The patient case that we are describing is a case of apparent erythrocytosis. The patient presents with very, very high levels of hematocrit and hemoglobin, which is associated with an increase in blood pressure. In this case, the patient was recently diagnosed with hypertension. This is also associated with an increase in the size of the spleen. The spleen is the filter of the blood. If you have too many blood cells going around in circulation, the spleen will commonly be enlarged as well.

So this was highly suggestive of a condition called polycythemia vera. One would need to do additional testing, including molecular testing for the

V617F mutation, which is present in about 96% of patients and in this particular patient, and a bone marrow biopsy to make sure that this is really being caused by the disease. In this case, this is apparent. The question is, Is the bone marrow biopsy necessary or not?

In the community setting, many people ask whether bone marrow is absolutely necessary as part of the diagnostic process in polycythemia vera. This comes from the recent modification in 2016 regarding the diagnostic process. The guideline that was published a couple of years ago says that a bone marrow biopsy should be done, but in the community setting, is this absolutely necessary? I would say that this is absolutely not necessary. Just like in our particular case, if there is apparent erythrocytosis and you have a

V617F mutation, iron deficiency, and low erythropoietin, what else can it be? So, in cases like this, with apparent erythrocytosis explained by all the other supportive factors, perhaps bone marrow is not necessary.

In a patient with apparent erythrocytosis, you would think that there might be a possibility for having disease in the bone marrow, which makes these red blood cells grow without control. There are other findings that would be suggestive of the disease. That would be an increase in the spleen, which is a filter of the blood. That would catch all these red blood cells that grow around the circulation. Then the symptomsthe patient has symptoms from an enlarged spleen, as well as symptoms of a general nature like headache and fatigue. Once the circulation is impaired, there is a problem with getting oxygen to tissue around the body and patients have these systemic symptoms.

Many times, although not in this particular case, patients would also have an increase in the white cells, or platelets. About 40% to 60% of patients with polycythemia vera would have those findings as well. Other silent findings in the blood may include microcytosis. Here the small size of the red blood cells (MCV [mean corpuscular volume]) that is automatically obtained when you do the complete blood count would indicate iron deficiency. One can then extend the testing in the blood into iron deficiency by measuring the iron ferritin, which is typically low. More specifically, in polycythemia vera, you can test for the

V617F mutation, which is seen in about 97% to 98% of patients with polycythemia vera.

In addition, one can also measure erythropoietin to see whether these red blood cells grow without control. This is a growth factor that boosts the production of red blood cells. In polycythemia vera, it&rsquo;s not necessary. The body shuts down the production of erythropoietin because red blood cells grow on their own. So, erythropoietin is a blood test that can also be done.

The combination of very high red blood cells, enlargement of the spleen, and symptoms that are often associated with the enlargement or increasing cell counts of platelets, iron deficiency, and low erythropoietin would help conclude polycythemia vera. In this case, the red blood cell count is so high that there is no other real possibility, once you have documented a

V617F mutation, that there is anything else causing that increase in red blood cells. It is polycythemia vera, even without the bone marrow biopsy.

Testing for Polycythemia Vera

Once we are sure that the patient has polycythemia vera, the next step is to determine the patient&rsquo;s risk for thrombosis. We know that patients with polycythemia vera are at increased risk for blood clotting, or thrombosis, in general. We can divide them into 2 groups. This is based on 2 factors. One factor is age over 60, and the other factor is history of blood clotting. If the patient has one or the other, he or she is at high risk for thrombosis.

In our particular case, the patient is newly diagnosed with polycythemia vera, never had a blood clot, and is younger than age 60. Therefore, the patient is at low risk for thrombosis. Patients who are at low risk for thrombosis with polycythemia vera are treated in a simple way. They are given baby aspirin (81 mg) to make the blood flow easier. The other treatment is phlebotomy. The aim of a phlebotomy is to decrease the hematocrit level, and the goal is to decease the hematocrit level to below 45%.

