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.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by10 School of Life Sciences, UNIST, Ulsan, Republic of KoreaResponse of high-risk MDS to azacitidine and lenalidomide is impacted by baseline and acquired. . .peripheral blood cytopenia and a variable risk of evolution into acute myeloid leukemia (AML) [1]
MDS frequently show mutations in genes involved in RNA splicing (e.g., SF3B1, SRSF2, U2AF1, ZRSR2; approximately 40–60% of patients) [2, 3], DNA methylation (i.e., DNMT3A, TET2, IDH1, IDH2; approximately 30–40%) or chromatin remodelling (i.e., ASXL1, EZH2; approximately 15–25%), that are retrieved at diagnosis or can be acquired during follow-up [4, 5]
ASXL1 mutations are associated with impaired hematopoiesis and are predictive of a poor outcome [6, 7], and TP53, EZH2, SF3B1, and SRSF2 mutations have been recognized as being unfavorable for survival [8,9,10]
Summary
Response of high-risk MDS to azacitidine and lenalidomide is impacted by baseline and acquired. MDS frequently show mutations in genes involved in RNA splicing (e.g., SF3B1, SRSF2, U2AF1, ZRSR2; approximately 40–60% of patients) [2, 3], DNA methylation (i.e., DNMT3A, TET2, IDH1, IDH2; approximately 30–40%) or chromatin remodelling (i.e., ASXL1, EZH2; approximately 15–25%), that are retrieved at diagnosis or can be acquired during follow-up [4, 5]. Specific gene mutations, such as those affecting TET2, have been associated with a favorable response to azacitidine [11], while the acquisition of TP53 or NRAS mutations has recently been related to resistance to lenalidomide [12, 13]. For the MDS patients that are refractory or not suitable to the conventional strategies, the combination of these two drugs could be effective and is clinically investigated [16, 17]
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