TY - JOUR
T1 - Response of high-risk MDS to azacitidine and lenalidomide is impacted by baseline and acquired mutations in a cluster of three inositide-specific genes
AU - Follo, Matilde Y.
AU - Pellagatti, Andrea
AU - Armstrong, Richard N.
AU - Ratti, Stefano
AU - Mongiorgi, Sara
AU - De Fanti, Sara
AU - Bochicchio, Maria Teresa
AU - Russo, Domenico
AU - Gobbi, Marco
AU - Miglino, Maurizio
AU - Parisi, Sarah
AU - Martinelli, Giovanni
AU - Cavo, Michele
AU - Luiselli, Donata
AU - McCubrey, James A.
AU - Suh, Pann Ghill
AU - Manzoli, Lucia
AU - Boultwood, Jacqueline
AU - Finelli, Carlo
AU - Cocco, Lucio
PY - 2019/9/1
Y1 - 2019/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85061772096&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061772096&partnerID=8YFLogxK
U2 - 10.1038/s41375-019-0416-x
DO - 10.1038/s41375-019-0416-x
M3 - Article
C2 - 30787430
AN - SCOPUS:85061772096
VL - 33
SP - 2276
EP - 2290
JO - Leukemia
JF - Leukemia
SN - 0887-6924
IS - 9
ER -