The germline JAK2 GGCC (46/1) haplotype and survival among 414 molecularly‐annotated patients with primary myelofibrosis

JAK2 mutations in myeloproliferative neoplasms (MPNs) are associated with the germline GGCC (46/1) haplotype. In 2010, we reported an association between shortened survival in primary myelofibrosis (PMF) and nullizygosity for the JAK2 46/1 haplotype. In the current study, we have increased the number of informative cases from 130 to 414 (median age 63 years; 63% males), in order to revisit with the phenotypic and prognostic relevance of the JAK2 46/1 haplotype in PMF. JAK2 46/1 haplotype was documented in 69% of the study patients, including 25% in homozygous and 44% in heterozygous state. Driver mutation frequency in patients homozygous/heterozygous/nullizygous for the 46/1 haplotype was 78%/60%/56% JAK2 , 10%/20%/18% type 1‐like CALR , 3%/2%/5% type 2‐like CALR , 4%/8%/7% MPL, and 6%/10%/14% triple‐negative ( P = .02). In univariate analysis, nullizygosity for the JAK2 46/1 haplotype was associated with inferior overall survival (HR 1.5, 95% CI 1.1‐1.9), most pronounced in JAK2 ( P <.001), as opposed to CALR / MPL mutated ( P = .48) or triple‐negative cases ( P = .27). Multivariable analysis that included karyotype, driver mutational status and high‐molecular risk mutations confirmed the independent prognostic contribution of nullizygosity for the 46/1 haplotype ( P = .02; HR 1.4, 95% CI 1.1‐1.8). Nullizygosity for 46/1 also remained significant in the context of the genetically‐inspired GIPSS risk model ( P = .04), but not in the context of the integrated genetics‐clinical MIPSS70+ version 2.0 model ( P = .4). Leukemia‐free survival was not affected by the 46/1 haplotype ( P = .6). The current study confirms the association of nullizygosity for the JAK2 GGCC (46/1) haplotype with inferior survival in JAK2 ‐mutated PMF.