at the JAK2 mutation, perhaps not even quantitatively, and some patients with MF progressed to ML, we'd of course see some patients with loss of JAK2 clone because there would be emergence of another one or more other mutations. And thank you for that lively conversation. That was fantastic. Aaron, let me come back to you and the issue of MF and treatment emergent anemia on JAK inhibitors. Can you talk about the differences in JAK inhibitors and perhaps a proclivity to induce anemia?
- [20:13]
A
I think that's a great question. When you have a patient with myelofibrosis associated anemia, there's really kind of four things you're thinking about for that individual. You know, first and foremost, are they a transplant candidate? We know that anemia is predictive for bad things to come. And so if a patient is a potentially a transplant candidate, you know, you definitely want to be engaging your transplanters and thinking about that as your overall part of your overall treatment plan. At some point. You also want to be thinking about what are the patient's spleen and symptoms doing at the moment. Do they. Are they suffering from a lot of splenomegaly or heavy symptom burden. Are they already on a JAK inhibitor as well as what their erythropoietin level is? Because it might help you determine what anemia supportive agent you might select going forward. And you brought up a nice point about the different JAK inhibitors. There are four JAK inhibitors that are now FDA approved here in the United States for the treatment of myelofibrosis and all I have a somewhat differential effect on red cell counts and hemoglobin levels. I'll start off by saying that all the JAK inhibitors can lead to anemia. Right. If you look at all the clinical trials with all these JAK inhibitors, even the ones that are supposed to be anemia supportive can in fact themselves cause anemia. So just because it's an anemia supportive JAK inhibitor doesn't mean it can't cause anemia. We definitely think about ruxolitinib being kind of central to these conversations because it's the first, it's been around the longest. But it can also be myelosuppressive. And we do see fair amounts of patients developing anemia on ruxolitinib. Whether that's completely drug induced or a form of progression of disease, it certainly happens at a very high rate. Similarly, we do see quite a bit of myelosuppression anemia with fedratinib and then pivoting to the other two, momelotinib and pacritinib. We often think about these as JAK inhibitors that can also alleviate anemia. Both inhibit ACVR1, which then can lower hepcidin levels, thus alleviating the anemia inflammatory block. As we discussed earlier, anemia is generally multifactorial in these patients, so it only works really on that kind of facet of anemia. But we think in those patients, we may be able to help their anemia with the JAK inhibitor, or at least the jak inhibitor. The ACVR1 inhibition that comes along with the JAK inhibition may counter each other to some degree. It's kind of unclear what the exact mechanism between the interplay between jak inhibition and ACVR1 inhibition might be in any given individual. But certainly we see fewer patients becoming anemic. I think that one of the best examples is the Simplify1 trial prospective randomized trial in the frontline setting comparing ruxolitinib with momalotinib. And we saw more patients develop anemia and transfusion dependency on ruxolitinib as compared to momelotinib in that study. So I Think that's a pound for pound, drug for drug. Kind of straightforward comparison where you can start to make these inferences on how the JACK inhibitors might influence anemia levels depending on the treatment that they're on.
- [23:02]
B
Aaron, can you talk further about when you have the MF patient in front of you, how you decide on whether to dose reduce JAK in amber, change JAK inhibitors and when you bring in, for example, ESAs and even the possibility of erythroid maturation agents like lousepatocept, which granted, it's not yet FDA approved for mf, but certainly it's used on an off label basis.
- [23:22]
A
Absolutely. I think I start with the easy scenarios. First you have a patient who was very symptomatic, had a big spleen, goes on ruxolitinib, for example, develops anemia, but is still on 20 twice daily, feeling well and is just anemic, really had a nice symptom of spleen response. You want to maintain that because that is at least improving their quality of life and probably their functionality. So in those instances they have good spleen control, they have good symptom control. Those are the places where you would add on anemia supportive agent. If the erythropoietin level is lower, say less than 125, you would come in with an ESA potentially like a Darba Poetin. If the EPO level is higher, then you would potentially use a drug like as you mentioned, Luspatercept. And these would both be off label.
- [24:07]
D
Of course.
- [24:08]
A
Third option in that vein would be adding on Danazole. So it is safe to add on either of those agents along with ruxolitinib when there is an optimal spleen and symptom response. I think it gets a little trickier when a patient is on a JAK inhibitor and their response isn't great. Right. You know, maybe a little spleen reduction, maybe some improvement in their symptoms, but they're not kind of to that optimal place. And then if they are on a full dose of JAK inhibitor at that point, it would make sense then to switch to say a momelotinib, where you can still address their spleen symptoms but potentially address their anemia as well. I think the hardest situation is the one that you propose where say a patient's on 15 milligrams twice daily of ruxolitinib and they develop anemia and their symptoms are somewhat controlled, but maybe not fully. Do you dose, reduce and try to add an esa because are there symptoms being driven by the anemia? Are there symptoms being driven by the myelofibrosis itself, or do you switch to another agent there in these gray areas? I think you can kind of take solace that there are lots of options and one does not preclude you from the other. Right. So if you decide to back off the JAK inhibitor to see if their anemia will improve, or add a supportive agent on instead of switching to another JAK inhibitor like a momelotinib, if it works, great. If not, then you have the option to change. I think that's probably the most important part. Part of JAK inhibitor selection in myelofibrosis is that there are lots of options now and you have the freedom to change what you're doing. We aren't beholden to a single JAK inhibitor anymore, and we have that flexibility in the care plan.
