Targeted deep sequencing in primary myelofibrosis

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 age-adjusted 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 P 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 = 80), 1 or 2 (n = 93), or 3 or more (n = 9) adverse variants/mutations were 8.5, 4, and 0.7 years, respectively ( P U2AF1 and JAK2 mutations ( P = .04) and U2AF1 mutations and anemia ( P = .003) and thrombocytopenia ( P = .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.