CALR mutations possess unique prognostic relevance in myelofibrosis—before and after transplant

The prognostic relevance of karyotype and mutations in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) has long been recognized and continues to be heavily promoted [1]. The same is turning out to be true for myelofibrosis (MF), which is a related stem cell-derived myeloid neoplasm with shared genetic signature [2]. Mutations in primary MF (PMF) can be practically organized into three prognostic categories: (i) favorable (CALR type 1/like), (ii) unfavorable with karyotype-independent impact (ASXL1, SRSF2, U2AF1-Q157), and (iii) unfavorable with impact that might not be independent of karyotype or other high molecular risk (HMR) mutations (EZH2, IDH1, IDH2, CBL, KRAS, NRAS, TP53) [3,4,5,6,7]. These mutations have been incorporated into formal risk models for PMF, including the mutation-enhanced international prognostic systems, MIPSS70 [6] and MIPSS70+ version 2.0 (MIPSSv2) [3], and the genetically inspired GIPSS [8]; the first two include clinical risk factors while GIPSS is based on karyotype and mutations, only. The prognostic relevance of ASXL1 mutation was more recently reiterated in PMF but not in post-essential thrombocythemia (ET) or post polycythemia vera (PV) MF [9], while SF3B1 mutation was associated with shortened survival in post-ET/PV but not primary MF [10]. In addition, EZH2 mutation was recently implicated in leukemic transformation [11] while RAS-pathway mutations were associated with poor response to ruxolitinib therapy.