 Ruben, I’m going to turn to you. For our viewers, Ruben chairs the NCCN  MPN Guidelines committee. I would like you to comment on what the NCCN recommends for initiation of cytoreductive therapy. When do you consider that in terms of that choice? Then, follow-up on that with the comment of whether it is hydroxyurea or interferon: how do you use those?

First, to give proper credit, I did initiate that group as the initial panel, but it is now chaired by our friend and colleague Aaron Gerds. I am very familiar with the NCCN Guidelines. They’re a key piece. Srdan and I were on that initial wave helping to set these up. They were positive in that they brought some evidence-based standards to our US–based treatment.

Cytoreductive need for high-risk patients in PV is aimed at both decreasing that difficult risk of thrombosis and bleeding as well as trying to improve the disease burden with symptoms. 2 options are listed as initial therapy; we’re building on that base and assuming that people have already been on phlebotomy and aspirin. That’s a base: control of hematocrit and aspirin. The cytoreduction, then to try to achieve a European leukemia net response: phlebotomy independence, control of the white blood cell count, control of the platelet count, and resolution of splenomegaly if they’re in control of symptoms.

With that, either hydroxyurea or long-acting interferons: both are thought to be clinician’s choice, between them and the patients. There are increasing data; there are randomized data from earlier studies showing that hydroxyurea is superior to phlebotomy alone. It’s an older drug, but people are frequently comfortable using it.

Deficiencies can be difficulties with cytopenias, mouth ulcers, cutaneous malignancies, and sometimes other associated adverse effects. For interferons, there is an update coming up at this year’s EHA. We saw it in the late-breaking abstracts regarding the pegylated interferon given every 2 weeks. In the US most commonly, the pegylated interferon alpha 2A has been the available construct.

When trying to achieve a good control of the counts, on the downsides with interferon, it can cause mood disorders, or rarely, autoimmune problems such as hypothyroidism, or flu-like symptoms. Both have their pluses and minuses, with interferon being the preferred choice in women of childbearing age or individuals who are pregnant.

Videos

Treatment Options for High-Risk Polycythemia Vera

 Krisstina, coming back to you, I want you to concentrate now on a low-risk patient. They don’t have any cardiovascular risk factors, and they’re not as aged as most of the panel members today: over 60. They haven’t had a thrombotic episode. They might be having microcirculatory symptoms, dizziness, fatigue, or confusion, trouble finding words, whatever it might be. Migraine headaches, for example. Comment on the use of phlebotomy and low-dose aspirin in that group of patients. Does the patient have to have symptoms for you to initiate phlebotomy and aspirin therapy for that low-risk patient?

For low-risk polycythemia vera patients, we approach all patients with low-dose aspirin, 81 mg or 100 mg daily, with concurrent phlebotomy, with that important hematic profile that Dr Jamile Shammo mentioned, or that 4-fold increase in thrombotic events or cardiovascular death. As a blanket recommendation, for those who are diagnosed with low-risk PV, we approach those patients in that way.

Regarding the symptoms, certainly there are a group of patients who will have significant associated microvascular symptoms: pathognomonic aquagenic pruritus and very symptomatic fatigue. In fact, this is the most commonly associated symptom, which was beautifully shown in a landmark study that patients are afflicted with it, and it can affect their activities of daily living.

In these patients, although we are definitely treating them and optimizing their hematic profile and decreasing their thrombotic risks with recurrent aspirin, we need to be assessing their symptom burden as an end point of care in combination with the hematologic parameters we’re targeting.

Regarding the microvascular symptoms, you can increase the dose of aspirin in some patients and have some modest benefit. There are some additive, supportive care maneuvers that you can certainly entertain for the pruritus, and gabapentin has been used to some additional help. I’d be interested in some of the other panel members’ unique supportive care maneuvers that they’re doing for symptom burden.

Thinking about symptom burden as equally important as the hematologic profile. Direct your therapy for your low-risk disease, and if it’s not adequately controlled, then think about second-line therapies.

 Krisstina, give our viewers a bit more understanding: How often are you monitoring a CBC or a hematocrit in your patients with PV?

 There are different phases. As you’re initially meeting a patient, you’re in an induction phase. You’re trying to be more aggressive: assess more aggressively and treat more aggressively, perhaps with more frequent phlebotomies.

