Evolving discussions on polycythemia vera
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Key findings of an extensive survey of MPN patients,
funded by Incyte Corporation

This article, published in BioMed Central Cancer, reviews the findings of the MPN Landmark Survey, the first study ever to assess patient perceptions of MPN disease burden and health care. These findings support those of previous research about symptom burden experienced by patients with MPNs.

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Article subject to copyright. Review publisher’s permissions and terms of use for the article.
MPN = myeloproliferative neoplasm

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Recognizing and treating the patient with high-risk disease

Incyte Corporation has partnered with Dr Kim-Hien Dao—who treats primarily high-risk patients at Oregon Health & Science University in Portland, Oregon—to discuss 2 controversial issues in the recognition of patients with high-risk polycythemia vera (PV). A variety of clinical presentations point to higher-risk features of PV, in addition to age >60 years and prior thrombotic events. Additionally, patients with poorly controlled hematocrit should be followed and managed very closely to reduce life-threatening complications from PV.

Insights from this collaboration can be found in our third full article from the PV State of Mind platform, an ongoing program that provides a framework for the discussion of topics and recent developments to help clinicians better understand this serious disease.

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Kim-Hien Dao, DO, PhD
Oregon Health & Science University, Portland, Oregon

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Focus on aggressive polycythemia vera

Incyte Corporation has partnered with Dr Jerry L. Spivak— a highly regarded expert in chronic myeloproliferative disorders—to discuss the phenotypic variability of polycythemia vera (PV), the need for identification and early institution of therapy for the subset of patients who may be at risk for a more aggressive disease course, and the data surrounding gene expression profiling as a clinical assessment to help inform future patient identification analyses and risk management.

Insights from this collaboration can be found in our second full article from the PV State of Mind program, an ongoing program that discusses important controversial issues in this progressive field.

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Jerry L. Spivak, MD
The Johns Hopkins Hospital and Johns Hopkins Center for the Chronic Myeloproliferative Disorders, Baltimore, Maryland

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Emerging diagnostic and risk stratification criteria

Incyte Corporation has partnered with Dr Rami S. Komrokji—Clinical Director of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida—to explore the evolution of diagnostic and risk stratification criteria in polycythemia vera (PV), particularly in relation to their ability to predict disease progression, hematologic transformation, and overall survival.

Insights from this collaboration can be found in our first full article from the PV State of Mind program, an ongoing series that discusses the relevant topics in PV today.

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Rami S. Komrokji, MD
Moffitt Cancer Center, Tampa, Florida

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About PV State of Mind

See polycythemia vera through the eyes of experts

PV State of Mind provides a framework for the discussion of topics and recent developments to help clinicians better understand this serious disease. Areas of investigation may include:

  • Limitations of current diagnostic criteria
  • Evolving risk stratification models
  • Emerging indicators for more aggressive forms of disease

See how new models are being developed to reflect a more contemporary understanding of diagnosis and risk in PV.

Download the full articles or podcasts to learn about these thought leaders' perspectives in polycythemia vera.

Kim-Hien Dao, DO, PhD

Recognizing and treating the patient with high-risk polycythemia vera

Jerry L. Spivak, MD

Focus on aggressive polycythemia vera

Rami S. Komrokji, MD

Polycythemia vera:
Emerging diagnostic and risk stratification criteria

Click below to hear audio clips from the interviews. Feel free to download or share the clips with colleagues.

Kim-Hien Dao, DO, PhD

What are some signs that may help identify patients with high-risk polycythemia vera (PV)?
Polycythemia vera may be less alarming than most cancers because of its long... Read More clinical course. This may cause clinicians not to manage the disease aggressively. Dr Dao has identified indicators that can help clinicians recognize patients with polycythemia vera who are at higher risk than may be apparent.
I guess really the patients that are in danger are the patients who don’t have access to a hematologist. They get managed by their primary care who may not fully understand the risks of having PV and uncontrolled hematocrit. That’s the scenario that I’ve seen. And then for the hematologist, I think that because patients do well for a while, I think sometimes they forget the hematocrit goal or don’t realize how important it is to reduce the patient’s risk for thrombotic events by getting the hematocrit below 45 for men and then below 42 for women.

