Polycythemia vera (PV) is classified in the group of Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) that also includes essential thrombocythemia (ET) and primary myelofibrosis (PMF). Chronic myelogenous leukemia was historically classified as a MPN, but is now considered a separate entity. PV is an acquired primary clonal polycythemic disorder. Primary polycythemias result from abnormal intrinsic properties of erythroid progenitors that proliferate independently or excessively in response to extrinsic regulators; low serum erythropoietin is their hallmark. PV is the most common primary polycythemia. It arises from mutation(s) of a pluripotent hematopoietic stem cell, which results in excess production of erythrocytes and variable overproduction of granulocytes and platelets. It is often accompanied by splenomegaly. Most patients with PV have a somatic mutation of the Janus-type tyrosine kinase-2 gene (JAK2) that is detectable in blood myeloid cells. The mutation results in constitutive hyperactivity of JAK2 kinase stemming from loss-of-function of its negative regulatory domain. The most common mutation is JAK2V617F, which is present in virtually all cases of PV; a small minority of PV patients have a mutation in other parts of JAK2 (exon 12). The JAK2V617F mutation is also found in many patients with ET and myelofibrosis (MF), albeit at lower frequency (55 percent in ET and 65 percent in MF). As with other clonal hematologic disorders, PV can undergo a clonal evolution to PMF (JAK2V617F-positive) or acute leukemia (either JAK2V617F-negative or positive). In virtually all JAK2V617F-positive PV patients, at least some progenitors exist that become homozygous for the JAK2V617F mutation by uniparental disomy-acquired mitotic recombination. The majority of these progenitors account for the erythropoietin-independent erythroid colonies detected in vitro by clonogenic burst-forming unit–erythroid assay. The JAK2V617F mutation is often not the initial cause of clonal proliferation, but may be preceded by other germline and somatic mutation(s) (e.g., TET2).
Arterial and venous thromboses are a major cause of morbidity and mortality in PV, and a small proportion of patients develop secondary myelofibrosis (sometimes called the spent phase) and/or an invariably fatal acute leukemic transformation. Myelosuppressive therapy has been an effective mode of therapy, with drugs such as hydroxyurea, busulfan, pipobroman, and radioactive phosphorus useful in controlling proliferation of all blood cell lineages. However, while myelosuppressive therapy controls the cellular proliferation and decreases the incidence of thrombotic complications, many of these drugs have leukemogenic potential. In contrast, pegylated interferon-α may lead to complete hematologic remission and restoration of polyclonal hematopoiesis and avoid the leukemogenic complications. Targeted therapy with JAK2 kinase inhibitors is currently being evaluated in clinical trials and, thus far, have been found effective in decreasing the need for phlebotomies, decreasing the number of white cells and splenomegaly, and improving the patient’s quality of life.
Acronyms and Abbreviations
AML, acute myelogenous leukemia; BFU-E, burst-forming unit–erythroid; ECLAP, European Collaboration on Low-Dose Aspirin in Polycythemia Vera; EEC, endogenous erythroid colony; ELN, European Leukemia Net; ET, essential thrombocytosis; HDAC, ...