For those patients, I’m seeing them every 2 to 4 weeks and making adjustments and recommendations for phlebotomy until we obtain adequate control. Once they’ve attained adequate hematologic and symptomatic control, you can start stretching out that monitoring frequency to every 2 to 3 months.

Management of Low-Risk Polycythemia Vera

 Jamile, we have identified a specific hematocrit hemoglobin level above which we do not want to see our patients. Can you review for us the data that support that? How often do you have to check if the patient is above that level, and when do you intervene?

 There are data to suggest that optimization of the hematopoietic parameters in patients who have PV [polycythemia vera] are extremely important. In fact, let me start with the hematocrit, for example. There are data that came from the CYTO-PV study that suggests that maintaining a hematocrit level below 45% is associated with a 4-fold decrease in mortality from cardiac event and major thrombotic events, and that’s something we can easily do as practitioners, as hematologists: maintain the hematocrit below 45%.

How often should you look for that? It depends on the stage of the disease. If you’re starting a new patient on phlebotomy, for example, you might do it twice a week and have someone checking those numbers twice a week. As the disease goes on or as you’re getting closer to optimization, the frequency of checking the hematocrit becomes less and less. We have to try as much as possible to keep this below 45%. I don’t want to put my patients at risk by that parameter.

The other thing is the platelet count. Practitioners have to realize that, as you phlebotomize patients, the platelet count is likely to go up; we’re inducing a state of iron deficiency by doing phlebotomy. People get nervous, and then they start to think, “Now the platelet count is rising.” The only issue there is perhaps the platelet count interfering with the administration of antiplatelet therapy.

It’s OK to have a mildly elevated platelet count, and it’s OK to give aspirin. But if you’re concerned, you could check for acquired Von Willebrand factor deficiency. I always worry that perhaps trying to chase the platelet count in the setting of phlebotomy may be misleading to some in terms of initiation of other treatments, or even suggesting that maybe this isn’t a disease that’s responding.

Finally, leukocytosis is something we need to pay attention to, because it is an indicator of myeloproliferation. For some people, there’s a lot of debate about whether they may be associated with increasing thrombotic events, mostly with data pointing to retrospective analysis of the association between leukocytosis and thrombotic events.

We [at Rush University Medical Center] did 520 patients who had PV, and we looked at the risk and didn’t find it in this retrospective analysis. These were private institutions that submitted data to evaluate that piece, but what it was associated with is disease progression. It’s something we need to pay attention to. Perhaps if you have ongoing leukocytosis, maybe this would be the time to evaluate the patient fully and see exactly if there is progression. Are they compliant with their medication? We don’t even talk about that. We then move forward. The most important piece when it comes to blood counts is that.

Any time you talk about MPNs [myeloproliferative neoplasms], there’s also this piece about splenomegaly and a piece about constitutional symptoms. Every time you see patients in the clinic, those would be things that we need to pay attention to, to assess how is disease doing and what we need to pay attention to in terms of disease control.

Polycythemia Vera: Monitoring Patients

 Krisstina, I’d like to turn back to you and have you comment about risk assessment and polycythemia.

Risk assessment is based primarily on 2 factors with polycythemia vera. No. 1, how old is the patient? Greater than 60 years of age or less than 60 years of age? No. 2, did they have a prior history of a thrombotic event? If they are young and have not had a history of thrombotic events, then they are a low-risk polycythemia vera patient. On the flip side, if they are more advanced age—as I’m aging into the 40s, that advanced age at 60 is hard to state. But as they’re getting older, it’s not a magic cutoff. If they’re 59 years old and they turn 60, that does not mean that, all of a sudden, their thrombotic risk goes up. We have to take that into consideration as we’re treating these patients and look at some of the other factors that we’re thinking about when we’re assessing thrombotic risk.

What are some of those factors? Those are the cardiovascular factors that we would assess as a primary care physician. Do they have underlying diabetes? Underlying coronary artery disease? Hyperlipidemia? Are they obese? Are they a smoker? It’s a personalized approach when you’re assessing polycythemia vera and their thrombotic risk, and it leads to an opportunity for discussion with our patients in regard to these lifestyle measures.

That’s an area of my own personal passion; we’re treating patients. We’re not treating CVCs [central venous catheters] or hematologic profiles. As hematologists, it’s important to be assessing these risk factors, to be assessing lifestyles, and to be addressing them. Not just identifying them but talking about these things.

