Polycythaemia vera (PV)

  • Method:
  • Anticoagulant:
  • Recommendation:
  • Method:
    Cytomorphology
  • Anticoagulant:
    EDTA
  • Recommendation:
    obligatory
  • Method:
    Immunophenotyping
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    facultative
  • Method:
    Chromosome analysis
  • Anticoagulant:
    Heparin
  • Recommendation:
    obligatory
  • Method:
    FISH
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    facultative
  • Method:
    Molecular genetics
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    obligatory

Based on the current guidelines and the current state of research, there are different diagnostic recommendations for patients with polycythemia vera. We have summarized the most important information on classification and diagnostic methods at the MLL. In addition, we provide further literature and links on prognosis and therapy in polycythemia vera, so that you can inform yourself in more detail.

Polycythemia vera: Classification

Polycythemia vera (PV) is one of the myeloproliferative, BCR::ABL1-negative neoplasms (MPN). Usually, panmyelosis is present in PV. Nevertheless, PV is characterized by a predominant proliferation of erythrocytes, which is why secondary erythrocytosis (e.g., reactive polyglobulia due to stress, smoking, cardiac causes, and infections) should always be excluded for differential diagnosis. The PV variant with exclusive proliferation of the red cell line is called polycythemia vera rubra, but occurs very rarely. The subset of PV formerly referred to as the "masked" form of PV, which has lower hemoglobin and hematocrit values than the form originally defined in WHO 2008 (Barbui et al. 2014) is categorized as MPN, NOS according to the new WHO 2022.

Clinically, polycythemia vera is divided into 2 phases (WHO 2022):

  • Chronic phase (pre-polycythemic and polycythemic phase): Overproduction of erythrocytes and associated elevated hemoglobin and hematocrit levels
  • Late phase (post-PV myelofibrosis): Transition of the disease into secondary myelofibrosis

Table 1: WHO diagnostic criteria for polycythemia vera (WHO 2022)

According to the WHO classification, the diagnosis of polycythemia vera requires either all three major criteria or the first two major criteria and the minor criterion.

Major criteria:

  • Elevated hemoglobin concentration (♂: >16.5 g/dL, ♀: >16g/dL) or elevated hematocrit (♂: >49%*, ♀: >48%).
  • Bone marrow biopsy showing age-adjusted hypercellularity with trilineage growth (panmyelosis), including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size)**.
  • Presence of JAK2 V617F or JAK2 exon 12 mutation

Minor criterion:

  • Subnormal serum erythropoietin level

* Hematocrit for diagnosis in the absence of a JAK2 mutation. A higher hematocrit target could be considered (e.g., 0.52) in men before further investigation may be required.

** Major criterion 2 (bone marrow biopsy) may not be required in patients with sustained absolute erythrocytosis (hemoglobin concentrations of >18.5g/dL in men or >16.5g/dL in women or hematocrit values of >0.555 in men or >0.495 in women), if major criterion 3 and the minor criterion are present.


The clinical differentiation of PV within the myeloproliferative neoplasms is based, among other things, on the detection of clonal erythrocytosis according to the WHO classification 2022 (Table 1). Currently, however, there are no specific disease markers, molecular or otherwise, that unequivocally diagnose polycythemia vera, which is why a diagnosis should always be made on the basis of a combination of clinical and bone marrow histological findings.

After a median observation period of 10 years, the rate of leukemic transformation of PV patients is approximately 2.3-14.4%, and 5.5-18.7% after 15 years.

Table 2: Selected risk factors for leukemic transformation (WHO 2022)

Age

Leukocytosis

  • Leukocyte count ≥ 15 x 10 /L9
  • Leukocyte count > 13 x 10 /L9

Aberrant karyotype

  • Most common: del(20q), +9, +8, double anomalies, complex karyotype (≥3 aberrations involving chromosomes 1, 5, 7, and 9).

Cytoreductive agents

  • Pipobroman,32 P, chlorambucil

Mutations

  • SRSF2, IDH2, RUNX1
  • TP53
  • ASXL1, SRSF2; IDH1, IDH2
  • Acquisition of one or more additional mutations during the chronic phase

Polycythemia vera: Diagnostic methods

Polycythemia vera: Prognosis and therapy

Due to strong variation, risk factors affecting survival expectancy should be assessed individually for each patient to the greatest extent possible. Untreated patients with polycythemia vera show an extremely shortened life expectancy (1.5 years) compared to that of treated patients (median survival between 14 and 19 years) (Tefferi & Barbui 2019).

The risk stratification for the therapy decision is based on the risk of thrombosis. The risk factors for this are age (≥ 60 years) and previous thromboembolism. Prognostic models are predominantly based on clinical data (Bonicelli et al. 2013, Tefferi et al. 2013, Vannucchi et al. 2018) However, because patients are primarily at risk for disease progression toward secondary myelofibrosis (SMF), a "Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM)" was developed by Passamonti's group (Passamonti et al. 2017). An aberrant karyotype and mutations in the SRSF2 gene, among others, are included in the MIPSS-PV (mutation-enhanced international prognostic score) in the calculation of risk (Tefferi et al. 2020, Tefferi & Barbui 2023). High JAK2 V617F variant allele frequency (VAF) is also considered a prognostic negative factor for overall survival (Kanduła et al. 2023), which also influences thrombosis risk and progression (Zhang et al. 2020, Moliterno et al. 2023, Tefferi & Barbui 2023).

The main goals of therapy are to reduce the risk of thrombosis, to control clinical symptoms, and to delay or prevent myelofibrosis, MDS, or acute leukemia. An overview of therapeutic options is provided in the Onkopedia guideline Polycythemia vera. In a summary by How et al. there is also a review of selected therapeutics already approved or in clinical development for MPNs (How et al. 2023).

Polycythemia vera: Recommendation

In addition to the collection of clinical and laboratory parameters, histological and cytomorphological examination of bone marrow and blood, cytogenetic analysis, and molecular genetic studies are recommended (JAK2 V617F mutation, if negative exon 12 of the JAK2 gene, if negative CALR and MPL and "non-driver" mutations should also be investigated).

Status: November 2023

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