Polycythaemia vera: molecular genetics, diagnostics and therapeutics

Abstract

Polycythaemia vera is one of several classical myeloproliferative neoplasms that may occur in a juvenile onset or late-onset adult forms. It is linked to specific genetic mutations that cause a deleterious elevation in the patient's red cell mass. The discourse on genetics includes an exposé on the molecular biology of the disease and how a shared JAK2 V617F mutation can co-exist among three distinct neoplasms. Concepts of genetics and immunology help define the origin and behaviour of the disease: the tracking of allele burdens of mutations (genetic dosage), the timing or order of acquired mutations, the import of bystander mutations and the onco-inflammatory response; all theories are invoked to explain the progression of disease severity and potential transformational leukaemia. The World Health Organization's diagnostic criteria are accessed to focus on the subtleties of the Hb laboratories and sifting through the challenging listing of differential diagnoses that mimic PV, and our report includes an overview of manual and automated phlebotomy (erythrocytapheresis) procedures, enumerating their clinical indications, significance of temporary phlebotomy resistance and optimizing safety/ efficacy, quality and cost. Stratification of low and high-risk disease distinguishes when to commence chemo-cytoreductive therapy in the high-risk patient to prevent thrombotic complications. Drug resistance is circumvented by artfully switching drugs or using novel drug designs.

Keywords: JAK inhibitors; JAK2 V617F mutations; myeloproliferative neoplasms; paediatric/juvenile/adult polycythemia vera; tyrosine kinase inhibitors.