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Myelodysplasias

Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms

Leukemia volume 28, pages 78–87 (2014)Cite this article

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Abstract

We hypothesized that specific molecular mutations are important biomarkers for response to DNA methyltransferase inhibitors (DNMT inhibitors) and may have prognostic value in patients with myelodysplastic syndromes (MDS). Mutational analysis was performed in 92 patients with MDS and related disorders who received 5-azacytidine (n=55), decitabine (n=26) or both (n=11). Mutational status was correlated with overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) by univariate and multivariate analysis. Risk stratification models were created. TET2, DNMT3A, IDH1/IDH2, ASXL1, CBL, RAS and SF3B1 mutations were found in 18, 9, 8, 26, 3, 2 and 13% of patients, respectively. In multivariate analysis, TET2MUT and/or DNMT3AMUT (P=0.03), platelets⩾100 × 109/l (P=0.007) and WBC<3.0 × 109/l (P=0.03) were independent predictors of better response. TET2MUT and/or DNMT3AMUT (P=0.04) status was also independently prognostic for improved PFS, as were good or intermediate cytogenetic risk (P<0.0001), age<60 (P=0.0001), treatment with both 5-azacytidine and decitabine (P=0.02) and hemoglobin⩾10 g/dl (P=0.01). Better OS was associated with ASXL1WT (P=0.008) and SF3B1MUT (P=0.01), and, similar to PFS, cytogenetic risk (P=0.0002), age (P=0.02) and hemoglobin (P=0.04). These data support the role of molecular mutations as predictive biomarkers for response and survival in MDS patients treated with DNMT inhibitors.

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Acknowledgements

This study is supported partially or in full by the following granting agencies: RVT (MDS Foundation YIA grant), AA & MDS International Foundation YIA, Cleveland Clinic Institutional Seed Support, Scott Hamilton CARES Grant, JPM (Celgene grant), and FT (FAPESP grant 2011/20750-9 and 2012/09982-8).

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Authors and Affiliations

  1. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    F Traina, V Visconte, A Tabarroki, A M Jankowska, E Hasrouni, Y Sugimoto, H Szpurka, H Makishima, C L O'Keefe, Y Saunthararajah, J P Maciejewski & R V Tiu

  2. Hematology and Hemotherapy Center - INCT do Sangue, University of Campinas - UNICAMP, Campinas, SP, Brazil

    F Traina & S T Olalla Saad

  3. Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, SP, Brazil

    F Traina

  4. Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA

    P Elson

  5. Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    M A Sekeres, A S Advani, M Kalaycio, E A Copelan, J P Maciejewski & R V Tiu

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Correspondence to R V Tiu.

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Mikkael A Sekeres is a consultant for Celgene and Amgen. Jaroslaw P Maciejewski receives honoraria from Celgene. The other authors declare no conflict of interest.

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Traina, F., Visconte, V., Elson, P. et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia 28, 78–87 (2014). https://doi.org/10.1038/leu.2013.269

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