In the history of polycythemia vera, we always looked at the experimental information from dogs or other animal models. How would an increased risk of thrombosis correlate with the increased numbers of red blood cells that secrete around the blood, which is polycythemia vera? A few years ago, there was finally a prospective, randomized study done in Europe. The study randomized patients with polycythemia vera with an aim to maintain the hematocrit level below 45% or not to be so strict and allow the hematocrit level to be between 45% and 50%. This prospective, randomized study was stopped early, after about 3 years of follow-up, because it was quite clear that the group that had tight control of hematocritbelow 45%&mdash;had fewer thromboembolic events, or fewer clotting episodes. This led to fewer deaths from the complications of having those clots.

The main cause of death in polycythemia vera is linked to a thromboembolic event. So, if we follow what this prospective, randomized study showed (that tight control of hematocrit below 45% leads to fewer thromboembolic events, eventually decreasing the risk for death), that&rsquo;s the ultimate goal. We should all be following tight control of hematocrit (45%) as the goal of therapy.

Importance of Hematocrit Control in Polycythemia Vera

Our patient, who is younger than age 60 and has never had a thrombotic episode, is at low risk for thrombosis among the population of patients with polycythemia vera. Our patient was properly started on therapy with low-dose aspirin (81 mg) and phlebotomy with a goal to decrease the hematocrit level to below 45%. Now, a few months later, the patient is back in our office with continuous requirements for phlebotomies and continuous presence of general symptoms. This would be reflective of uncontrolled red blood cell count, or, in other words, uncontrolled polycythemia vera. One needs to remember that we are talking about a person, not just about controlling a number. We control the number to decrease the risk of thrombosis to save the life of the patient but also to improve their quality of life. So, there is a goal to control thrombotic risk. A secondary goal of therapy for polycythemia vera is to control the symptoms.

Despite the phlebotomies, this patient is still symptomatic. In this case, it is very reasonable to say that something else needs to be done. If the phlebotomies are not controlling the symptoms, and the control of the blood cell count does not project into improvement in quality of life, then one needs to think about the introduction of cytoreductive therapy. Cytoreductive therapy is treatment that works to control the blood cell count without allowing the blood cell count to go up and down.

Basically, phlebotomy is introduced when the number is high. Then you lower it. Then it goes up. Then you lower it with phlebotomies. So, it goes up and down and up and down. The symptoms are obviously not very well controlled if you allow a time period when the blood cell count is high. Cytoreductive therapy will level it off and keep the number low all the time. This will likely result in better control of the symptoms. So, in our particular case, although the patient is at low risk for thrombosis, it is reasonable to introduce cytoreductive therapy. I would introduce hydroxyurea as a first-line option.

Initiating Cytoreductive Therapy in Polycythemia Vera

Although we have 2 factors that we use to separate patients in terms of risk for thrombosis (age over 60 and history of thrombosis), there is a possibility that there is a need for introduction of cytoreductive therapy. Let&rsquo;s talk about hydroxyurea as a frontline, first-choice option. Occasionally, there is reason to introduce hydroxyurea as treatment in low-risk patientsyounger patients, like the one in our case. This would be used for uncontrolled symptoms. You may have control of the blood cell count, but you may not have good control of the symptoms. You need to do something about it. Or you need to frequently do a phlebotomy. Maybe the patient is tired of having phlebotomies or is tired of the side effects of treatment. It is also good to mention progressive leukocytosis, meaning an increase in white cell count, or symptomatic thrombocytosis, increasing platelets, or progressive splenomegaly. These are rare but good-to-remember reasons to introduce hydroxyurea as frontline therapy, even in patients who are at low risk for thrombosis&mdash; younger than age 60 and no history of a thrombotic episode. In our case, the patient has uncontrolled symptoms, so it is reasonable to introduce hydroxyurea.

