Listen to Ciro Rinaldi, MD, PhD, and Alessandro M. Vannucchi, MD, as they discuss contemporary topics in diagnosing essential thrombocythemia (ET) and polycythemia vera (PV).
In this podcast episode, Ciro Rinaldi, MD, PhD, and Alessandro M. Vannucchi, MD, as they discuss contemporary topics in diagnosing essential thrombocythemia (ET) and polycythemia vera (PV), including:
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
Full 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
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Global Experts Discuss Diagnostic Considerations in ET and PV
Prof. Vannucchi:
My name is Alessandro Vannucchi, I am professor of hematology at the Careggi Hospital and University of Florence in Italy.
And I’m here together with Professor Ciro Rinaldi from the United Lincolnshire Hospitals NHS Trust and University of Lincoln to discuss about contemporary diagnosis of patients with PV and ET.
Ciro, welcome, and thanks for your contribution to this discussion. So, we know that we have two recent classification systems for patients with MPNs, with myeloproliferative neoplasms.
And these are from the WHO, this is the fifth edition, and from the International Consensus Conference.
So, beyond the reasons why we have two contemporary classifications of hematological neoplasms.
What is relevant for this discussion is that the diagnostic criteria for making a diagnosis of PV and ET are essentially the same in the two classifications, and this is, of course, good for us as clinicians in order to address the different aspects for reaching a correct diagnosis.
In these classifications, in both classifications, there is a significant role for bone marrow biopsy.
And Ciro, why do you think it’s extremely important to have a bone marrow biopsy for all patients where we want to reach a correct diagnosis of PV and also of ET?
Prof. Rinaldi:
Thank you, Alessandro. This is a very good point. I think it’s, despite all the molecular, you know, evolution of MPNs, I think we still rely quite a lot on morphology. I believe for two reasons. You know, if you think about essential thrombocythemia, we don’t have other way to identify, you know, prefibrotic myelofibrosis, for example. Some patients present exactly in the same way, so if you look at accidental finding of, you know, thrombocytosis, is really, really difficult. Without seeing the patients, without, you know, understanding the, you know, the clinical picture, you know, to be able to say, you know, this is a true ET, or it could be a prefibrotic. So there is a requirement, you know, to understand what bone marrow looks like, you know, to perhaps give that confirmation.
PV is another one. We have quite often, and I can see this in my center very, very, very regularly, accidental finding of erythrocytosis. And some of those patients, you know, might either mask, you know, a different type of MPN, because there could be a potential of overlap with some other condition. But, for example, they might not show an increase in hematocrit, you know, and present with an anomaly, you know, such as an unexplained thrombosis, and the blood picture is not convincing. So those patients, I think, benefit from a histological evaluation, because you’re not going to be able to classify them otherwise. And there is an impact, not just to give the diagnosis correctly, but also how we prognosticate those patients. You know, what is the type of follow-up, management, treatment, etc. So I still feel that that is the reason why, you know, bone marrow biopsy is required.
But I do see a problem here, and I will, I guess, ask back to you what you think. There is also a need for expertise in evaluation of those bone marrow. Because, you know, hematopathologists, you know, could be dedicated hematopathologists to MPN, so they have their own ability to recognize those, you know, those subtle changes. But there are a lot of non-MPN hematopathologists, where you still might have a problem and a gap. So, you know, whether or not there is a further requirement to centralizing… to centralizing some of those review, that’s, I guess, what I was going to ask you back.
Prof. Vannucchi:
You are right, this is a painful note, because unfortunately, the number of expert hematopathologists, and I’d say particularly of younger hematopathologists, is really decreasing in our countries. We are facing the same issues in Italy. So, I think that, of course, the revised classification helped a lot, because there are very strict criteria that have been described in this classification for attributing one feature to one disease rather than the other. But, of course, experience is mandatory. And there’s, there’s really need of sharing expertise. And this may happen in a different way. In these times, it may be that we might be also helped by artificial intelligence, by the easiest way to share slides through the web. And these are all actions that even smaller centers might start to do with centers of reference. But you are right that in some cases the same slide could be sent for review and for confirmation to a reference center. This is something that we do also in our institution, where we have some experience, I’d say, over the years for making this kind of diagnosis, but in some cases, we’ll still… another idea, another look to the same bone marrow biopsy. Of course.
We now can take a great advantage of molecular biology, as you mentioned, because we know that polycythemia vera is in 99% of cases, I would say, characterized by the presence of a mutation in JAK2, that is 95–97% JAK2 V617F, and in the other 2–3%, are the mutations in exon 12. So this helps a lot in distinguishing particularly early cases of polycythemia vera, even with very low variant allele frequency (VAF) of the mutations, from reactive erythrocytosis. The same help we can have in ET, because we know that 60% of patients with ET are JAK2 V617Fmutated, about 20% are mutated in CALR (calreticulin), and about 5% are mutated in MPL. So, overall, 90% of patients with ET have a driver mutation. However, there is still a 10% of patients with a picture of essential thrombocythemiawho do not have a mutation. These are called triple negative.