- [25:34]
B
Thank you. And that's a wonderful explanation of what we have available to us in terms of therapeutic armamentarium. Let me pivot to you, Andreas. As you well know, there are substantially different prognoses of these myeloid lymphatic neoplasms with tyrosine kinase gene fusions. Can you talk about the differences in prognosis between these entities and where you may just quote, unquote, get away with a tyrosine kinase inhibitor alone versus the role of using these as a bridge to transplantation?
- [26:01]
D
Just to repeat it. So we have several tyrosine kinases. We have PDGFR alpha, PDGFR beta, and also FGF01, CHEK2, FA2 and ABEL1 in combination with ATV6 as partner gene. And I always say they are somehow lumped all together in one subcategory. But basically we have two, absolutely two different groups. So this is on one side, the patients with PDGFR alpha and PDGFR beta fusion genes, they show excellent responses on imatinib. So on 100 milligram imatinib per day, also the PDGFA beta fusion genes. So there are now several reports in the literature. So the initial dose was always 400 milligram, but you can test 100 milligram so patients achieve rapid and durable complete hematologic and also molecular remission. We have just recently tested a patient with fib1 iron, PDGFRA on a weekly basis, and he was already negative by our TPCR after four weeks of treatment. By now, I mean, this is really very rapid, durable, and for FIB1, IBM PDGFRA, and this was published by us and also by others. We meanwhile stop to the treatment. So we have not developed Such fantastic criteria like for cml, but basically when the patient has achieved something like two or three years on complete molecular remission. So the problem is we do not have such a good quantitative PCR like in the cml. But after two, three years in complete molecular remission, we dare to stop the drug. And most patients remain in remission, some may relapse, and then you can just start again with 100 milligram. And most patients again achieve remission after four or five weeks. And meanwhile, we have also started the very first patients, you know, really in our personal care, even with PDGF or beta fusion genes to stop imatinib after achievement of responses. And we may see in the foreseeable future the same thing also treatment, free remission, all these things that we have learned from cml, but the other fusion genes are completely different. Most of these patients either already present in something like blast face acute leukemia or what I said before about this extramedullary disease, which is in fact an extramedullary blast phase. And you first have to consider intensive chemotherapy in case of a T lymphoblastic lymphoma or tall. And then the tyrosine kinase inhibitor is something like maintenance treatment after treatment with intensive chemotherapy. And then for all these patients, if they are eligible, you should definitely go ahead with allogeneic stem cell transplantation as early as possible. So the second scenario for, let me say the poor prognostic fusion genes is that the patient is diagnosed in chronic phase. I mean, we know that now from the FGF01 fusion genes. We have two drugs in clinical trials. And I think pemigatinib is meanwhile, it's not approved in Europe. And with pemigatinib in patients with FGF4.1 fusion genesis in chronic phase disease, patients also achieve complete hematologic complete cytogenetic remissions. And for these patients, we do not yet absolutely know whether we should keep the patients in this remission and for how long can we keep them in remission or should we go for allergenic stem cell transplantation if they are eligible for transplantation? And I think this is all a question also whether you have alternatives. I mean, you know, this is easy in CML, a disease in which I now have 5, 6 tyrosine kinase inhibitors and now with ASIM in so I can speculate, if the patient has a relapse, I can treat him with a second generation inhibitor. But for FGF01 fusion genes, we only have putibatinib, to the best of my knowledge. I mean, I Think this is not even approved in the US for the treatment with FGF01 fusion genesis. So you have to discuss with the patient. So this is a very individual decision, whether in chronic phase disease, whether it is either FGFR1 on pemigatinib, FLT3 on a FLT3 inhibitor or ETV6 ABL1 with one of these CML inhibitors, what to do when the patient has achieved complete remission. My personal view is that you should really check every individual patient whether he's a candidate for, let me say, relatively rapid allogeneic stem cell transplantation.
- [30:49]
B
Great, thank you very much Andreas. Perhaps this is a good time to ask all three of you to provide some forward looking comments on what excites you about your respective fields or topics that you've included in the review series. Clear. Can you maybe touch on what do you think are the major clinical research priorities that we should be pursuing in terms of further establishing the impact of cell reduction in low risk PV patients or more broadly PV in general?
