Listen to Ciro Rinaldi MD, PhD, and Alessandro M. Vannucchi, MD, as they discuss contemporary management of essential thrombocythemia (ET) and polycythemia vera (PV), as well as novel investigational approaches.
In this podcast episode, Ciro Rinaldi MD, PhD, and Alessandro M. Vannucchi, MD, discuss contemporary management of essential thrombocythemia (ET) and polycythemia vera (PV), as well as novel investigational approaches, including the following:
Presenters:
Ciro Rinaldi MD, PhD
Chief Medical Officer, United Lincolnshire Teaching Hospital
Honorary Professor of Haematology, University of Lincoln
Honorary Professor De Montfort University Dubai
Consultant Haematologist
Lincoln, United Kingdom
Alessandro M. Vannucchi, MD
Professor of Hematology
University of Florence
Director of Hematology Department
Director of Oncology Department
Azienda Ospedaliera Universitaria Careggi
Florence, Italy
Content based on an online CME program supported by an educational grant from Merck.
Link to full program:
https://bit.ly/4u09lKd
This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Prof. Ciro Rinaldi: Good morning, everybody. So, I'm extremely honored to be today, with, Professor Vannucchi, from Hospital Careggi in Florence. I am Professor Rinaldi, and I am a hematologist from the UK, working in a University of Lincoln and United Lincolnshire Teaching Hospitals. We would like to talk about, a current treatment approach for PV and ET, and I would like to invite Alessandro to, you know, give his, opinion around the current treatment approach for polycythemia vera. Alessandro, welcome.
Prof. Alessandro Vannucchi: Yeah, my pleasure, Ciro. So, polycythemia vera is an old disorder that has received, let's say, within brackets, old treatment approaches until very recently. And now we are in a time where a lot of things are changing in our ideas, in our feeling about how we can approach the disorder. So there are some milestones. The first one is that we need to reach and maintain as better as possible a target hematocrit level of 45% and less. This has been shown to be associated with about a four-fold lower risk of thrombosis in a prospective Phase III study. And so this is really a stronger rule for all patients with polycythemia. And the second milestone is about the use of prophylactic aspirin, low-dose aspirin, because again, in a prospective study, this has been shown to reduce the risk of thrombotic events without significantly increasing the risk of bleeding events.
Prof. Alessandro Vannucchi: So, aspirin is fine, so the issue is, to discuss is how can we target and reach and maintain the hematocrit less than 45%? Here, we are used to separate patients with PV into broad categories, low risk and high risk. Low-risk are younger patients, say, less than 60. So this number is not a law. It depends, of course, on the number of comorbidities you have. So, some 65 patients are good enough. So, age and prior history of thrombosis. If you are younger than 60, 65, and have no history of thrombosis, you are a low-risk patient. And in this case, according to the standard criteria, you can use phlebotomies to maintain the target hematocrit. If you are a high-risk patient, then cytoreduction is needed, and the standard, the good standard drug is hydroxyurea. So, we know that this is fine. Most patients are actually able to maintain the target hematocrit level. Some patients receiving hydroxyurea may develop side effects from the drugs in terms of cytopenias, and so it's difficult to maintain an effective dose of the drug, otherwise patient may become leukopenic or thrombocytopenic. Maybe also subjected to some skin toxicities, for example, ulcers, mouth ulcers, and so on. And so this is the standard treatment.
Prof. Alessandro Vannucchi: Now we have more recent drugs. We have a drug for second-line treatment of PV, and this is the JAK inhibitor ruxolitinib, but it has been approved for patients who are refractory or intolerant of hydroxyurea. Again, two Phase III studies that's shown an impact of the drug on spleen volume reduction, control of hematocrit, and improvement of symptoms. And now we have also data about the impact of pegylated interferon at different forms of pegylated interferon, and recently the approval of ropeginterferon, that is a long-acting interferon for treating these patients with maintenance of hematocrit, no needed further phlebotomies, and improvement also of splenomegaly and symptoms in a proportion of the patients. So these, these are, broadly speaking, the drugs that we can use. What I'd like, finally, to mention is that our ideas about management on… of PV are changing in the sense that now we have some evidence that drugs such as pegylated interferons, ropeginterferon, and also ruxolitinib may actually reduce the burden of the disease. And this is indirectly suggested by the fact that some patients present progressive decrease of the JAK2 variant allele frequency, and in some patients, the mutation may become very, very low, or even being undetectable. And so the idea is that with these new drugs, we might be in a position to… to… to be disease modifier. Also, and this is very important, because recent data suggests that patients who have molecular response have better event-free survivals in terms of less thrombosis, less evolution to myelofibrosis, and improved survival. And is… what about ET, Ciro?
