This is a classic presentation of polycythemia vera [PV]. A 75-year-old gentleman presents to his primary physician with marked pruritus with bathing. The physician examines the patient, finds him to have a lot of rubor, or kind of a red-in-face presentation. But the rest of the exam is pretty unremarkable. He does not find any enlargements of the spleen and takes a thorough history. There&rsquo;s been no prior blood clot or bleeding. But the blood tests demonstrate marked erythrocytosis, very high hemoglobin, hematocrit, and erythropoietin levels, which is the lower limits of normal, which is consistent with a potential myeloproliferative neoplasm. Subsequently, the physician orders the test for

V617F, which confirms the diagnosis of polycythemia vera.

The physician, trying to meet the diagnostic criteria of the World Health Organization [WHO], recommends a bone marrow aspirate and biopsy to the patient. The patient declines. Yet one can say by prior WHO criteria, as well as accepted clinical practice, the patient has polycythemia vera.

Patients can present with polycythemia vera in a range of ways. They may present because of symptomsin particular, pruritus being 1 of the most common; or they might present with headaches, fatigue, or night sweats. They might present because they actually had a thrombotic event. It&rsquo;s not uncommon that this is diagnosed in the hospital when a patient had an unexpected heart attack, stroke, deep vein thrombosis, or pulmonary embolism. There are certain blood clots in unusual spots that are more common with polycythemia vera. Splenic vein thromboses or sagittal vein thromboses in the skull&mdash;any of these atypical areas are, in particular, very suspicious for polycythemia vera.

Finally, there are individuals who present because they are having a routine complete blood count for some other reason. Maybe they are screening for a health insurance physical or a pre-employment physical and are found to have marked erythrocytosis or leukocytosis or thrombocytosis. So that work-up typically begins with, first, a clinical suspicion and evaluation of the peripheral blood counts, as well as the analysis of the serum erythropoietin level, which typically is either normal or low because there is this feedback loop, an inappropriate suppression of the erythropoietin level, and then finally a confirmation in the majority of individuals of an MPN [myeloproliferative neoplasms]driver mutation. That is primarily the

V617F, which is found in about 90% to 95% of patients, with a

exon 12 mutation being present in a small minority. Most laboratories now will perform a reflex

exon 12 mutation analysis if they suspect PVif the

, the more common mutation, is not present.

In the real world, patients might present in a whole range of ways. They may present initially with a high white count or a high platelet count, and because of pre-existing iron deficiency they may not be fully manifesting their erythrocytosis. This is not uncommon in women of menstrual age, who may have a chronic or severe iron deficiency as part of the equation.

Individuals who go on clinical trials typically will meet very specific eligibility criteria, have the classic distribution of marked erythrocytosis, and depending upon the study, may have other prerequisite features such as splenomegaly or leukocytosis above a certain threshold.

Impressions of a 75-Year-Old Man With PV

The misdiagnosis of polycythemia vera has decreased sharply in the era of the presence of the

Certainly, secondary causes of erythrocytosis include, most commonly, sleep apnea and a high affinity of hemoglobins. Being an active smoker can certainly lead to erythrocytosis or leukocytosis. So can living at a high altitude. All of these are potentials, as well as rarer things such as erythropoietin-producing tumors or even rare genetic variance. The presence of

or the exon 12 certainly helps make it clear that there is a bone marrow disorder as the driver and helps exclude many of those secondary causes.

MPN [myeloproliferative neoplasm] patients and polycythemia vera patients, in particular, can have many difficult symptoms. To aid in assessing this, my colleagues and I helped develop a series of patient-reported outcome forms: The MPN symptom assessment form or the MPN10, where patients can fill out, serially, a series of 10 questions rating each symptom from 0 to 10 in a very neutral way so that you&rsquo;re able to assess their symptoms both at baseline and then serially over time. Their value is, 1, to help to facilitate or quantify for you, their physician, what their symptoms are at that moment. Is it better or worse than when you first saw them? Should you adjust your therapy up or down based on the difficulties that those symptoms have?

We have found, and others have found when we look at patient-reported outcomes, that filling out a form is much more neutral for the patient than just asking them how they feel. When we just ask about symptoms, patients, for a variety of reasonseither concerns that their visit is going to be too short or not enough time to get to their discussion questions&mdash;may sometimes underplay their symptoms. Additionally, just verbally asking patients how they are feeling in terms of their itching or other things makes it more difficult to both quantify and record those symptomatic profiles.

