Polycythaemia rubra vera (PRV)

Polycythemia vera (PV) has been recognized as the main cause of primary erythrocytosis (1).

In polycythaemia rubra vera, as with all myeloproliferative disorders, there are excess granulocytic, and megakaryocytic elements, all derived from a single multipotent stem cell (neutrophilia in approximately two-thirds and thrombocytosis in 50% of PV cases can be seen) (1)

However, in polycythaemia vera the erythroid precursors dominate, and hence there is an absolute increase in red cell mass and blood volume. In polycythaemia rubra vera the erythroid offspring are unusual in being sensitive eg to insulin-like growth factor ± interlukin-3 - they are also do not require erythropoietin to avoid apoptosis (programmed cell death).

Polycythaemia rubra vera presents at an average age of 60 years (1). Annual incidence may vary widely between 0.2/100,000/year to a highest of 28/100,000/year (in Goteborg, Sweden) (1)

Haematocrit (Hct) values may be underestimated in iron deficient anaemia and may result in masking of polycythaemia vera (1).

Polycythaemia vera is a myeloproliferative neoplasm known to be associated with dysregulated signalling of the Janus associated kinases JAK1 and JAK2.

The identification of JAK2 mutations in almost all PV patients has revolutionised the diagnosis of PV. The JAK2 V617F mutation can be found in over 95% of PV patients (and an exon 12 mutation in most remaining patients)

• testing for JAK2 V617F in peripheral blood is sensitive and bone marrow samples are not required to identify this
• testing for JAK2 V617F is advised as a stage 1 investigation and should confirm the diagnosis the vast majority of PV patients

Recommended diagnostic criteria for PV:

JAK2-positive polycythaemia vera (requires both criteria)

• A1 High haematocrit (> 0.52 in men, > 0.48 in women) OR raised red cell mass (>25% above predicted)
• A2 Mutation in JAK2

JAK2-negative polycythaemia vera (requires A1-A4 plus another A or two B criteria) *

• A1 Raised red cell mass (>25% above predicted) OR haematocrit >=0.60 in men, >=0.56 in women
• A2 Absence of mutation in JAK2
• A3 No cause of secondary erythrocytosis
• A4 Bone marrow histology consistent with polycythaemia vera
• A5 Palpable splenomegaly
• A6 Presence of an acquired genetic abnormality (excluding BCR-ABL1) in the haematopoietic cells
• B1 Thrombocytosis (platelet count >450 x 10^9/l)
• B2 Neutrophil leucocytosis (neutrophil count >10 x 10^9/l in non-smokers, >=12.5 x 10^9/l in smokers)
• B3 Radiological evidence of splenomegaly
• B4 Low serum erythropoietin

*This is a very rare clinical entity

Pegylated interferon formulations have overall shown similar efficacy to hydroxyurea (3)

• interferons are a reasonable cytoreductive alternative to hydroxyurea, and are recommended for first-line consideration in younger patients and pregnant women

NICE stated that

• ruxolitinib is recommended, within its marketing authorisation, for treating polycythaemia vera in adults who cannot tolerate hydroxycarbamide (also called hydroxyurea) or when the condition is resistant to it

Ruxolitinib is an orally available small-molecule tyrosine kinase inhibitor that is a potent and selective inhibitor of JAK1/JAK2

Reference:

• McMullin MF. The classification and diagnosis of erythrocytosis. Int J Lab Hematol. 2008;30(6):447-59
• McMullin MF et al. A guideline for the diagnosis and management of polycythaemia vera. A British Society for Haematology Guideline.British Journal of Haematology, 2019, 184, 176-191
• How J, Hobbs G. Use of Interferon Alfa in the Treatment of Myeloproliferative Neoplasms: Perspectives and Review of the Literature. Cancers (Basel). 2020;12(7):1954. Published 2020 Jul 18. doi:10.3390/cancers12071954
• NICE (October 2023). Ruxolitinib for treating polycythaemia vera