P221 | Low Jak2v617f Allelic Burden in Myeloproliferative Neoplasms: Diagnostic Challenges From a Clinical and Molecular Standpoint
Year: 2025
Type: article
Abstract: The identification of the JAK2V617F mutation is pivotal in diagnosing myeloproliferative neoplasms (MPNs). Clinically, a variant allele frequency (VAF) above 2% is typically considered positive- a threshold also used in defining Clonal Hematopoiesis of Indeterminate Potential (CHIP). However, per WHO/ICC guidelines, high-sensitivity techniques are recommended for detecting JAK2V617F mutations with VAFs below 1%. Despite these advances, interpretation remains challenging, particularly as low-burden mutations can also be found in individuals without hematological disease, and no definitive cut-off has been established for MPN diagnosis. This study aimed to evaluate the clinical and molecular profiles of patients referred for suspected MPN with JAK2V617F VAF <2%. A cohort of 55 patients (median age 64 years, range 15–86) was assessed for erythrocytosis (n=31) or thrombocytosis (n=24). Mutation analysis was performed using quantitative PCR (ipsogen® JAK2MutaQuant®, LoD 0.0014%). Median JAK2V617F VAF at diagnosis was 0.354%, higher in thrombocytosis than erythrocytosis cases (0.451% vs. 0.25%, p=0.047). Median erythropoietin level was 5.4 mU/mL, with 51% of polycythemic patients showing reduced levels. At initial testing, none met MPN diagnostic criteria. During follow-up, 4 cases of polycythemia vera (PV), 1 pre-fibrotic myelofibrosis (PMF), and 7 essential thrombocythemia (ET) diagnoses were established. CALR mutations were found in 3 thrombocytosis patients, all meeting ET criteria. The median follow-up was 31.7 months; the JAK2 clone remained detectable and below 2% in all cases. The median interval from JAK2 detection to MPN diagnosis was 21.06 months. Patients who developed MPNs had significantly higher initial VAFs than those who did not (0.532% vs. 0.24%, p=0.02). Seventeen patients (30.9%) experienced thrombotic events—8 myocardial infarctions, 2 critical limb ischemias, 2 pulmonary embolisms, 2 portal vein thromboses, and 3 lower limb venous thromboses. Thrombosis occurred irrespective of MPN diagnosis, but was significantly associated with higher JAK2V617F VAF (0.44% vs. 0.23%, p=0.038). In summary, comprehensive evaluation of patients with low JAK2V617F VAF (<2%) led to an MPN diagnosis in 21.8% of cases. Importantly, a low allelic burden was associated with elevated thrombotic risk, independent of formal MPN diagnosis. These findings underscore the need for longitudinal studies to improve diagnostic precision and risk stratification in this patient population.
Authors: E. Morsia, D. Lame, M. Pianelli, S. Mancini, S. Rupoli, A. Poloni.
Institution: Marche Polytechnic University
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7093121297
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