Active Surveillance of JAK2V617F Clonal Hematopoiesis Toward Myeloproliferative Neoplasms

The aim was to characterize longitudinal JAK2V617F (JAK2) variant allele frequency (VAF) trajectories in individuals without MPN undergoing active surveillance, and to assess whether MPN can be detected at an earlier stage, resulting in lower clonal burden and less bone marrow fibrosis. In the Danish General Suburban Population Study (N=19,958, 2010-2013), we used retrospective measurement of JAK2 on biobanked samples in 2016-2017 and identified 92 JAK2-positive individuals with VAF≥1% that were without MPN at baseline in 2010-2013. Of these, 20 were diagnosed with MPN by clinical referral between 2010-2018. The remaining 72 were reinvited for active MPN surveillance (2018-2026), of whom 61 are included in the present study. Longitudinal JAK2 VAF was quantified using droplet digital PCR, and mixed-effects models were used to estimate clonal growth and blood cell trajectories. Median follow-up to MPN diagnosis was 7.4 years. Referral-diagnosed MPN cases exhibited a relative clonal growth rate of 34.3% per year (p<0.001). Among the 61 undergoing surveillance, 20 were diagnosed with MPN, exhibiting a relative clonal growth rate of 12.7% per year (p=0.003), whereas the remaining 41 did not develop MPN nor showed VAF progression (p=0.628). Within-individual and between-individual variance in VAF was 4.9% and 95.1%, respectively. Platelet counts increased 10.3×10⁹/L/year for surveillance-detected MPN and 44.5×10⁹/L/year for referral-diagnosed MPN. Surveillance-detected MPN had lower VAF at diagnosis (median 13.0% vs 41.3%) and less bone marrow fibrosis (grade 0: 80% vs 15%) than referral-diagnosed MPN. Active surveillance detects MPN with lower clonal burden and less bone marrow fibrosis.