Prognostic impact of RAS-pathway mutations in patients with myelofibrosis Journal Article
| Authors: | Santos, F. P. S.; Getta, B.; Masarova, L.; Famulare, C.; Schulman, J.; Datoguia, T. S.; Puga, R. D.; de Melo Alves Paiva, R.; Arcila, M. E.; Hamerschlak, N.; Kantarjian, H. M.; Levine, R. L.; Campregher, P. V.; Rampal, R. K.; Verstovsek, S. |
| Article Title: | Prognostic impact of RAS-pathway mutations in patients with myelofibrosis |
| Abstract: | 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. © 2019, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | signal transduction; adolescent; adult; aged; myelofibrosis; gene mutation; major clinical study; overall survival; somatic mutation; allogeneic stem cell transplantation; clinical feature; validation process; united states; incidence; prevalence; cohort analysis; genetic association; genetic variation; prediction; risk factor; sex ratio; high risk patient; age; clinical evaluation; disease duration; brazil; oncogene k ras; genetic risk; cbl protein; leukocytosis; disease exacerbation; oncogene ras; patient care planning; protein tyrosine phosphatase shp 2; oncogene n ras; cd135 antigen; genetic transformation; acute myeloid leukemia; high throughput sequencing; flt3 gene; ruxolitinib; prognosis; human; male; female; priority journal; article; cbl gene; ptpn11 gene |
| Journal Title: | Leukemia |
| Volume: | 34 |
| Issue: | 3 |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2020-03-01 |
| Start Page: | 799 |
| End Page: | 810 |
| Language: | English |
| DOI: | 10.1038/s41375-019-0603-9 |
| PUBMED: | 31628430 |
| PROVIDER: | scopus |
| PMCID: | PMC7158221 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 April 2020 -- Source: Scopus |
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