Harry P. Erba, MD, PhD: Let’s move on now and talk specifically about one of the myeloproliferative neoplasms, and that’s polycythemia vera. We’re going to start with making the diagnosis. Srdan, how do these patients typically present? What are their signs and symptoms, and what should be part of the initial evaluation of these patients?

Srdan Verstovsek, MD, PhD: Polycythemia vera, as the name implies, means that all the cells are growing without control, but we are talking really about erythrocytosis. This is the unique underlying feature of this particular MPN, and it’s present in everybody, provided there is enough iron. We already said that some patients don’t have an extraordinarily high erythrocytosis because they already have iron deficiency at presentation. Because of too many cells in the blood circulation, about half of patients, about 40% to 60%, will have high white cells and high platelets. You have too many cells and circulation is impaired, so you have a multitude of symptoms ranging from fatigue, blurred vision, headaches, and shortness of breath. Then, you have skin involvement with some itching and sensitivity. You have systemic symptoms from impaired circulation. You can also have abdominal symptoms from an enlarged spleen. It is something people develop slowly over time that leads them to a doctor to complain, where they are found to have an abnormal blood cell count on the regular CBC test.

This comes with an increased risk of thrombosis, and we’ll talk about it. A number of patients present, even at this time and age, with an event. They present with a clotting event upfront, undiagnosed, and they are diagnosed at the time of having their event. They’re hospitalized for a clot in the leg or in the lungs, and then they are actually recognized to have a blood disorder that predisposes the clot. That may be 25% to 30% of patients still presenting with the event itself. That is actually the major issue with this disease: impaired circulation and increased risk of thrombosis. The therapies that we have and prognostication that we have in place are all aimed to address the thrombotic risk that comes with the disease.

In terms of risk assessment, once we are done with the diagnostic process—the diagnostic process would include erythrocytosis—we would test in blood or in bone marrow, but blood is equal to bone marrow for the JAK2 V617F mutation. We would look at the bone marrow biopsy to see panmyelosis with increased erythrocytes and the granulocytes. The bone marrow would be tested for the JAK2 mutation, high hemoglobin, and hematocrit. You can also look at erythropoietin in the blood, which is one of the minor criteria, as it will be low because the bone marrow does not need to produce it anymore. That’s a growth factor for the red blood cells. Putting these diagnostic criteria together, you are confident to have PV.

The next question, which I mentioned already, is what is the thrombotic risk? Traditionally, we have 2 factors that would determine how we act: that patient with PV is 60 years of age or older or has a history of blood clotting. If you are one or the other, you are a patient with PV with a high risk of blood clotting. If you are neither of the 2, then you are at low risk for blood clotting. There are some other factors that we can talk about, and we should, like white blood cell count. Maybe there is a role for monitoring white blood cell count, cautiously. But 2 factors, age and history of thrombosis, will divide the patients into 2 groups. If you are at low risk, you receive phlebotomy and baby aspirin. If you are at high risk, you receive phlebotomy and baby aspirin, and you start cytoreductive therapy to decrease or normalize the blood cell count, eliminating the need for phlebotomy and maintaining patients at low levels all the time, without spikes, to decrease the thrombotic risk.

Harry P. Erba, MD, PhD: Let me challenge some of these things. In the new WHO criteria for diagnosing PV, the threshold for diagnosis has been lowered to a hemoglobin of 16.5 g/dL for men and 16 g/dL for women to pick up on this polycythemia vera. But will a clinician out there be at risk if they have a patient who normally has a high hemoglobin and they don’t perform a bone marrow biopsy or a JAK2 mutation test? How do you decide who you’re going to do that evaluation on? Is it everyone, or just the ones who have the symptoms?

Srdan Verstovsek, MD, PhD: This is a really important question, and it extends to the other side of the coin. Is all this workup absolutely necessary if it’s obvious that it’s PV? In cases where you would normally have high hemoglobin or hematocrit, as you properly said, the threshold for diagnosis has been lowered to normal levels. It would be 16 g/dL for women and 16.5 g/dL for men, so why not then test anybody who is above those numbers? But you have to have a suspicion for polycythemia vera. That is the clinician’s input here, otherwise anybody can do it just based on the numbers. You have to have symptoms. You may have high white cells or high platelets. You may have a low MCV (mean cell volume), which would probably suggest iron deficiency. There must be something other than the number of red blood cells, a hemoglobin or hematocrit above 17. Otherwise, everybody would be testing for PV, but it’s expensive and unnecessary. There needs to be a clinical suspicion. On the other hand, to flip the coin, if you have obvious erythrocytosis or a hematocrit of 20, you have a JAK2 mutation on blood analysis, or you have low erythropoietin and low MCV with iron deficiency, why do you need the bone marrow biopsy? You probably don’t.

Transcript Edited for Clarity