The transition from CHIP to overt myeloproliferative neoplasms: A 13-year longitudinal study of JAK2 positive citizens

Abstract Background: Clonal hematopoiesis is associated with thromboembolic complications as well as an increased risk of progression to hematological malignancies, including myeloproliferative neoplasms (MPN). The prevalence of the JAK2V617F (JAK2) mutation as clonal hematopoiesis of indeterminate potential (CHIP) in the Danish general population is 3.1%. The progression from CHIP to overt MPN is increasingly recognized as a biological continuum; however, the factors influencing this transition and its temporal dynamics remain poorly understood. Aim: The study investigated the risk factors associated with the transition from JAK2 CHIP to MPN and characterized the time course of this progression. Methods This study was based on the Danish General Suburban Population Study, which enrolled 21,205 citizens from January 2010 to October 2013 (baseline). In 2018, JAK2 mutation status was assessed using digital droplet PCR on 19,985 biobanked DNA samples. Of these, 599 citizens had JAK2 CHIP at baseline, including 507 with a variant allele frequency (VAF) <1% and 92 with a VAF ≥1%. The present study includes data from 86 citizens with JAK2 CHIP with a baseline VAF ≥1% of whom 38 progressed to MPN within 13 years from baseline, and 48 who did not progress. 6 were lost to follow-up. Citizens were followed until March 25, 2025. Data included baseline questionnaires, JAK2 measurements and complete blood counts at regular intervals, lifestyle factors, comorbidities, medication usage, and bone marrow biopsies. Statistical analyses were conducted in R version 4.5.0 using mixed-effects models and distributional comparison methods, such as Fisher's exact test and the Wilcoxon rank-sum test. Two-sided p-values <0.05 were considered statistically significant. Results Among the 38 JAK2-positive citizens who progressed to MPN, 19 were diagnosed through screening (“MPN Screening”). The other 19 were diagnosed following referral by their general practitioner (“MPN Referral”) prior to the screening study. The 48 JAK2 CHIP citizens (“CHIP”) used for comparison remained without evidence of MPN by March 25, 2025. Median follow-up time was 12.9 years from baseline and 6.6 years from the date of MPN diagnosis for the incident cases. At baseline, no risk factors including sex, lifestyle, or comorbidities differed significantly between groups. However, citizens in the CHIP group were significantly older (median 65.0 years, p = 0.003) than those in the Screening (57.3 years) and Referral (62.3 years) groups. The median baseline VAF was lowest in the CHIP group (2.5%), slightly higher in the Screening group (4.5%), and highest in the Referral group (13.9%) (p = 4.9 × 10-5). The CHIP group also had significantly lower platelet counts (median 295.0 × 109/L, p = 0.0006) and leukocyte counts (median 7.2 × 109/L, p = 0.003) at baseline compared to the Screening group (median 363.0 and 8.3 × 109/L) and the Referral group (median 433.0 and 8.7 × 109/L). A mixed effects model showed a non-significant annual VAF increase of 0.2% in the CHIP group, while significant increases were observed in the Screening group (1.2% per year, p = 2.7 × 10⁻7) and the Referral group (4.7% per year, p < 2 × 10⁻16). At the time of MPN diagnosis, both erythrocyte and platelet counts were significantly elevated in the MPN Referral group compared to the MPN Screening group (p = 0.02 and 0.02). The distribution of MPN subtypes - essential thrombocythemia, polycythemia vera, and primary myelofibrosis - was comparable across the two groups (p = 0.9). The JAK2 VAF at diagnosis was significantly lower in the MPN Screening group, with a median of 13% (interquartile range [IQR] 7.8-30%), compared to 36.6% in the MPN Referral group (IQR 26-46.5%, p = 0.01). Notably, 78.9% of citizens in the MPN Screening group had bone marrow fibrosis grade 0, while 15.8% of the Referral group had fibrosis grade 0 (p = 7.7 × 10-5). In each group, only one individual had primary myelofibrosis. The proportion of citizens with at least one thromboembolic event prior to diagnosis was 26.3% in the MPN Screening group and 36.8% in the MPN Referral group (p = 0.4). Conclusion Although no clear risk factors for progression from JAK2 CHIP to MPN were identified, the study suggests that screening citizens with JAK2 CHIP facilitates earlier diagnosis of the disease. These findings support the potential value of early detection strategies to reduce fibrotic bone marrow progression and thromboembolic events associated with MPN.