Response of High-risk MDS to Azacitidine and Lenalidomide is Impacted by Baseline and Acquired Mutations in a Cluster of Three Inositide-specific Genes

Overview

Journal Leukemia

Specialties Hematology
Oncology

Date 2019 Feb 22

PMID 30787430

Citations 11

Authors

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

Affiliations

Soon will be listed here.

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.

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