Targeted deep sequencing in primary myelofibrosis

Abstract

Key Points• More than 80% of patients with PMF harbor DNA variants/mutations other than JAK2/ CALR/MPL.• Some of these variants/mutations adversely affect overall or leukemia-free survival independent of conventional risk stratification.A myeloid neoplasm-relevant 27-gene panel was used for next-generation sequencing of bone marrow or whole blood DNA in 182 patients with primary myelofibrosis (PMF). DNA sequence variants/mutations other than JAK2/CALR/MPL were detected in 147 patients (81%), with the most frequent being ASXL1 (36%), TET2 (18%), SRSF2 (18%), and U2AF1(16%); furthermore, 35%, 26%, 10%, and 9% of the patients harbored 1, 2, 3, or 4 or more such variants/mutations, respectively. Adverse variants/mutations were identified by ageadjusted multivariable analysis of impact on overall survival or leukemia-free survival and included ASXL1, SRSF2, CBL, KIT, RUNX1, SH2B3, and CEBPA; their combined prevalence was 56%. Adverse variants/mutations were associated with inferior overall survival (median, 3.6 vs 8.5 years; P , .001) and leukemia-free survival (7-year risk, 25% vs 4%; P , .001), and the effect on survival was independent of both the Dynamic International Prognostic Scoring System Plus and JAK2/CALR/MPL mutational status, with respective hazard ratios of 2.0 (95% confidence interval [CI], 1.3-3.1) and 2.9 (95% CI, 1.9-4.4).Additional prognostic information was obtained by considering the number of adverse variants/mutations; median survivals in patients with zero (n 5 80), 1 or 2 (n 5 93), or 3 or more (n 5 9) adverse variants/mutations were 8.5, 4, and 0.7 years, respectively (P , .001).Additional data were obtained on pattern of mutation co-segregation and phenotypic correlation, including significant associations between U2AF1 and JAK2 mutations (P 5 .04) and U2AF1 mutations and anemia (P 5 .003) and thrombocytopenia (P 5 .006). We conclude that DNA variants/mutations other than JAK2/CALR/MPL are prevalent in PMF and are qualitatively and quantitatively relevant in predicting overall and leukemia-free survival.

JAK2 V617F hematopoietic clones are present several years prior to MPN diagnosis and follow different expansion kinetics

“…A recent study of 182 MF patients identified many with JAK2 V617F and SRSF2 P95 co-mutation, including several aged ,70 years (n 5 21, age range 39-84 years). 19 Taken together, these observations suggest that younger individuals with SRSF2-mutant clonal hematopoiesis may be at a high risk of progression to a hematological neoplasm.…”

Diagnostic and prognostic contribution of targeted NGS in patients with triple‐negative myeloproliferative neoplasms

“…1 However, a subset (10-15%) of MPN Ph-patients, the so-called triplenegative (TN), do not present any of those driver mutations, but may harbor others that might be associated with inferior overall survival (OS) or leukemic transformation. 2,3 Based on this, and considering that there are just a few studies on this subgroup of patients, our aim was to assess the utility in terms of diagnosis and prognosis by performing targeted deep sequencing (TDS) of myeloid-related genes in TN MPN patients.…”

Screening for ASXL1 and SRSF2 mutations is imperative for treatment decision‐making in otherwise low or intermediate‐1 risk patients with myelofibrosis

“…In transplant‐eligible patients, the change in outlook might encourage pursuing AlloSCT sooner than later or provide additional comfort for decision to defer. We are well aware of the existence of other adverse mutations in PMF (Tefferi et al , ), but focused on ASXL1 and SRSF2 because of their relatively higher prevalence (36% for ASXL1 and 18% for SRSF2 ), compared to other adverse mutations (1% for EZH2 and 3% for IDH2 ), and also because of the abundance of supporting data for the former (Vannucchi et al , ).…”