Key Biological Pathways in Polycythemia Vera and Assessing Patient Risk
Subject matter expert reviews biological mechanisms underpinning myeloproliferative neoplasms and standard-of-care risk assessment for patients with PV.
Prithviraj Bose: We just went over the WHO criteria for a diagnosis of PV. So just to sort of rephrase it and try to define PV and how it's unique within the MPNs, et cetera, what I'll say is that PV is, as the name suggests, a polycythemia. So it is marked by increased production of all three lineages, not just red cells. So red cells, white cells, and platelets. You see this hypercellular bone marrow, you see a panmyelosis, as it is called in the bone marrow, pancytosis in the blood. Again, basically saying that all the three cell lines are elevated. You see megakaryocytes, which are the platelet precursors of different shapes and sizes. We call that pleomorphic. So these are some of the morphologic hallmarks of PV. Now, as far as key biologic pathways in PV, PV is actually relatively simple to understand because this is the classic consequence of the JAK2V617F mutation. So in mouse model studies, for example, if you introduce that mutation, PV is the disease it leads to. That's the phenotype you see classically as a result of the JAK2V617F mutation. And different groups have shown that if you introduce that mutation, that is sufficient in the lab to create a PV phenotype. PV is the most common of the MPNs. US prevalence is about 44 to 57 per 100,000. So that's something to note. But again, biologically, it's very homogenous. It's all JAK2. 95% have V617F, 4% have exon 12. So you don't have CALR in PV typically, just very occasional case reports. But so it's a homogenous disease. There are some other mutations, not very frequently seen, but some have been described as somewhat adverse, like SRSF2, IDH2, and ASXL1. So these have been seen and they could be somewhat adverse, particularly SRSF2. But generally other mutations, chromosomal abnormalities are not that common in PV. It gets a lot more complicated in myelofibrosis.
Risk assessment in PV has actually not changed in a long time. It's surprisingly simple. So as it stands, the official risk stratification for PV is simply based on age and history of a blood clot. So if the patient is younger than 60 and has never had a blood clot, that's a low-risk patient. And a patient that is 60 or older and or has had a blood clot, that's a high-risk patient. And I was alluding to this slightly when we discussed our case where the patient was 67. So that alone makes the patient high risk. Now that is, again, relatively simple and easy to remember. But there are other factors that are increasingly becoming apparent in terms of their importance. So the white cells, for example, our patient started with a white count of 13. There is a growing body of evidence suggesting that baseline leukocytosis is related to thrombotic risk. There's been a number of studies, slightly different cutoffs, 15, 11, 12, but elevated white cells do seem to impact the risk of thrombosis. Now, if you have a trajectory of white cells that are, if you have an upward trajectory, I should say, if they're going up kind of over time, that is a clear risk factor for disease evolution to myelofibrosis and acute myeloid leukemia, both of which are clearly bad outcomes, particularly the AML, that's a horrible outcome. But, you know, PV can progress to myelofibrosis. And if you see this elevated white count over time, that's a red flag for that. The JAK2 allele burden is also a risk factor for progression to myelofibrosis as well as for thrombosis, particularly venous thrombosis, JAK2 allele burden over 50% is a risk factor for that and also higher JAK2 allele burdens are a risk factor for progression to myelofibrosis. I alluded to this earlier, there are some bad mutations, SRSF2 is a good example. In fact, there is now a model for risk assessment in PV called MIPS PV. I think it's mutation inspired or, yeah, mutation inspired, international, mutation enhanced international prognostics scoring system for PV. And basically it takes into account age and it takes into account the SRSF2 mutation, leukocytosis, like I just discussed over 15 in that particular model and a prior clot, so prior thrombosis. So these factors portend worse survival. So it's a little- It's important actually to be a little careful about what we are talking about. So there's survival, there's thrombosis, there's progression to myelofibrosis. So they're all a little bit different. So age, clotting history, white count, I would say for thrombosis, allele burden as well, but you're not going to- it's not certainly very easy to change that, although some newer therapies may be impacting that. But for thrombosis, which is our primary goal in management of PV, it's those things, whereas for survival and progression to MF and AML, it is some additional factors as I just outlined.