Symptoms associated with PV is a marker of cytokine levels in their blood, and uncontrolled symptoms might be a marker that their PV is very active and their hematocrit is very high. The ultimate red flag, of course, is presenting with a thrombotic event.
Do you consider other risk factors beyond advanced age and history of thrombosis?
In addition to advanced age and history of thrombosis—the classic risk... Read More factors for a thrombotic event in polycythemia vera (PV)—there are other factors that might influence prognosis.
I consider classic cardiovascular risk factors as something that would worry me and want me to make sure that a patient has a better controlled hematocrit. Someone who has diabetes or had a high-grade heart attack, those are patients I would worry about in addition to age and prior thrombosis of wanting to control their hematocrit tightly. I’m worried about what resistance to prior therapy means in terms of hematocrit control, not by itself being necessarily a biomarker that they have worse disease. And then excessive symptoms or complications with PV—that’s a concerning feature that would want me to make sure that a patient has a better controlled hematocrit.
Do patients with polycythemia vera and resistance or intolerance to hydroxyurea present a special problem?
Hydroxyurea is often the first-line myelosuppressive agent, but patients can be... Read More intolerant of or develop resistance to hydroxyurea. These patients present a special problem.
If the patient is intolerant, sometimes those early symptoms include fatigue, fevers, night sweats, and then, of course, ulceration. The ulcers can happen any time, but intolerance like nausea, gastrointestinal upset, fevers, and fatigue can happen within days or weeks of starting therapy.
I think if you were looking at true failure, not because of intolerance, but truly that you can’t control the hematocrit, I usually give Hydrea® (hydroxyurea) 2 to 3 months with escalating doses before we call it a failure.
What would you say is the most common mistake in the management of polycythemia vera (PV)?
Dr. Dao has seen one clinical practice repeatedly that she thinks puts patients... Read More at unnecessary risk and compromises outcomes.
The mistake I see over and over again is that these patients are not being managed close enough when they first get diagnosed with PV. Look for treatment effectiveness of the hydroxyurea dose, especially and frequently in that early phase, in that first 6 months when you’re trying to get patients to a steady-state level of hydroxyurea and control. What I see all too often is that these patients get diagnosed, they start Hydrea® (hydroxyurea) but they don’t get follow-up for 3 to 6 months and their hematocrit is still uncontrolled, you know, like 50. My advice would be that early PV management is very important, so institute phlebotomies immediately if needed to bring their hematocrit below 45—and it could be very frequent initially. And then frequent check of their CBC (complete blood count) the first 6 months; check their CBC every 4 weeks, probably until they’re at a steady-state target hematocrit, and then you can bring down the frequency of follow-up.

Jerry L. Spivak, MD

Patients with polycythemia vera can present with various combinations of elevated levels of red cells, white cells, and/or platelets. Is there any prognostic value to these presentations?
Polycythemia vera may present as erythrocytosis, leukocytosis, thrombocytosis, or... Read More various combinations of the above. In his clinical experience, Dr Spivak has seen different outcomes associated with these different presentations.
Polycythemia vera is a disease that involves a stem cell and so, therefore, you’re gonna have increased numbers of red cells, increased numbers of white cells, and increased numbers of platelets. Now, the disease is very variable in that regard. You can have patients who have the JAK2V617F mutation that only have erythrocytosis. They’re not common but they can live; we’ve seen them for at least 10 years or more. Then you will have patients who have an elevation of the red cells and the platelets, okay, and not the white cells. When I see that, I find that generally is a clue that they’re gonna do very well. Then you have patients who come in and they’re making too many red cells, too many white cells, and too many platelets. They have the more sort of aggressive-type disease in a way; they’re more likely to get splenomegaly and do things, you know, in a more aggressive fashion. So polycythemia vera comes in all flavors. Now, the important thing to remember is that it’s not the platelets or the white cells that determine prognosis, it’s the stem cell.
A subset of patients with polycythemia vera will do poorly.
Dr Spivak published a study in the New England Journal of Medicine in which... Read More he described the identification of a subset of patients with aggressive, high-risk polycythemia vera.
If you go back in the literature, and you can go back into the early ‘60s and just come forward, what you’re gonna find repeatedly is that there is a segment of polycythemia vera patients, and it’s a minimum of 10%—it might be 15%—that have a more aggressive disease, but the rest of the patients do not. And what we did very simply was we said we interrogated what genes are these stem cells making. And we could divide polycythemia vera patients into 2 groups: those are gonna do well and those who are gonna do poorly. People who do badly, their stem cells are making a different set of genes than the people who do well. And that is immutable data, that is, genetic data.
Do you think differently when assessing polycythemia vera in men and women?
The CYTO-PV Study used a hematocrit target of <45% in polycythemia vera and... Read More saw a significantly lower rate of cardiovascular death and major thrombosis than in patients with a hematocrit target of 45% to 50%.
The reason that I differentiate women with polycythemia from men with polycythemia is that under normal circumstances, women have a smaller blood volume than men do. And if you use the male hematocrit for a female with polycythemia vera, then you are essentially allowing the female patient to have a larger blood volume than a normal woman would have. So this is just common sense physiology. So, if you come back to where we find most patients with polycythemia vera these days, we sort of diagnose them early because people tend to go to doctors more frequently and we have tests that we apply across the board, you know, in terms of complete blood counts. So people are picked up earlier and their hematocrits aren’t as high, so this—the idea of seeing someone with hematocrit of 55 or 60%— which should always be a red light, isn’t usually there. And so you will see women coming in with hematocrit of 48% or 46%. But a normal female hematocrit begins at 36 and sort of goes up and sort of ends about 42%. So, if you leave them at 45% or higher, you’re not completely treating them.

