From essential thrombocythemia to polycythemia vera (ET-2-PV): rationale and design of a multicenter ELN study

Essential thrombocythemia (ET) and polycythemia vera (PV) are traditionally viewed as distinct Philadelphia chromosome–negative myeloproliferative neoplasms, yet both frequently harbor the JAK2V617F mutation, suggesting a biological continuum. Occasional reports describe progression from JAK2-mutated ET to overt PV, but this evolution has never been systematically studied. We present the background and design of ET-2-PV, an international, multicenter, retrospective observational study conducted by the Mayo Clinic and European referral centers. Approved by the Lombardy Territorial Ethics Committee and registered at ClinicalTrials.gov (NCT07203768), it includes patients initially diagnosed with JAK2V617F-positive ET according to 2022 ICC criteria who, after at least one year, newly fulfill diagnostic criteria for PV—minimizing misclassification. The study employs two analytical frameworks: (1) a nested case–control analysis comparing ET-to-PV cases with matched JAK2-mutated ET controls without progression to identify clinical, proliferative, and molecular predictors of progression; and (2) a retrospective cohort comparison assessing outcomes of ET-to-PV patients versus matched individuals with de novo PV. The primary objective is to define the clinical and biological significance of phenotypic evolution from JAK2-mutated ET to PV and its prognostic impact. Secondary aims include identifying risk factors for progression, characterizing clonal dynamics, and determining whether PV arising after long-standing ET differs from de novo PV in vascular risk, disease evolution, and survival. By integrating molecular data with robust epidemiologic design, ET-2-PV aims to define phenotypic evolution from ET to PV as a distinct and clinically meaningful entity, informing risk-adapted monitoring and therapeutic strategies.