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 / were detected in 147 patients (81%), with the most frequent being (36%), (18%), (18%), and (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 , , , , , , and ; their combined prevalence was 56%. Adverse variants/mutations were associated with inferior overall survival (median, 3.6 vs 8.5 years; < .001) and leukemia-free survival (7-year risk, 25% vs 4%; < .001), and the effect on survival was independent of both the Dynamic International Prognostic Scoring System Plus and // 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 ( < .001). Additional data were obtained on pattern of mutation co-segregation and phenotypic correlation, including significant associations between and mutations ( = .04) and mutations and anemia ( = .003) and thrombocytopenia ( = .006). We conclude that DNA variants/mutations other than // are prevalent in PMF and are qualitatively and quantitatively relevant in predicting overall and leukemia-free survival.