Rami S. Komrokji, MD

Proposed revisions to the WHO diagnostic criteria for PV
Diagnostic criteria for polycythemia vera have evolved since... Read More the Polycythemia Vera Study Group, and continue to evolve. Since the 2008 revision of the World Health Organization Diagnostic Criteria for polycythemia vera there have been several proposals for further revision, particularly in the last few years.
There had been different set of criteria in the past to diagnosis. There were the P.V. study group diagnostic criteria. Most recently, what's mostly used was the WHO criteria which require hemoglobin more than 18.5 in men or 16.5 in female and the presence of JAK2 V617 or JAK2 exon 12, the (cloning) marker. Those are the two major criteria. Then the minor criteria include bone marrow findings that are consistent with MPN such as hypercellularity, megakaryocyte clustering, low serum EPO and endogenous erythroid colony formation in vivo. Those are the current criteria and you either have two major or you have one major and two minor. The proposal for revision by the WHO includes changing the threshold for hemoglobin to 16.5 in male and 16 grams per deciliter in female. And obviously presence of a JAK2 mutation remained. The proposal for the revision includes the suggestion to move the bone marrow findings as well to a major criterion. The only minor criteria that will remain would be the low serum EPO level.
Most of the cases actually, if they are straightforward, you will make the diagnosis by the presence of erythrocytosis and the JAK2 mutation. You probably don't need the bone marrow to make the diagnosis.
What prognostic factors are currently used to guide selection of therapy?
Currently, patients are divided into low-risk or high-risk groups... Read More according to two factors: age greater than 60 years and a prior thrombotic event.
There are two types or two ways of risk stratification. The classic one to guide treatment and a more comprehensive one to predict outcome. One is basically to decide on treatment, and this is the classical way that we've used for P vera and for essential thrombocythemia. So, we divide the patients into two risk groups: those that are at increased risk of developing thrombosis and that include patients above age of 60, and those that had history of thrombosis, whether arterial or venous. So, those are coded with the high risk group compared to a low risk – lower risk group that are below age of 60 and never had an event.
Obviously, this is a good starting point but it does have some limitations. Yes, patients above age of 60 do have increased risk of thrombosis but events do occur in younger patients. Now, the type of events may be different, younger patients may be getting more DVT or PE while older patients sometimes tend to get more arterial events. But younger patients are not immune from getting thrombotic events. We know now that there are other factors that may contribute to increased risk of thrombosis such as the leukocyte count, the platelet count.
What are some of the additional risk factors proposed in the literature?
In addition to the conventional risk stratification factors of age and thrombotic... Read More history, new factors are being proposed that may be prognostic for survival, disease progression, or hematologic transformation.
We also look at different variables. We definitely look at the leukocyte count. I think there is evidence that the higher leukocyte count, maybe the higher the thrombotic event. Platelet count being high could correlate with thrombotic event. Some people look at like, for example, the JAK2 allele burden related homozygotic or heterozygotic because that could have implications many more on disease progression to fibrosis rather than risk of thrombosis. And then we are starting to see people looking at molecular profiling in those patients, looking at other molecular events which are probably more studied in myelofibrosis at this point. We're starting to learn about those as well in P vera but they are not yet established into any risk stratification.

As part of the PV State of Mind program, a slide kit summary from each interview is available to download at your convenience.

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Kim-Hien Dao, DO, PhD

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Jerry L. Spivak, MD

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Rami S. Komrokji, MD