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

ABSTRACT 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 × 10 9 /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.