Characteristics of Polycythemia Vera

Harry Erba, MD, PhD:The chronic myeloproliferative disorders were first classified by William Dameshek around 1950. He was a physician practicing in Boston, and he recognized that there were patients that presented with a constitution of findings that he grouped together. These patients tended to have constitutional symptoms such as fevers, night sweats, and weight loss. They often had splenomegaly, and one of their blood counts might be elevated.

And, at that time, he classified together three myeloproliferative disorders. And those are: polycythemia vera, an elevation of the red blood cell count; chronic myeloid leukemia, an elevation of the white cell count; and essential thrombocythemia (ET), an elevation of the platelet count. Now, since then we have learned that there are other overactive bone marrow syndromes that could be classified with the myeloproliferative disorders, and since these are all known to be driven by somatic mutations, they are now classified as myeloproliferative neoplasms.

Patients with polycythemia vera may have a variety of different symptoms and can present at a variety of different ages. This is a disease that can affect young people in their early 30s or older patients with other significant comorbidities. And the effect of the disease may vary at the time of presentation and over time as the disease evolves. Patients may suffer from symptoms of the disease, such as fevers or night sweats, pruritus (one of the more intractable symptoms), and symptoms related to splenomegaly, such as early satiety or abdominal fullness. Patients may also have thromboembolic disorders or suffer from microvascular circulatory events, such as migraines and erythromelalgia. So, the disease can present and affect patients in a variety of different ways.

So, what was truly prescient about Dameshek’s observation in 1950 is he hypothesized that what we were going to find out about the chronic myeloproliferative disorders is that these were due to overactive signals that govern normal hematopoiesis, and he was exactly right. And we found this out first in 1960 in subsequent studies in CML, chronic myeloid leukemia, showing that this disease is due to activation of the ABL tyrosine kinase. Since then, in 2005, JAK2 mutations were found in patients with other Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms, most commonly seen in polycythemia vera, where about 95% to 96% of patients will have a single activating mutation in the JAK2 tyrosine kinase.

But, the JAK2 mutation, the veiling to phenylalanine switch at codon 617, or V617F, can be found in other myeloproliferative neoplasms, such as ET, and it can be found in chronic myelomonocytic leukemia with thrombocytosis or even acute myeloid leukemia. It’s also been recognized in CML. And so clearly, it’s not just the presence of the specific mutation in JAK2 that drives the phenotype. Yes, it’s important in the pathogenesis of the disease, but we are learning that the phenotype of each of these diseases may depend on other mutations that interact with JAK2 and the sequence in which these mutations are obtained by the myeloid stem cell.

A Patient with Disease Progression on Hydroxyurea

Case 1: