Response of high-risk MDS to azacitidine and lenalidomide is impacted by baseline and acquired mutations in a cluster of three inositide-specific genes

Matilde Y. Follo, Andrea Pellagatti, Richard N. Armstrong, Stefano Ratti, Sara Mongiorgi, Sara De Fanti, Maria Teresa Bochicchio, Domenico Russo, Marco Gobbi, Maurizio Miglino, Sarah Parisi, Giovanni Martinelli, Michele Cavo, Donata Luiselli, James A. McCubrey, Pann Ghill Suh, Lucia Manzoli, Jacqueline Boultwood, Carlo Finelli, Lucio Cocco

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Abstract

Specific myeloid-related and inositide-specific gene mutations can be linked to myelodysplastic syndromes (MDS) pathogenesis and therapy. Here, 44 higher-risk MDS patients were treated with azacitidine and lenalidomide and mutations analyses were performed at baseline and during the therapy. Results were then correlated to clinical outcome, overall survival (OS), leukemia-free-survival (LFS) and response to therapy. Collectively, 34/44 patients were considered evaluable for response, with an overall response rate of 76.25% (26/34 cases): 17 patients showed a durable response, 9 patients early lost response and 8 patients never responded. The most frequently mutated genes were ASXL1, TET2, RUNX1, and SRSF2. All patients early losing response, as well as cases never responding, acquired the same 3 point mutations during therapy, affecting respectively PIK3CD (D133E), AKT3 (D280G), and PLCG2 (Q548R) genes, that regulate cell proliferation and differentiation. Moreover, Kaplan–Meier analyses revealed that this mutated cluster was significantly associated with a shorter OS, LFS, and duration of response. All in all, a common mutated cluster affecting 3 inositide-specific genes is significantly associated with loss of response to azacitidine and lenalidomide therapy in higher risk MDS. Further studies are warranted to confirm these data and to further analyze the functional role of this 3-gene cluster.

Original languageEnglish
Pages (from-to)2276-2290
Number of pages15
JournalLeukemia
Volume33
Issue number9
DOIs
Publication statusPublished - Sep 1 2019

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ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Follo, M. Y., Pellagatti, A., Armstrong, R. N., Ratti, S., Mongiorgi, S., De Fanti, S., Bochicchio, M. T., Russo, D., Gobbi, M., Miglino, M., Parisi, S., Martinelli, G., Cavo, M., Luiselli, D., McCubrey, J. A., Suh, P. G., Manzoli, L., Boultwood, J., Finelli, C., & Cocco, L. (2019). Response of high-risk MDS to azacitidine and lenalidomide is impacted by baseline and acquired mutations in a cluster of three inositide-specific genes. Leukemia, 33(9), 2276-2290. https://doi.org/10.1038/s41375-019-0416-x