In the United States, by and large, hydroxyurea is the first choice when we talk about introducing cytoreductive therapy in polycythemia vera. Typically, this is given as a 1-pill-a-day regimen (500 mg). There is really no ability to give a 400-mg or 350-mg dose. It&rsquo;s a 500-mg pill, so most doctors will start with 1 pill a day. Then you can increase the number of pills per daynot every day, but the patient may need 2 pills on weekends. You find your way of managing a patient with a 500-mg pill, either by adjusting the number per day or by cutting back. Some people need 1 pill every other day, not every day. So, 1 pill a day would be the usual starting point.

In patients who have really fast-growing cells, meaning that phlebotomy requirement is very high, or in cases where progressive leukocytosis happens, where the white cell count starts to grow, you may even introduce 2 pills a day (1000 mg). It is very reasonable to try 1 or 2 pills, but the point is that not everybody is the same. You need to follow that patient and, in 3 or 4 weeks, reassess to see whether the dose that was prescribed is perhaps too strong or not good enough. You may need to adjust the dose.

The first 3 or 4 months is a time period where one should see the patient who started on hydroxyurea more oftenmaybe every 3 or 4 weeks&mdash;to be able to adjust properly and achieve the goal. The goal is to normalize the blood cell count and eliminate the symptoms.

Using Hydroxyurea in a Patient With Polycythemia Vera

Our young patient was in need of cytoreductive therapy. Hydroxyurea was introduced, and the patient comes in for follow-up. After a few months, he still has uncontrolled symptoms, an uncontrolled red blood cell count, an uncontrolled white cell counthis white cell count is increasing&mdash;and abdominal symptoms from an enlarged spleen. This is a totally uncontrolled case of polycythemia vera.

To step back for a second, what is the goal of therapy? Once you introduce cytoreductive therapy, we talk about 5 different factors. First is to control the red blood cell counta hematocrit level below 45%, which I hope everybody knows about. The second is to control the white cell count. If the white cells are increased, they should be normalized. If the platelets are increased, they should be normalized. If the spleen is increased, that should be normalized. And the symptoms should be controlled.

We usually talk about controlling polycythemia vera by looking at those 5 factors, not only red blood cell count, like in the past. In this particular case, we have no control of the symptoms and no control of the spleen, the white cell count is high, and the red blood cell count is high. This is all happening despite being treated with hydroxyurea. Plus, the patient has side effects from hydroxyurea. Leg ulcers are the most common side effect from hydroxyurea.

Side effects from hydroxyurea are not very common. Perhaps up to 10% of patients have some side effects. In 9 of 10 cases, when we talk about side effects, we see a leg ulcer, usually on a lower area of the leg, that won&rsquo;t heal unless hydroxyurea is stopped. So this is a good reason to stop hydroxyurea. Even with a good control of the blood cell count, if you have side effects, that&rsquo;s not satisfactory. You want to have a safe drug doing the job.

There have been a number of studies, in a retrospective way, in which patients with polycythemia vera were analyzed to see whether an elevated white blood cell count was linked to the risk for thrombosis. By and large, we all agree that this is the case. General guidelines do not currently include increasing white cell count as one of full-fledged thrombotic risk factors. It is still only age over 60 and history of thrombosis.

In our everyday practice, however, we are sensitive to increasing white blood cell count. What would make a white blood cell become accounted for in everyday, national guidelines practice? That would require a prospective randomized study with a goal of controlling the white blood cell count. That is difficult to do, but there is enough evidence to be sensitive to that number. Elevation of the blood cell count would guide one to either modify the dose to control it or, in some cases, to change the therapy.

Assessing Response to Hydroxyurea Treatment

The change in therapy is particularly tricky. What is the cutoff for the white blood cell count to be significant? One would say above normal, which would be above 11. More reasonably, we say progressive leukocytosis, which means a steady increase in white blood cell count over time. We don&rsquo;t really know which number or which cutoff to use to say that it&rsquo;s significant or not. In my own practice, I&rsquo;m sensitive to progressive leukocytosis as a factor that will lead me to introduce cytoreductive therapy, even in a low-risk patient who otherwise has good control of the red blood cell count with phlebotomy.