Polycythemia Vera: Risk Assessment

 I want to turn the attention of the panel to maybe the 2 most important and most frequent questions I get about testing in PV [polycythemia vera]. The first is if the 

 allelic burden at the time of diagnosis is important. The second is about reports of splice site variance: Are those artifacts, or are those clinically important? I’m going to turn it back to Srdan to start on that. The 

 allele burden; how about if it was really low? Could this just be CHIP [clonal hematopoiesis of indeterminate potential]?

The testing is usually done in the clinical setting, where you are suspicious of polycythemia vera. We are not randomly testing people to see whether they have a low level of the 

 mutation, which can then be achieved. We are testing in the setting of suspicion of polycythemia vera, where there would be a high-normal or above-normal red blood cell count. You would also look for high white blood cells, high platelets, iron deficiency, and erythropoietin level, and in that setting, you would also test for the 

The presence of mutations on its own is not in the diagnostic criteria for any of the MPNs [myeloproliferative neoplasms] because they might have the CHIP. If you have the mutation in the context of all these other tests, Dr Shammo has articulated that very well; on borderline cases for mass PV, you would do this testing and account for all these factors to make sure that you don’t miss PV because the therapeutic approach must be different than if there is no PV; phlebotomy is mandatory.

On the other hand, it may be important, but we are not routinely doing that testing to follow. There is good literature on high allelic burden being prognostic in terms of progression to myelofibrosis or exposing people to high-risk of thrombosis itself.

 If the allele burden at the time of diagnosis is less than 10% or less than 5%, could that be consistent with PV?

It can be, in the context of hyperproliferative bone marrow, high red blood cell count, low erythropoietin, and iron deficiency. However, that would be unusual because the median allelic burden in PV is about 45%. It would be an unusual case.

 Ruben, what do we do with these reports of exon splice site variance where exons are dropped out? Is that just an artifact of the assay, or are they clinically important?

We don’t fully know yet. As we continue to get more genetic information, it is a very rapidly moving target. What is an activating mutation and what really is genetic artifact? The annotation of our genetic reports is a very active process that is not fully baked. I’ll try to look them up as they arise, as well as whether they have the potential to alter our understanding of what we should be doing for those patients.

In terms of our decision support as hematologists moving forward, trying to keep track of all these things is quite difficult because there’s such a river of information as it relates to different types of mutations, allelic burden, and other sorts of pieces. As we get supported over time, that will be an important part as we’re trying to digest what the mutual impact of half a dozen or a dozen mutations is, some of which are in nontraditional splice sites. It becomes more and more difficult to interpret that information.

I fully agree with Ruben. This is the area of research, but specifically on the 

 gene variance, what is done in a community setting is you have a hot spot test that you do: a 

 V617F. We don’t look for the whole gene; only if you have a negative result do you then do the 

 exon 12. In some academic centers they analyze the whole gene.

In some cases, you will then find the variance in addition to the hot spot mutation that you are looking for. It seems that the presence of variance or other genetic abnormalities within those genes make a difference for the outcome for the aggressiveness, but it’s completely new area of research.

Polycythemia Vera: Prognostic Markers

 I want to point out 1 other thing in the small print. Because is the case for many pathologists on that committee, they say “If you don’t do it, you miss some important prognostic information on the presence of fibrosis.” Of course, I don’t know what to do with that prognostic information, so that doesn’t sway me 1 way or the other. How about you?

That’s a good point because the patients always worry about the long-term outcome of the disease. By default, they say it’s benign, but there is a proportion of the patients, about 20% to 25% of patients who, over their life span, may progress to myelofibrosis, and a certain small percentage who will develop leukemia.

Myelofibrosis in particular is the worry because, when you transform officially, the life expectancy can shorten. The bone marrow biopsy can provide some useful information to semi-intelligently prognosticate for the future. This is all relative, but if you have a cytogenetic abnormality, an abnormality of chromosomes, which is very rare but not impossible, that would perhaps prejudice most people to have a high risk of change.

The presence of fibrosis at the time of diagnosis of PV [polycythemia vera] is present in up to 20% of the cases; on a scale from 0 to 3, grade 2 is already seen in up to 20% of the patients. I repeat it because it’s important. These patients with PV are at a higher risk of a change to full-blown myelofibrosis during their life span.

