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Chronic myeloproliferative neoplasms

Prognostic impact of RAS-pathway mutations in patients with myelofibrosis

Leukemia volume 34, pages 799–810 (2020)Cite this article

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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.

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Acknowledgements

This research was supported by a Federal research grant from the Brazilian Ministry of Health (PROADI-SUS SIPAR no. 25000179520/2011-36) to FPSS, PVC, and NH and a Research Grant from the AMIGOH organization (Study no. 1937-14) to FPSS; by Cancer Center Support Grant/Core Grant to Memorial Sloan Kettering Cancer Center (P30 CA008748); NCI 1K08CA188529-01 (to RKR); by MD Anderson Cancer Center support grant P30 CA016672 from the National Institutes of Health (National Cancer Institute).

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  1. These authors contributed equally: Fabio P. S. Santos, Bartlomiej Getta

Authors and Affiliations

  1. Centro de Hematologia e Oncologia Familia Dayan-Daycoval, Hospital Israelita Albert Einstein, São Paulo, Brazil

    Fabio P. S. Santos, Tarcila S. Datoguia, Renato D. Puga, Raquel de Melo Alves Paiva, Nelson Hamerschlak & Paulo Vidal Campregher

  2. Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Bartlomiej Getta, Ross L. Levine & Raajit K. Rampal

  3. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Lucia Masarova, Hagop M. Kantarjian & Srdan Verstovsek

  4. Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Christopher Famulare, Jessica Schulman, Ross L. Levine & Raajit K. Rampal

  5. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Maria E. Arcila

  6. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Ross L. Levine

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Correspondence to Fabio P. S. Santos, Raajit K. Rampal or Srdan Verstovsek.

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Conflict of interest

HMK and SV have received research funding from Incyte Corp. SV has received research funding from Roche, NS Pharma, Celgene, Gilead, Promedior, CTI Biopharma Corp, Genentech, Blueprint Medicines Corp, and Novartis. SV has served as a consultant for Incyte Corp, Constellation, Pragmatist, Sierra, Novartis, Celgene. RKR has received consulting fees from Incyte corporation, Celgene corporation, Agios Pharmaceuticals, Apexx oncology, BeyondSpring, Partner Therapeutics, and Jazz Pharmaceuticals, and has received research funding from Constellation pharmaceuticals, Incyte corporation, and Stemline Therapeutics. FPSS and NH have received research funding from Novartis, Inc. FPSS served as a consultant and speaker for Novartis, Inc. The other authors declare that they have no conflict of interest.

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Santos, F.P.S., Getta, B., Masarova, L. et al. Prognostic impact of RAS-pathway mutations in patients with myelofibrosis. Leukemia 34, 799–810 (2020). https://doi.org/10.1038/s41375-019-0603-9

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