Considerations When Assessing Patients Suspicious of PV

Risk stratification for polycythemia vera [PV], unlike myelofibrosis, is primarily around the risk of thrombosis, or bleeding, and is less tied to the issue of survival. That may evolve over time, but primarily we are evolving in that part. As we come up with treatment for patients with polycythemia vera, we are, ideally, 1, trying to decrease that risk of blood clots or bleeding; but 2, decrease the burden that that patient faces. Now if you look at the burden that PV patients face, it includes the burden of risk of thrombosis, which we want to diminish; the potential burden of symptomatic difficulties; the potential burden of splenomegaly if it is present; and finally the potential burden of the risk of progression. Something that is very much on patients&rsquo; minds as they seek to avoid progression with the disease.

Progression with polycythemia vera has many potential features associated with it. One, there are signs of inadequate therapy. That may be inadequate control of the counts, inadequate control of the symptoms, a thrombotic event, a hemorrhagic eventall of those really are a sign of failure of your goal of therapy. Signs of progression to a different state might include features of moving toward myelofibrosis. That might be further enlargement of the spleen. That might be a change in the symptoms such as inadvertent weight loss or bone pain or fevers. It might be the development of anemia or cytopenias.

And then finally, there can be evidence of moving toward acute leukemia. That tends to be an increase in blasts and further cytopenias. That said, the majority of patients with PV will likely progress to myelofibrosis before they progress to acute leukemia. In this era, it would be very atypical for patients to progress from PV directly into acute leukemia if they had been seen in the past when we used leukemogenic therapy. Back in the era of radioactive phosphorous, there were patients who would have a therapy-associated acute leukemia type of phenotype develop, but fortunately, that is now rare.

Risk Stratification and the Management of Patients With PV

When planning my treatment options for patients with polycythemia vera [PV], I first consider their risk and their disease burden. How likely are they to have blood clots or bleeding? And then, what is their burden as it relates to that risk as well as symptoms and splenomegaly?

First, I view that all patients benefit from control of the hematocrit. I think that part is very clearwith a hematocrit that is clearly under 45% pretty much at all times for all patients with polycythemia vera.

There are individual patients who may benefit from that being a little lowerperhaps in women, perhaps in people in which that&rsquo;s inadequate for their symptoms. The limitations of phlebotomy are it can be hard on the veins, it can lead to iron deficiency, it might exacerbate some of the disease-associated symptoms. Sometimes that&rsquo;s where medical therapy, in that control, comes into play. But we need to maintain a hematocrit under 45% at all times for all PV patients after diagnosis.

Second, aspirin. There have been randomized studies [that] clearly show that a low-dose baby aspirin is helpful in patients with PV, particularly high-risk PV. Given that aspirin is a fairly benign therapy, we largely recommend low-dose aspirin81 mg, or 100 mg in Europe&mdash;for all patients with PV. Limitations just being if you&rsquo;re aspirin allergic or are already on warfarin or other blood thinners. Then it may exacerbate the risk of bleeding. If somebody is already on other antiplatelet therapy, we may be able to just leave them on clopidogrel or what other therapy they were on.

In many individuals, the limitation of both of these therapiesphlebotomy and aspirin&mdash;is that they don&rsquo;t fully control all those aspects of the burden of the disease. Our current guidelines for a response in PV includes a control of symptoms, control of splenomegaly, and having blood counts adequately controlled&mdash;the white cells, the platelets, and the red cells.

If a patient is on phlebotomy and aspirin, it may help the symptoms some. It may help the red cells, but it&rsquo;s not going to do anything for the white cells, the platelets, the spleen, and sometimes multiple other symptoms.

I believe that the majority of patients with PV benefit from cytoreductive therapy. Our current frontline cytoreductive therapy is either hydroxyurea or interferon, according to our current NCCN [National Comprehensive Cancer Network] Guidelines. Hydroxyurea is a pill. It is simple to take for most. Its downside is that it&rsquo;s a nonspecific therapy, and it can lead to neutropenia or thrombocytopenia. It frequently is just not active enough against symptoms, splenomegaly, or other difficulties that people may have. It can increase the risk of cutaneous malignancies. Controversially, it may have a slight impact in increasing the long-term risk of acute leukemia. That&rsquo;s difficult to prove, but it&rsquo;s also very difficult to disprove. I find that hydroxyurea, where it lets us down, is really in the limitation of its activity. It&rsquo;s a very nonspecific therapy, best used for controlling the counts, but it frequently leaves us disappointed with other potential goals.

