Open AccessPrognostic impact of RAS-pathway mutations in patients with myelofibrosis
Author(s) -
Fábio Pires de Souza Santos,
Bartlomiej Getta,
Lucia Masárová,
Christopher Famulare,
Jessica Schulman,
Tarcila Santos Datoguia,
Renato D Puga,
Raquel de Melo Alves Paiva,
Maria E. Arcila,
Nelson Hamerschlak,
Hagop M. Kantarjian,
Ross L. Levine,
Paulo Vidal Campregher,
Raajit K. Rampal,
Srđan Verstovšek
Publication year - 2019
Publication title -
leukemia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.539
H-Index - 192
eISSN - 1476-5551
pISSN - 0887-6924
DOI - 10.1038/s41375-019-0603-9
Subject(s) - kras , myelofibrosis , ruxolitinib , leukocytosis , medicine , mutation , oncology , myeloid leukemia , international prognostic scoring system , proportional hazards model , ptpn11 , myeloid , idh1 , gene , cancer research , biology , genetics , myelodysplastic syndromes , bone marrow
RAS-pathway mutations are recurrent events in myeloid malignancies. However, there is limited data on the significance of RAS-pathway mutations in patients with myelofibrosis (MF). We analyzed next-generation sequencing data of 16 genes, including RAS-pathway genes, from 723 patients with primary and secondary MF across three international centers and evaluated their significance. N/KRAS variants were present in 6% of patients and were typically sub-clonal (median VAF = 20%) relative to other genes variants. RAS variants were associated with advanced MF features including leukocytosis (p = 0.02), high somatic mutation burden (p < 0.01) and the presence of established "molecular high-risk" (MHR) mutations. MF patients with N/KRAS mutations had shorter 3-year overall survival (OS) (34% vs 58%, p < 0.001) and higher incidence of acute myeloid leukemia at 3 years (18% vs 11%, p = 0.03). In a multivariate Cox model, RAS mutations were associated with decreased OS (HR 1.93, p < 0.001). We created a novel score to predict OS incorporating RAS mutations, and it predicted OS across training and validation cohorts. Patients with intermediate risk/high-risk DIPSS with RAS mutations who received ruxolitinib had a nonsignificant longer 2-year OS relative to those who did not receive ruxolitinib. These data demonstrate the importance of identifying RAS mutations in MF patients.