Targeted deep sequencing in polycythemia vera and essential thrombocythemia

Abstract

Polycythemia vera (PV) is characterized by <i>JAK2</i> and essential thrombocythemia (ET) by <i>JAK2</i>, calreticulin (<i>CALR</i>), and myeloproliferative leukemia virus oncogene (<i>MPL</i>) mutations; we describe the occurrence and prognostic relevance of DNA sequence variants/mutations other than <i>JAK2</i>/<i>CALR</i>/<i>MPL</i>. A myeloid neoplasm-relevant 27-gene panel was used for next-generation sequencing of bone marrow or whole blood DNA and conventional tools were used for analysis. "Adverse variants/mutations" were identified by age-adjusted multivariable analysis of impact on overall, leukemia-free, or myelofibrosis-free survival. Fifty-three percent of 133 Mayo Clinic patients with PV and 53% of 183 with ET harbored 1 or more sequence variants/mutations other than <i>JAK2</i>/<i>CALR/MPL</i>; the most frequent were <i>TET2</i> and <i>ASXL1</i>. "Adverse variants/mutations" in PV included <i>ASXL1</i>, <i>SRSF2</i>, and <i>IDH2</i> and in ET <i>SH2B3</i>, <i>SF3B1</i>, <i>U2AF1</i>, <i>TP53</i>, <i>IDH2</i>, and <i>EZH2</i>; combined prevalence was 15% and 15%, respectively. Adverse variants/mutations were associated with inferior survival in both PV (median, 7.7 vs 16.9 years) and ET (median, 9 vs 22 years) and the effect was independent of conventional prognostic models with respective hazard ratio (95% confidence interval) of 2.8 (1.5-5.1) and 2.6 (1.4-4.8); these observations were validated in 215 Italian patients with PV and 174 with ET. In both Mayo Clinic and Italian cohorts, leukemic or fibrotic progression was also predicted by adverse variants/mutations. Number of mutations did not provide additional prognostic information. We conclude that targeted deep sequencing in PV and ET allows for genetic risk stratification that is independent of clinically derived prognostic models.