Interferons, or the long-acting interferons, and now the pegylated interferon alfa-2b in Europe, is an additional frontline therapy. It is an injectable agent. It&rsquo;s a biologic agent administered once to twice a week. It can help to lower the counts. It may help to improve symptoms, particularly if they&rsquo;re related to the counts. Its impact on splenomegaly is probably less. Indeed, the European indication is for PV patients who don&rsquo;t have splenomegaly. Its impact on significant symptoms is probably more modest. Between hydroxyurea and interferon there is a hope, a hope more than being truly proven beyond a shadow of a doubt at this moment, that it may have a greater impact on delaying disease progression.

Now, in many individuals, this frontline therapy will be inadequate. For those who fail hydroxyurea, in particular, we have ruxolitinib approved as a therapy. This is a JAK1 and JAK2 inhibitor that is particularly helpful in controlling the hematocrit for individuals who are continuing to have difficulty but have a need for phlebotomies, have become intolerant for phlebotomy, have progressive splenomegaly, have difficult symptoms, or have been resistant or intolerant to hydroxyurea. That medication, as well, is an oral medication. It&rsquo;s a pill. Its limitations are not many. It perhaps has the greatest activity against splenomegaly and symptoms of any of the PV medications. Its toxicities that we monitor for are an increased risk of herpes, or shingles, and the potential of lowering blood counts. There is also a slightly higher risk for nonmelanoma skin cancers.

Available Treatment Options for Patients With PV

The goal of therapy, simply put, is to have the polycythemia vera [PV] be as neutral in the patient&rsquo;s life as possible. I judge that by trying to decrease the risk of thrombosis in bleeding, improve symptoms, improve splenomegaly if present, and hopefully use a well-tolerated therapy.

An individual who&rsquo;s age 75, such as the patient we are presenting: Their risk of progression is certainly a minority. In aggregate, PV patients have about a 10% to 15% risk of progression to myelofibrosis. Certainly, time is a major factor in that equationtypically, people have the disease for 10 years or more. So I&rsquo;m much more concerned about risk of progression to myelofibrosis in the 40-year-old patient who I saw with polycythemia vera than the 75-year-old individual. All that said, it certainly can occur anytime.

The goals of therapy really first start with prevention of thrombosis and bleeding. That is what we know can cause the greatest morbidity and mortality. It&rsquo;s important that we always keep that foremost in our minds. But in addition to that, we want to be able to control the counts as a surrogate for decreasing that risk of blood clots or bleeding. We want to reverse disease-associated symptoms. We want to control splenomegaly if present, and certainly we need to monitor for evidence of progression.

Ruxolitinib is a JAK1 and JAK2 inhibitor. In polycythemia vera, very clearly, the overactivation of the JAK/STAT pathway is front and center in the pathogenesis of the disease. So we very much view this as an important targeted therapy that directly has an impact on decreasing that myeloproliferation, with the resulting impact being individuals becoming phlebotomy independent, having long-term control of leukocytosis and thrombocytosis, as well as seeing an improvement in the whole inflammatory milieu and improvement in symptoms, and a reduction in splenomegaly.

The clinical trials that led to the approval of ruxolitinib were the RESPONSE and RESPONSE-2 studies. In the RESPONSE trial, individuals who had failed hydroxyurea needed phlebotomies and had a splenomegaly were enrolled. Ruxolitinib was vastly superior to best alternative therapy in control of the hematocrit, symptomatic improvement, and then strong trends were seen for a decrease in thrombotic events, etc.

The RESPONSE-2 study was a confirmatory study, with the same population of people who had failed hydroxyurea who did not have splenomegaly. So really, the splenomegaly is there, it will improve, but it is not a necessary feature to really see a response.

