Targeted deep sequencing in polycythemia vera and essential thrombocythemia

Abstract

Key Points• More than half of patients with PV or ET harbor DNA mutations/ variants other than JAK2/CALR/MPL.• The presence of some of these mutations adversely affects overall, leukemia-free, or myelofibrosis-free survival.Polycythemia vera (PV) is characterized by JAK2 and essential thrombocythemia (ET) by JAK2, calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) mutations; we describe the occurrence and prognostic relevance of DNA sequence variants/mutations other than JAK2/CALR/MPL. A myeloid neoplasm-relevant 27-gene panel was used for nextgeneration 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 JAK2/CALR/MPL; the most frequent were TET2 and ASXL1. "Adverse variants/mutations" in PV included ASXL1, SRSF2, and IDH2 and in ET SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2; 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.

Calreticulin variant stratified driver mutational status and prognosis in essential thrombocythemia

“…It is important to note that the latter effect was independent of anemia, which is another independent risk factor for fibrotic progression. Preliminary data presented at the 2015 American Society of Hematology meeting suggests additional prognostic impact of mutations other than JAK2/ CAL/MPL, in all three MPNs including ET, PV, and PMF [23,24].…”

Mutations in MPNs: prognostic implications, window to biology, and impact on treatment decisions

“…51 Recently, the prevalence and relevance of somatic mutations was reported in a different cohort, including 133 PV and 181 ET patients. 52 In PV, 44% were reported to have mutations, including 29% with 1 mutation, 14% with 2 mutations, and 1% with 3 mutations. The most common mutations involved TET2 (18%), ASXL1 (11%), SH2B3 (5%), and SF3B1 (3%).…”

“…In a multivariable analysis, SRSF2 and RUNX1 affected overall survival, IDH2 and RUNX1 impacted leukemia-free survival, and ASXL1, IDH2, RUNX1, KIT, and SETBP1 predicted fibrotic progression. 52 In ET, 46% of patients had somatic mutations; the most common mutations involved TET2 (13%), ASXL1 (11%), DNMT3A (6%), SF3B1 (5%), CEBPA (4%), and TP53, SH2B3, EZH2, and CSF3R (2% each). The number of mutations (HR, 6.6 for 3 mutations and HR, 2.2 for 1 or 2 mutations) impacted overall survival, but not leukemia or MFfree survival.…”

“…In multivariable analysis, EZH2 and SF3B1 mutations impacted survival. 52 At present, there is little evidence to suggest the incorporation of testing for nondriver mutation in routine clinical care of patients with ET or PV.…”

Prefibrotic versus overtly fibrotic primary myelofibrosis: clinical, cytogenetic, molecular and prognostic comparisons

“…The degree of BM reticulin fibrosis was based on "real life" BM reports from Mayo Clinic haematopathologists and often in accordance with the European consensus scoring system (Thiele et al, 2005). Targeted next generation sequencing was used to screen for prognostically-relevant mutations (Tefferi et al, 2015). Statistical analyses considered clinical and laboratory parameters obtained at time of BM examination that was graded for reticulin fibrosis.…”