Prof. Ciro Rinaldi: Thanks, Alessandro. So ET, again, is an old, condition. I think, there's been still, quite a lot discussing around, you know, classifying the level of risk for those patients, and I think I just wanted to make a point that you touch on regarding the aim of treating those patients, which still is, you know, the risk of thrombosis or bleeding, you know, rather than, you know, the approach to, you know, eradicate the condition or to change the, you know, final outcome of those patients. However, there might be some changes recently. So one of the things that has been, you know, part of our debate for a while is how we do, you know, stratify those patients, because some of the ET patients might not require treatment for a long period of time, and some of those patients require treatment earlier on.
Prof. Ciro Rinaldi: So, one point, you know, that we probably made initially was the requirement to differentiate a prefibrotic myelofibrosis to ET patients, that doesn't have an impact currently in the treatment management. Those patients will probably receive the same, but it does give us an indication to discuss further, and how we then monitor those patients and how we do, you know, tend to follow them up. But we still stratify those patients based on a few factors. You know, one of that is age. You know, we still split the population in three groups, you know, where you have low risk, intermediate, high, you know, based on an age value of 40 years, 40, 60, and over 60. And there is some discussion around the intermediate group, you know, the one in between, and how we can probably look at those, you know, a little bit more carefully, you know, identifying some of the comorbidities, cardiovascular risk factors, etc.
Prof. Ciro Rinaldi: And then platelet count. You know, we still have a cutoff for platelets of 1500, where what we are trying to do, reducing the levels of platelets, is actually not the thrombotic complications, but to avoid bleeding risk because of the, you know, potential von Willebrand-acquired defect, etc. And we're still stuck there, you know, that hasn't changed. You know, we still look at those patients, you know, stratifying according to age and platelets, and according to potential comorbidities and, you know, risk factors. But then once we make a decision, what do we do?
Prof. Ciro Rinaldi: And I think at the moment that the skeleton of the treatment is still, you know, the backbone is still, you know, either interferon-based regimen or cytoreductions. And then the cytoreduction, you know, these days is very much around hydroxycarbamide, very old drugs, you know, that we've been using for decades, which is still extremely effective. But the aim is always the same, is to reduce the platelets. You know, try to bring it down to a 400 or below, which is our optimal response, to reduce the thrombotic risk.
Prof. Ciro Rinaldi: Now, interferon, pegylated interferon, you know, is clearly a, a very, very powerful drug. You know, there is some discussion around whether or not it has a disease modifier effect, you know, which probably, in some cases, had, has. Hydroxycarbamide doesn't do that, but it's a good antithrombotic drug in terms of, you know, reducing the risk of clots. The decision is based quite often on age, and sometimes patient's preference. But I would say, and, you know, happy to have a discussion around this, that even in the old time, you know, when we were a little bit more strict about when to use cytoreductions and not. I think we would probably prefer hydroxyurea in the over 60, and we would probably offer hydroxyurea in the over 60 to pretty much most of the patients. I think these days there is an opportunity to offer both. I think when I talk to my patients, I give both the options and say, you know, you have either a tablets form or an injections form, and I will include the pegylated interferon up front treatment also for the over 60. And sometimes patients prefer that, because of the concept of this might help the disease, and, you know, perhaps I can inject myself rather than taking tablets every day.
Prof. Ciro Rinaldi: And in the very young patients, younger than 40, I think there is not much of a choice. I think, you know, my view is always to go for interferon. And then, you know, in between the 40 and 60, again, same discussion. But I think we reach a point where, you know, those two drugs might probably be, often offered, you know, in frontline to most of our patients. I will probably pause here in a minute, and maybe that's the practice here in the UK. I would like to know, you know, what, Alessandro, you do in your clinic. Do you prefer one to another, you know, or do you offer both at the same time, you know, in the over 60 particularly?
