The Mutational Landscape in Polycythemia Vera: Phenotype, Genotype, and Prognostic Correlates

Polycythemia vera (PV) is invariably associated with a JAK2 mutation, with over 50% of patients harboring additional non-JAK2 mutations. In the current study, 319 patients with PV underwent NGS at diagnosis or in chronic phase PV (Group A: N = 270, 85%) or at the time of fibrotic (Group B; N = 37, 12%) or leukemic (Group C; N = 12, 4%) transformation. Mutational frequencies involving TP53/SRSF2/IDH1/U2AF1 were significantly (p < 0.05) different between patients in the mutually exclusive Groups A (2%/4%/2%/0.4%), B (8%/0%/0%/5%), and C (50%/25%/17%/8%). Analyses on phenotype/genotype associations and prognostic impact on overall (OS), leukemia-free (LFS), and myelofibrosis-free (MFFS) survival were limited to Group A patients. ASXL1^MUT was associated 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 was apparent between ASXL1 and IDH2 (p < 0.01) or SRSF2 (p < 0.01), SRSF2 and IDH2 (p < 0.01), and TP53 and NRAS (p = 0.01). Multivariable analysis identified SRSF2^MUT (p < 0.01; HR, 4.2, 1.9-9.5), IDH2^MUT (p = 0.01; HR, 5.3, 1.8-15.3), ASXL1^MUT (p = 0.04; HR, 2.0, 1.1-3.7), leukocyte count ≥ 15 × 10⁹/L (p < 0.01; HR 2.0, 1.3-3.1), and advanced age (p < 0.01) as risk factors for OS. Median OS in the presence (N = 235; 87%) or absence (N = 35; 13%) of any adverse mutation (i.e., SRSF2^MUT, ASXL1^MUT, or IDH2^MUT) was 8.8 versus 17.8 years (p = 0.01; HR 1.8, 1.1-2.9). In addition, ASXL1^MUT (p = 0.02; HR, 1.6-24.9), SRSF2^MUT (p = 0.06; HR, 11.9, 1.1-126.2), and advanced age (p = 0.04) were associated with inferior LFS, and SRSF2^MUT (p < 0.01; HR, 24.0, 5.5-103.8) and abnormal karyotype (p < 0.01; HR 3.8, 1.6-8.9) with inferior MFFS. The number of non-JAK2 mutations was significant in predicting outcome in univariate but not multivariable analysis. The observations from the current study highlight the prognostic significance of non-JAK2 mutations in PV and the prospect of their inclusion in future prognostic models.