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Polycythemia vera (PV) is classified in the group of Philadelphia chromosome–negative myeloproliferative neoplasms (MPN) that also includes essential thrombocythemia (ET) and primary myelofibrosis (PMF). PV is an acquired primary clonal disorder. Primary polycythemias result from abnormal intrinsic properties of erythroid progenitors that proliferate independently (or excessively) of extrinsic regulators such as erythropoietin; low serum erythropoietin is their hallmark. 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. Almost all 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 JAK2,V617F which is present in the vast majority of cases; a small minority of patients with PV have a mutation in other parts of JAK2 (exon 12). The JAK2V617F mutation is also found in many patients with ET and PMF, albeit at lower frequency; 55% in ET and 65% in PMF. 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 (BFU-E). The JAK2V617F mutation is often not the initial cause of clonal proliferation but may be preceded by other germline and somatic mutation(s) (eg, TET2).

Arterial and venous thromboses are a major cause of morbidity and mortality in PV, and a smaller 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 (HU), busulfan, pipobroman, and radioactive phosphorus useful in controlling proliferation of all blood cell lineages and decreasing the incidence of thrombotic complications. In contrast, pegylated interferon-α may lead to complete hematologic remission and restoration of polyclonal hematopoiesis in some patients. Targeted therapy with JAK2 kinase inhibitors has been found effective in decreasing the need for phlebotomies, decreasing the white cell count and splenomegaly, and improving the patient’s quality of life, without selective inhibition of the PV clone.

Acronyms and Abbreviations

AML, acute myelogenous leukemia; BFU-E, burst-forming unit–erythroid; CALR, calreticulin; CHIP, clonal hematopoiesis of undetermined prognosis; ECLAP, European Collaboration on Low-Dose Aspirin in Polycythemia Vera; EEC, endogenous erythroid colonies; ELN, European Leukemia Net; EPO, erythropoietin; ET, essential thrombocytosis; HDAC, histone deacetylase; HU, hydroxyurea; IFN-α, interferon-α, IWG-MRT, International Working Group for Myeloproliferative Neoplasms Research and Treatment; JAK2, Janus-type tyrosine kinase 2; LNK, lymphocyte adaptor protein; MDS, myelodysplastic syndrome; MF, myelofibrosis; ...

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