Prof. Alessandro Vannucchi: Well, well, you know, we are, I would say, on the extremes, is very simple. Because in the youngest one, indeed, pegylated interferon, I think, is the right choice. In the older one, most of the patients actually may have some comorbidity, for example, some of these may have some thyroid dysfunction, and some may not like, actually, the idea of using injection. So, there, the decision may be still mostly on hydroxyurea. The big issues for us is the middle age, as you mentioned, 40 to 60, more or less, because in these patients, I think it's very important also to have, really, an alliance with the patient.
Prof. Alessandro Vannucchi: For example, we now know that patients who are not mutated for JAK2, patients with ET, I mean, patients who have the calreticulin mutations, if they do not have additional cardiovascular risk factors, they probably are not required to take aspirin, because this has not been shown to be useful, unlike for JAK2 mutated, and sometimes may increase the risk of bleeding. So it's really a comprehensive approach to these patients with ET, where drugs and also still styles of life are really, are really very important.
Prof. Alessandro Vannucchi: The issue is that we do not have yet enough data, unlike for PV, as I mentioned before, that our approach is really disease-modifying. But… may I ask you if you are… you have some idea that this might change in the near future? Because we know that outside clinical practice, there are novel drugs that might help for both PV and ET, and some of these are really targeted drugs.
Prof. Ciro Rinaldi: Absolutely. I think, you know, we… we had, you know, for many years, a very, you know, simple approach to those conditions, because we didn't really have a lot of options. Things might be changing. There are some interesting drugs that I think it would be worth it to discuss. LSD1 inhibitors, you know, one drug particularly called bomedemstat, you know, is currently in clinical trials. You know, definitely there's been few trials in ET and in PV. And we've seen some very good results, not just in terms of managing, you know, platelet count, you know, the drugs actually reduce quite well, you know, the thrombocytosis, and it does have an impact on erythrocytosis as well. But there are some signals suggesting a disease modifier effect to these drugs. Which, you know, hasn't been a key, point of treatment for quite a while. You know, we started talking about some disease modification, I think, when the molecular profile of those conditions was a little bit more clear, but then that has been fading away. Up until now, I think those drugs seem to show some interesting data, and we need to see, and probably will take a long time to understand the impact of the possible disease modification.
Prof. Ciro Rinaldi: Another drug in PV is part of the class of the hepcidin mimetic. And there is a drug approved now, Rusfertide, that is… has been the first one trialed, that has a very clever way to sort of block the use of iron in the bone marrow and perform what probably we can friendly described as a chemical phlebotomy. You know, with the benefit of, you know, controlling hematocrit, but actually not getting the complication of phlebotomy, which is iron deficiency. And I think I would probably touch on some other approach, you know, immunotherapy in MPN hasn't been for ages, and now we're seeing some interesting trials, you know, with antibody, anti-mutated calreticulin, and even vaccines. What do you think about those?
Prof. Alessandro Vannucchi: Well, there's a lot of rumors about this kind of immunotherapies in a time where immunotherapies for other hematological disorders are well established. Here we have just heard about the first results of antibodies, monoclonal antibodies, against mutated calreticulin. And this… we are quite happy of that, and we are quite lucky, because you know that calreticulin is a cytoplasmic antigen, and as a such, it should not be targeted by antibodies. But it has been shown that calreticulin actually is exposed on the cell membrane linked to the receptor for thrombopoietin, and this allows, therefore, antibodies, and maybe in the near future, also CAR T cells to specifically target the cells that express on the membrane the mutated calreticulin. And this is clearly opening new avenues for the treatment of these disorders. And the hope, now results are still very preliminary, but they are really appearing. The hope is that these approaches might lead to the cure of these disorders.
Prof. Ciro Rinaldi: Which I think is, you know, still an unmet need, you know, because we've been focusing on some of the effect on those conditions, but we've never been able to eradicate, and I think there is an opportunity, you know, to actually meet that unmet need of, you know, cure, as you described, which is very exciting.