And here, it’s sometimes difficult to assess if this is really a myeloproliferativeneoplasm rather than another form of thrombocytosis. For example, familial forms of thrombocytosis, and this is something that should be very carefully asked to the patient and the relatives. And in other cases, we still need evidence of a molecular abnormality, maybe a non-driver mutation, a mutation in TET2, ASXL1, and so on, or, but this is quite rare, a cytogenetic abnormality. To establish the clonal nature of thrombocytosis. Even these are tests that are not usually performed in smaller centers, but are performed in reference centers over our countries. And here, again, there is the need to send these samples to this reference center to establish in a very safe way, the correct diagnosis of ET.
And you also mentioned the fact that in some cases, the diagnosis happens by chance when you see a patient with a thrombosis, particularly, say, an unusual vein thrombosis. Is something that you would like to explore a little bit more, Ciro?
Prof. Rinaldi:
Yeah, so I think it’s a very, very good point, and, you know, it probably linked into anomalies that I was talking about, you know, when we want to suspect that there is an MPN. I think in an unexplained clot, you know, particularly in an unexplained vein, is, is often suspicious. If we have a splanchnic thrombosis, and it could be a splenic thrombosis, a portal thrombosis, a mesenteric vein thrombosis. Those are not frequent, you know, DVTs, you know, this is not a clot that we normally see in patients unless there is an additional complication, you know, in some cases of liver disease or asplenic patients, etc. So for me, those needs to be investigated. And we know that, you know, MPNs, and particularly MPNs driven by, you know, JAK2 mutations, can clot to the blood in unexplained places. So, my suggestion for clinicians that are not necessarily hematopathologists, or clinicians that are not necessarily experts in MPN, is that if you do see, you know, a thrombosis affecting, you know, the splanchnic circulation, you probably want to request a JAK2 mutation, and perhaps you want to refer to a hematopathologist for further assessment. It’s more common to develop this type of clot in this setting than in any other form of thrombophilia, you know, and even in centers that look at coagulation specifically, they would probably request a JAK2. So I think this is an important one.
The other one that I would probably want to expand a little bit on is some arterial complications that we see in young patients that are not explained. You know, if you do develop a stroke when you shouldn’t have developed a stroke, because you don’t have cardiovascular risk factors, or even cardiac events. I think there is space there to perhaps consider some of those, because we’ve seen some of the, you know, ET patients presenting with some anomaly, abnormal presentations with TIA, where they shouldn’t have had TIA, so, you know, even a full-set stroke damage. And I think, again, in an unexpected presentation, I think we need to think about that. Some of those patients might have normal blood count, but actually, in some cases, if you go back, you can see a persistent thrombocytosis, that it wasn’t picked up. Because, you know, the way that some of those patients might behave, is obviously very asymptomatic up until, you know, there is an event. So, they don’t go to their general practitioner, or if they do, you know, they go very, unfrequently. So it’s difficult to sometimes pick up a pattern, and sometimes some levels of thrombocytosis are not that, you know, concerning. So, you know, and this is another message I really wanted to, sort of, share, and, you know, perhaps as a pulse for, you know, other practitioners. I think any level that persists,is higher than the 450 mark for platelets requires some attention. And I’m not sure that currently everybody do that. I think, you know, we tend to see patients much later on. And I guess this depends on what country you are and what kind of region. So I’m quite strong about that, and I think, you know, in the UK, for example, it’s even a criteria for unexplained cancer pathways if you have a persistent thrombocytosis, you know, because it could… it could represent a beginning of an MPN. So those were the points, I think, Alessandro, that I wanted to touch on. I think, you know, if you do develop an unexplained vein thrombosis, you know, there is a requirement for further investigation. If there is a, you know, early set of arterial complication in patients where you wouldn’t expect, I think there is some space there for investigation. And then, looking at the blood results for a full blood count, if you have a persistent thrombocytosis or erythrocytosis that is not explained by, you know, inflammation or COPD or other reactive trigger, you know, requires some attention.
Prof. Vannucchi:
So this is very important, because, of course, making… especially in case of splanchnicvein or cerebral sinus vein thrombosis, this changes the therapeutic approach to the patient, because if this thrombosis, as happens in more than 60%, 70% of splanchnicvein thrombosis syndrome, or of portal thrombosis and so on, this implies that the patient requires lifelong anticoagulation. That would not be the case, for example, if the reason, the cause of thrombosis is a different one. So, just to summarize what we have been discussing, of a patient who has abnormalities in blood values that are suggested for PV and ET, we have to go very in deep for the diagnosis, because we have molecular criteria, we have histopathological criteria. We have a lot of additional consideration, for example, exclusion, as you mentioned, of hidden cancer, exclusion of inflammation in the few cases that are negative for mutations, for driver mutations, but it’s very important to get a precise diagnosis, including bone marrow biopsy, for all cases, because these patients require correct diagnosis, correct prognostication, and correct treatment in order to prevent recurrence of thrombosis, and in order to correctly follow up the patients, especially since these are very long disorders over the life of an individual are subjected to the risk of transformation to post-PV, post-ET myelofibrosis, and also through, luckily enough, quite rarely, to a blast phase to an acute leukemia.
Thank you, Ciro, for your useful insights.
Prof. Rinaldi:
Thank you very much.