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Leukemia. 2019 Feb 20. doi: 10.1038/s41375-019-0416-x. [Epub ahead of print]

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

Author information

1
Cellular Signalling Laboratory, Human Anatomy Section, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. matilde.follo@unibo.it.
2
Bloodwise Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, and Oxford BRC Haematology Theme, Oxford, UK.
3
Cellular Signalling Laboratory, Human Anatomy Section, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
4
Department of Biological, Geological, and Environmental Sciences, University of Bologna, Bologna, Italy.
5
Department of Hematology "L e A SerĂ gnoli", University of Bologna, Bologna, Italy.
6
Chair of Hematology, Unit of Blood Disease and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
7
Department of Hematology and Oncology, University of Genova, Genova, Italy.
8
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
9
Department of Cultural Heritage, University of Bologna, Ravenna, Italy.
10
Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
11
School of Life Sciences, UNIST, Ulsan, Republic of Korea.
12
Cellular Signalling Laboratory, Human Anatomy Section, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. lucio.cocco@unibo.it.

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.

PMID:
30787430
DOI:
10.1038/s41375-019-0416-x

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