- [31:16]
C
I think the biggest thing here is we need to collect massive amount of data from and it's probably only going to come from the real world setting. So I'm excited about our ability to collate real world data and do these kind of machine learning kind of technologies. I mean Erin, you've led on some of these and we're trying a pace to put them in place across our systems in the UK and the National Health Service gives us the opportunity to do that. In some ways I think it would really be about exploring the utility of attaining deep molecular responses. Who's going to attain it, what to attain it with, but also which is the best agent and in the context of pv probably also true in if it's okay to segue a bit Jason, Actually I think also with the advent of more mutational targeted therapies, I'm super excited about protect this spectrum maybe of pseudokinase inhibitors or JAK2V6.17F mutation inhibitors and in CALR positive disease with those therapies. But we need to understand what the endpoints are for those and therefore we do really need to I think understand the benefit of molecular response and use also the more powerful and sophisticated laboratory tools like single cell sequence, et cetera.
- [32:43]
B
Thank you very much Claire and Erin, what are you excited about? What's on the horizon perhaps for new therapeutics for anemia?
- [32:51]
A
There's a lot of new therapeutics on the way for the treatment in myelofibrosis associated anemia. Different drugs that are targeting ACVR1 in a better and deeper way. There are drugs, you know, still looking at activin ligands and trapping those like our lettercept, that have shown some really great responses. But to me, these are kind of intermediaries, right? There's a step to a step and ultimate step, I think, really Claire hit on that point, are drugs that lead to deep and meaningful response responses, therapies that clean out disease, therapies that, dare I say, will put transplanters out of business someday. That's really what we're getting at. And I can say that as a recovering transplanter, that is the most exciting part. Right? I think these anemia agents can help patients today. And that's the important point. It's tools we have in our toolkit right now. But I think one of the most exciting things are these things that we're seeing down the road, even clues from ongoing trials. If you look at the Manifest 2 trial, with the addition of PalaBrACEB2 ruxolitanib, we're seeing anemia responses there. We hope that's because there is a deeper and more meaningful response happening on a microscopic level in the bone marrow niche. Right? We're cleaning out myelofibrosis cells, we're healing that bone marrow to a certain degree. And that's why we see some anemia improvements in those patients on that study in treated with combination therapy. So that is really, to me, the most exciting part. Can we deeply and meaningfully affect disease for a durable amount of time in these patients? And we don't even then need the anemia supportive agents, right. That this was something that we did in the past, but now we got these great new therapies.
- [34:23]
B
And Andreas, would you like to continue this aspirational thread?
- [34:26]
D
Well, I think that in my field, really, the most important scientific issue is that I'm sure that there are patients out there with a fusion chain which has not yet been identified. And I come back to your first question. You know, the clinical picture. We already know that there are patients without eosinophilia. And I would just like to report a patient we recently saw with a triple negative myelofibrosis with basophilia. And nobody really took care of these 5 to 10% basophils in every differential. But meanwhile, we know about fusion genes who do not have eosinophilia but basophilia, and it always depends on the partner gene. So these are certain partner genes for PDGF or beta or for FGFR1. And then the phenotype may be with more monocytosis, with more basophilia. And it could also be, we know, a fusion gene which 3, 4 cases, it's all very rare, but for, for the individual patient it's very important in which the phenotype was mastocytosis. Whenever I see a patient with KIT D816V negative systemic mastocytosis, I'm also suspicious that could probably also be such a cryptic fusion genes. And of course we will identify other tyrosine kinases which are involved in fusion genes. So this is number one really better diagnosis. And, and for treatment, of course, I mean for the pediatric alpha beta fusion genes, we have imatinib. We are, let me say, quite happy for that. However, we also see a few patients which are resistant, which become resistant to imatinib. So there are probably only 10 to 15 cases in the literature. And like in CML, these cases, resistant cases are associated with poor point mutations. And I have to say we do not really have effective drugs for point mutation driven resistance in FIB1L1PDGFR positive disease. So there's ponatinib, you can test that, maybe ivapritinib, but I'm not aware of a case that was successfully treated with ivapitinib. And the 10 cases, I'm aware from the literature says that the 10 patients who became resistant to imatinib, all the patients died within one to two years from diagnosis of resistance. So the disease has excellent prognosis in chronic phase, but obviously very poor prognosis when there's resistance. And here I really want to come back to what I said before, so that for first line treatment we may have drugs, but for second line treatments, so we are still short of drugs and this is obviously a very important field. And test inhibitors. And let me say a last point, many of these inhibitors have been tested in in vitro experiments in cells and mice and the inhibitors were effective. But we have seen in many patients that we could not take the in vitro data to effective treatment of the patients. In many of these patients, second line tyrosine kinase inhibitors are not really that effective. And if you ask me what we need, so we need better drugs for second line treatment. And finally, the question of when to perform allogeneic stem cell transplantation in which patient is still a very individual and tricky one.
- [37:59]
B
I want to thank Professors Harrison, Gerdes and Ryder for joining me today to introduce Blood's How I Treat series on myelopoliferup neoplasms. I think our conversation highlights several of the diagnostic and therapeutic challenges in mpn, but also the remarkable progress that has been made, which I'm certain will continue unabated.
- [38:21]
A
Thank you for listening to this bonus episode of the Blood podcast. To read these articles, visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.