Progressive leukocytosis, or a steady increase in white blood cell count, is a factor that we use to judge whether there is a need for dose adjustment of cytoreductive therapy or an introduction of cytoreductive therapy, even in the low-risk patient who has a phlebotomy in place with good control of the red blood cell count. You can imagine a case in which phlebotomy does the job of controlling the red blood cell count, but there is a steady increase in white blood cell count from 11 to 15, to 18, to 20. That bothers me as a physician. I would introduce cytoreductive therapy to control the white cell count.

The same can be said for a patient who is already on hydroxyurea. If the hydroxyurea is controlling some of the parameters that we look forred blood cells or platelets or the spleen&mdash;but there is steady progressive leukocytosis, where the white cell count is steadily increasing despite the dose adjustments, that is something that is clinically relevant for me. I would consider a change to second-line therapy.

Switching Therapy in Polycythemia Vera

There are several factors that we consider as resistance to hydroxyurea. Increasing white cell count while on a stable dose of hydroxyurea with inability to increase the hydroxyurea to counteract that increase in white cell count is certainly a sign of progressive disease or a loss of control. When we talk about what the benefit of cytoreductive therapy or hydroxyurea should be, the control of red blood cells, white cells, the spleen, symptoms, and platelets should all be accounted for5 factors. If you don&rsquo;t have that and the factors are progressing while you are on hydroxyurea&mdash;the white cell count is starting to go up, you suddenly need to phlebotomize patients again, the platelets are going up and people are sensitive to that and have symptoms from too many platelets, or the spleen is progressing&mdash;these are signs of hydroxyurea failure or progressive disease. These are factors that would lead one to change therapy.

Once we determine that the patient who is on hydroxyurea needs second-line therapy, ruxolitinib comes to mind. This is approved for patients who are not doing well on hydroxyurea. The starting dose is 10 mg, given twice a day. Unlike its indication in a similar condition, myelofibrosis, where you have a different starting dose based on a patient&rsquo;s platelets, here, in polycythemia vera, everybody starts at 10 mg twice a day.

Why do we start with what you would perhaps say is a lower dose? The maximum dose is 25 mg, given twice a day. We want to be safe. The expectation is that during the first 3 to 4 months, a majority of patients will need more. We analyzed this in the studies that led to its approval. Only about a third of patients stay at 10 mg twice a day. About 60% need more. They may go to 15 mg twice a day or 20 mg twice a day. There are even patients who need 25 mg twice a day. On the other hand, less than 10% of patients need less than 10 mg twice a day, which would be 5 mg twice a day. So, the expectation is that you will need more. That happens during the first 3 or 4 months, but you need to see patients more often.

Ruxolitinib was proved superior as the best available therapy in the second-line setting after hydroxyurea in all aspects that we care about when we talk about polycythemia veracontrol of blood cell count, symptoms, and spleen. There is a durable result. Now that we can follow patients on the phase III randomized studies that led to its approval for much longer (4 or 5 years), we have a good understanding of its overall benefit on quality of life and blood cell count and even in decreasing the thrombotic risk that comes from the safety analysis of those studies. If you have control of the blood cell counts, you will actually control the thrombotic risk. The safety analysis of the studies showed that to be the case.

The medication is very active. It inhibits a biological problem in this condition, which is hyperactivity of the JAK/STAT pathway. This is the pathway that is inside the bone marrow cells that leads to uncontrolled cell growth. We inhibit the growth. We also inhibit inflammation that comes with polycythemia vera. That&rsquo;s why people feel so much better within a month. Anti-inflammatory and antiproliferative effects are seen in a majority of patients with polycythemia vera in the second-line setting, and it&rsquo;s durable and safe.