This is the kind of information that we would like to have at the beginning for full understanding not only about diagnosis but also possible prognosis for transformation. Not for the thrombotic risk, which I already mentioned as a primary goal of therapy, but for the future. That needs to be highlighted: the presence of the fibrosis does not mean myelofibrosis by default. Fibrosis can to some degree be seen in PV.

 Thanks, Srdan. Ruben, do you want to add to that?

I just wanted to add an important point that I share with patients, which is that I agree that baseline bone marrow biopsy is helpful. The challenge is if we see a bit of fibrosis and they have that higher risk, we still don’t know what that means in absolute terms. If I compare 2 patients—1 without that fibrosis and 1 with—yes, the patient who has the fibrosis has a higher likelihood of progression through myelofibrosis, but that might be in 10 years compared with the other patient who will never progress during their life span.

As we think about these prognostic factors, it is worse as a population, but it’s always difficult to translate for a patient what that means. Additionally, all of that is in current science. We may well develop therapies, or some of our current therapies might alter that natural history further. So prognostic always has to be taken in appropriate consideration; sometimes patients can become very distressed by some of these prognostic findings as well.

 As everybody said, the bone marrow biopsy may or may not be important. The 1 piece I wanted to add in PV is for patients who may not meet the criteria. Let’s say you have a 

 V617F positivity, and you’re entertaining an MPN [myeloproliferative neoplasm]. Perhaps the hemoglobin isn’t 16.5 or 18.5 g/dL, where you don’t have to do a marrow, but perhaps it’s 13 g/dL. If you did the bone marrow and then you get an iron stain, which I highly recommend on anybody who has a marrow with the suspicion of an MPN, that has 0 iron in it. If you have absent iron stores, then your patient clearly is iron deficient and may have PV, even though the hemoglobin doesn’t necessarily meet the criteria.

In that sense, when the heme parameters do not fit the WHO [World Health Organization classification and diagnostic criteria for myeloproliferative neoplasms] 2016 as opposed to 2017, as it says in the NCCN [National Comprehensive Cancer Network] Guidelines, it has to be performed so that you can characterize the MPN a bit better and pay attention to the iron piece. I often see it done, yet nobody comments on it, and we could improve a lot on the prognostic accuracy of the characteristics of the MPN we’re looking for.

 I agree with that. The iron stain can be helpful in those borderline cases, and I often look for iron deficiency.

Polycythemia Vera: Bone Marrow Biopsies

 Let’s move on. Srdan, I’d like you to discuss how patients with PV [polycythemia vera] present and what the differential diagnosis of that presentation is.

Although polycythemia vera is the name, it implies that all the cells grow, which is true. 

 means high blood cell count: red blood cells, white blood cells, and lipids. Not everybody has high white cells and high platelets, but everybody does have high red blood cell counts. The cardinal feature of polycythemia vera is a high red blood cell count.

That can be in a setting of blood clots at the time of the presentation in about 20% of the patients, and it’s often associated with the systemic symptoms: itching, night sweating, low-grade fever, fatigue, flushing in the face, not feeling well overall, memory loss, and blurred vision are symptoms related to impaired circulation in the body because there are too many cells in the blood vessels. These are the characteristics of the patients we see, but not every patient who has a high red blood cell count has polycythemia vera.

As you alluded in your impression, there are other conditions that may resemble these kinds of presentations. Particularly in the setting of younger people, we need to be cautious when we look at the erythrocytosis associated with the use of certain medications like testosterone. Erythrocytosis is associated with problems with lung function—people who had sleep apnea, for example. There are also problems related to certain cancers—kidney cancer, for example.

Not everybody who has high a red blood cell count has polycythemia vera. The first goal is to make sure we are talking about the bone marrow neoplasm and not reactivated erythrocytosis, because the approach is different. With the disease, we have not only the number of cells increasing but also their activity. They are sticky, and that is the problem: too many cells that are sticking together, and that increases the risk of thrombosis. Therefore, the approach there is to decrease the thrombotic risk in polycythemia vera patients.

To go back to the diagnostic process, once we roll out the secondary diseases that would increase blood cell counts, which are usually benign, you would look at lung functions, medications, and other possible causes. You would focus specifically on the criteria for PV that, in 2016, has been simplified and modified to quite a significant degree. We now have 3 major criteria to fulfill, or you can fill at least 2 of them, and I’ll give you a brief summary of those.