The dosage of ruxolitinib in patients with polycythemia vera ranges from 10 mg twice a day up to 25 mg twice a day. Ten milligrams twice a day is the standard starting dosage. Indications for increasing it further would be after an adequate trial at that dosage of 3 months or 4 months, typically in my practice. If they still have difficult residual symptoms, particularly nonfatigue-related symptomsso night sweats, severe pruritus, difficult-to-control counts such as leukocytosis or thrombocytosis, ongoing need for phlebotomies&mdash;then we would go up further on that dosing and monitor for any toxicities as they would relate, in particular, to cytopenias.

Long term, the tolerability of ruxolitinib in polycythemia vera has been excellent. As we presented the long-term data now over 5 years from the RESPONSE trial, the majority of patients continue to remain on the drug and continue to be responding and benefiting from the drug.

Considerations for JAK Inhibition for the Treatment of PV

My real-world experience with ruxolitinib in polycythemia vera [PV] has been very consistent with the data that we presented in The RESPONSE trial. The agent is effective. People feel better on the drug. It helps to control their disease. These are people who&rsquo;ve already failed hydroxyurea. They have good control of the disease. They become phlebotomy independent. They have improvements in symptoms. And yes, if they had enlargement of the spleen, it certainly helps to improve that enlargement of the spleen.

Now from the dose, again, the majority are able to remain on 10 mg twice a day, with a few needing a higher dose for control of leukocytosis or refractory pruritus or things of that nature.

I do find that that risk of herpes-shingles is a little higher than in the general population. It&rsquo;s probably less than 10% of people, but I am mindful of that. In particular now, since we have the inactivated herpes-shingles vaccine, we have been utilizing that in patients. There&rsquo;s not a clinical trial to approve that for this group of patients. However, it&rsquo;s a safe and effective vaccine, so it is a reasonable consideration for these patients.

Finally, I do think that all MPN [myeloproliferative neoplasm] patients have a higher risk of nonmelanoma skin cancers. I think the JAK inhibitor era has just made us more aware of that fact. It&rsquo;s higher at baseline, and it&rsquo;s higher with therapy. So I am mindful of those skin-related issues and do involve a dermatologist as part of the patient&rsquo;s care team, particularly if they&rsquo;re older, to be mindful for any premalignant lesions or any squamous cell carcinomas, etc, if they occur.

Ruxolitinib was tested first in the second-line setting. Because of an unmet medical need, it was a logical place to begin. Ruxolitinib undoubtedly will be active in the frontline setting and will be beneficial in a range of ways. What the indications will be for that utilization in the frontline setting will need to be supported by a clinical trial. Obviously, there are health economic discussions and in which patients that would be appropriate. I think most likely what will evolve is we will have a better understanding of risk, disease burden, and risk of progression. I think it will become an option as frontline therapy for PV. Maybe not universally, but I suspect that we will find subsets in which it is an appropriate consideration in the frontline setting.

The unmet medical needs in PV begin with our gap in the understanding of why patients progress. Indeed, if I had 100 patients with PV in front of me at the time of diagnosis, we know that there&rsquo;s a subset who are going to progress to more aggressive, advanced disease. If we were to understand why they progress, how we can monitor that, how we help to prevent that from recurring, we would want to approach the disease differently. Maybe those individuals should start on ruxolitinib? Maybe they should be on ruxolitinib with interferon? They have complementary mechanisms of action. Maybe that&rsquo;s a possibility. Maybe that&rsquo;s dramatic overkill in somebody else with polycythemia vera who might be easily controlled with phlebotomy and aspirin and/or hydroxyurea? I think it&rsquo;s still a heterogeneous group. So that biological knowledge gap remains an important gap.

Secondly, in terms of therapies, we still do not have perfect clarity on this issue of hydroxyurea versus interferon. I think more data will help us really sort that out. Should hydroxyurea really evolve away from being our frontline option? Could there be more discussion of interferon and ruxolitinib? Certainly, many of my other MPN-focused colleagues and I view that those are clearly the 2 best agents we have in polycythemia vera, and hydroxyurea is probably a more distant agent as a nonspecific agent.

There clearly are other therapies in development, looking at everything from nutlin inhibitors and others that may have activity in this group of patients. All of that is slow in development but may potentially play a role as well.

Polycythemia Vera

Impressions of a 75-Year-Old Man With PV

Considerations When Assessing Patients Suspicious of PV

Risk Stratification and the Management of Patients With PV

Available Treatment Options for Patients With PV

Considerations for JAK Inhibition for the Treatment of PV

Treating PV With JAK Inhibition Now and in the Future