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Non-JAK2 mutations, particularly in SRSF2, ASXL1, and IDH2, were independently associated with worse survival outcomes in polycythemia vera, supporting their incorporation into future prognostic models. 

The research study published in the May 2025 issue of American Journal of Hematology examined the prevalence and prognostic impact of non-JAK2 mutations in individuals with polycythemia vera (PV).  

They performed an NGS on 319 individuals diagnosed with PV. Among these, 270 participants (85%) were evaluated either at diagnosis or during the chronic phase of PV (Group A: N = 270, 85%). Additionally, 37 individuals (12%) were assessed during fibrotic transformation (Group B; N = 37, 12%), and 12 individuals (4%) were evaluated at the time of leukemic transformation (Group C; N = 12, 4%).  

The results showed significantly different mutation frequencies for TP53, SRSF2, IDH1, and U2AF1 (P< 0.05) across Group A (2%/4%/2%/0.4%), Group B (8%/0%/0%/5%), and Group C (50%/25%/17%/8%). Phenotype–genotype and survival analyses—covering overall survival (OS), leukemia-free survival (LFS), and myelofibrosis-free survival (MFFS)—were restricted to Group A patients. ASXL1^MUT correlated with younger age (P< 0.01), SRSF2^MUT with older age and leukocytosis (P< 0.01), and TP53^MUT with leukocytosis (P< 0.01). Mutation co-segregation occurred between ASXL1 and IDH2 (P< 0.01), ASXL1 and SRSF2 (P< 0.01), SRSF2 and IDH2 (P< 0.01), and TP53 and NRAS (P= 0.01). Multivariable analysis identified risk factors for OS, including SRSF2^MUT (P< 0.01; HR, 4.2; 95%CI, 1.9–9.5), IDH2^MUT (P= 0.01; HR, 5.3; 95% CI, 1.8–15.3), ASXL1^MUT (P= 0.04; HR, 2.0; 95% CI, 1.1–3.7), leukocyte count ≥ 15 × 10⁹ /L (P< 0.01; HR, 2.0; 95% CI, 1.3–3.1), and older age (P< 0.01). Median OS was 8.8 years for those with adverse mutations (N = 235; 87%) and 17.8 years for those without (N = 35; 13%) [P= 0.01; HR, 1.8; 95% CI, 1.1–2.9]. ASXL1^MUT (P= 0.02; HR, 1.6–24.9), SRSF2^MUT (P= 0.06; HR, 11.9; 95% CI, 1.1–126.2), and older age (P= 0.04) were associated with inferior LFS. SRSF2^MUT (P< 0.01; HR, 24.0; 95% CI, 5.5–103.8) and abnormal karyotype (P< 0.01; HR, 3.8; 95% CI, 1.6–8.9) were linked to worse MFFS. The total count of non-JAK2 mutations influenced outcomes in univariate but not multivariable analysis.  

Investigators concluded that non-JAK2 mutations held prognostic relevance in PV and warranted consideration in future risk stratification models. 

Source: onlinelibrary.wiley.com/doi/10.1002/ajh.27717