Abstract
Polycythemia vera (PV) is mainly characterized by elevated blood cell counts, thrombotic as well as hemorrhagic predisposition, a variety of symptoms, and cumulative risks of fibrotic progression and/or leukemic evolution over time. Major changes to its diagnostic criteria were made in the 2016 revision of the World Health Organization (WHO) classification, with both hemoglobin and hematocrit diagnostic thresholds lowered to 16.5 g/dL and 49% for men, and 16 g/dL and 48% for women, respectively. The main reason leading to these changes was represented by the recognition of a new entity, namely the so-called “masked PV”, as individuals suffering from this condition have a worse outcome, possibly owing to missed or delayed diagnoses and lower intensity of treatment. Thrombotic risk stratification is of crucial importance to evaluate patients’ prognosis at diagnosis. Currently, patients are stratified into a low-risk group, in the case of younger age (<60 years) and no previous thromboses, and a high-risk group, in the case of patients older than 60 years and/or with a previous thrombotic complication. Furthermore, even though they have not yet been formally included in a scoring system, generic cardiovascular risk factors, particularly hypertension, smoking, and leukocytosis, contribute to the thrombotic overall risk. In the absence of agents proven to modify its natural history and prevent progression, PV management has primarily been focused on minimizing the thrombotic risk, representing the main cause of morbidity and mortality. When cytoreduction is necessary, conventional therapies include hydroxyurea as a first-line treatment and ruxolitinib and interferon in resistant/intolerant cases. Each therapy, however, is burdened by specific drawbacks, underlying the need for improved strategies. Currently, the therapeutic landscape for PV is still expanding, and includes several molecules that are under investigation, like long-acting pegylated interferon alpha-2b, histone deacetylase inhibitors, and murine double minute 2 (MDM2) inhibitors.
Highlights
Polycythemia vera (PV), together with essential thrombocythemia (ET) and myelofibrosis (MF), belongs to the so-called “classic” BCR-ABL1-negative myeloproliferative neoplasms (MPN), a heterogeneous group of diseases, characterized by the clonal expansion of an abnormal hematopoietic stem/progenitor cell
Compared with both ET and MF, PV is molecularly more homogeneous, being driven by JAK2 mutations in virtually all cases [2]; about 97% of such mutations are represented by JAK2V617F, which results from a somatic G to T mutation involving JAK2 exon 14, leading to a nucleotide change at position 1849 and the substitution of valine to phenylalanine at codon 617 [3]
A subsequent hazard ratio (HR)-based risk point allocation allowed the development of a three-tiered mutation-enhanced international prognostic system (MIPSS) whose performance was shown to be superior to other conventional scoring systems [39]
Summary
Polycythemia vera (PV), together with essential thrombocythemia (ET) and myelofibrosis (MF), belongs to the so-called “classic” BCR-ABL1-negative myeloproliferative neoplasms (MPN), a heterogeneous group of diseases, characterized by the clonal expansion of an abnormal hematopoietic stem/progenitor cell. Adverse variants/mutations, in terms of overall (OS), leukemia-free (LFS), or myelofibrosis-free survival, included ASXL1, SRSF2, and IDH2, with a combined prevalence of 15% The latter were associated with an inferior OS (median, 7.7 versus 16.9 years) and their effect was independent of other conventional prognostic models. In a large cohort of 906 molecularly-annotated patients, including 404 with PV, adverse mutations occurred in 8 (2%) PV patients and multivariable analysis identified spliceosome mutations (SRSF2) to adversely affect OS They suggested the independent survival effect of adverse mutations, age >67 years, leukocyte count ≥15 × 109/L, and previous thromboses in PV. A subsequent hazard ratio (HR)-based risk point allocation allowed the development of a three-tiered mutation-enhanced international prognostic system (MIPSS) whose performance was shown to be superior to other conventional scoring systems [39]
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