The cardinal picture is high red blood cell count. We are talking about decreased hematocrit or hemoglobin, as is routine when you do CBC [complete blood count]. That should be associated with the testing you can do in blood for the presence of 

 V617F mutation, which is present in about 95% of the patients, or in those who don’t have that 1, testing for 

That will cover almost everybody: either of the 2 mutations, and there is still a possibility of having anecdotal cases of patients who do not have any of these, which may be a matter of the sensitivity of the test, or they have something else that can link mutation for which we cannot test.

 mutation, and then the question of the bone marrow biopsy: Do you need to have it done? In the synopsis for the diagnostic criteria it says No. 1, high red blood cell count; No. 2, bone marrow biopsy; and No. 3, the 

 mutation. If you have all 3, you have PV, no question about it, but there is a minor criterion there which is suboptimal serum erythropoietin level, meaning low erythropoietin level.

It’s in case you cannot do genetic testing. The purpose of genetic testing is to fulfill diagnostic criteria, but sometimes you may not have it, or the testing is not available. You can use the high red blood cell count, the bone marrow, and the suboptimal erythropoietin as a combination for making diagnosis. This is the standard practice.

Many ask the question: Do we need to do a bone marrow biopsy in every single case? If you read the guidance on how the diagnosis process needs to be done, it clearly says in the small print—and that’s the problem, it’s very small—that you don’t need to do it every single time. If you have an above-normal red blood cell count, a 

 mutation, and a suboptimal erythropoietin level, there is no other disease than polycythemia vera that can cause this trifecta of findings.

In that case, with very high red blood cell count above normal, 

 mutation on blood protein, and a low erythropoietin level, that’s PV. I don’t do the bone marrow biopsies, and the small print in the guidance says not to do it.

I hope I simplified for you what needs to be done to get the diagnosis of PV.

Polycythemia Vera: Diagnostic Work-up

®, titled “Updates in the Management of Myeloproliferative Neoplasms.” I am Dr Harry Erba from Duke Cancer Institute. Joining me today in this virtual discussion are my colleagues Dr Krisstina Gowin from the University of Arizona Cancer Center; Dr Ruben Mesa from the University of Texas Health San Antonio MD Anderson Cancer Center; Dr Jamile Shammo from Rush University Medical Center; and Dr Srdan Verstovsek from The University of Texas MD Anderson Cancer Center.

Today we are going to discuss a number of topics pertaining to the management of myeloproliferative neoplasms, including practical information for community oncologists. Let’s get started on our first topic. I’m going to turn to you, Dr Gowin, if you don’t mind. Krisstina, can you provide an overview of the myeloproliferative neoplasms?

Absolutely. Good morning. Myeloproliferative neoplasms are a type of chronic myeloid malignancy that are characterized by overproduction of mature blood cells. They are characterized by a 

 nipple or other clonal mutations. They are also characterized, and this recently been described more eloquently over the last decade, by a very heterogenous symptom burden.

 That’s great. There are various types. Those are similarities; how do we distinguish these?

What’s interesting about myeloproliferative neoplasms is that it’s truly a spectrum of disorders. There’s a dynamic nature within the different umbrella of myeloproliferative neoplasms.

When we’re looking at these patients, we’re first asking if this is a classical myeloproliferative neoplasm or is there a Philadelphia chromosome involved, and that would be more diagnostic and a CML [chronic myelogenous leukemia]–type of picture. Within the classical myeloproliferative neoplasms, there are 3 different entities: polycythemia vera, myelofibrosis, and essential thrombocythemia. Polycythemia vera is classified based on a tri-lineage hematopoiesis, a very symptomatic splenomegaly, and a diffuse, heterogenous symptom burden.

Myelofibrosis, in contrast, is more of a fibrosis: scarring of the bone marrow that can lead to more of a cytopenic phase, rather than the hyperproliferative phase that we see with polycythemia. You can get this cyto-proliferation, this high burden of both white blood cells and platelets within myelofibrosis, as well. They tend to be more symptomatic and have a worse associated prognosis.

Finally, essential thrombocythemia is characterized by increased thrombocytosis as well as a very significant symptom burden. The treatment goals are different within these categories in that, for both polycythemia vera and essential thrombocythemia, it’s looking at the thrombotic and hemorrhagic complications of the disease; in myelofibrosis, we’re focusing more on spleen reduction and symptom burden.

Ruben A. Mesa, MD, FACP, UT Health San Antonio MD Anderson Cancer Center

Articles