Response of high-risk MDS to azacitidine and lenalidomide is impacted by baseline and acquired mutations in a cluster of three inositide-specific genes
Follo, Matilde Y.; Pellagatt, Andrea; Armstrong, Richard N.; Ratti, Stefano; Mongiorgi, Sara; Fanti, Sara De; Bochicchio, Maria Teresa; Russo, Domenico; Gobbi, Marco; Miglino, Maurizio; Parisi, Sarah; Martinelli, Giovanni; Cavo, Michele; Luiselli, Donata; McCubrey, James A.; Suh, Pann-Ghill; Manzoli, Lucia; Boultwood, Jacqueline; Finelli, Carlo; Cocco, Lucio
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.
Follo, Matilde Y., & Pellagatt, Andrea, & Armstrong, Richard N., & Ratti, Stefano, & Mongiorgi, Sara, & Fanti, Sara De, & Bochicchio, Maria Teresa, & Russo, Domenico, & Gobbi, Marco, & Miglino, Maurizio, & Parisi, Sarah, & Martinelli, Giovanni, & Cavo, Michele, & Luiselli, Donata, & McCubrey, James A., & Suh, Pann-Ghill, & Manzoli, Lucia, & Boultwood, Jacqueline, & Finelli, Carlo, & Cocco, Lucio. (February 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), p.2276-2290. Retrieved from http://hdl.handle.net/10342/8321
Follo, Matilde Y., and Pellagatt, Andrea, and Armstrong, Richard N., and Ratti, Stefano, and Mongiorgi, Sara, and Fanti, Sara De, and Bochicchio, Maria Teresa, and Russo, Domenico, and Gobbi, Marco, and Miglino, Maurizio, and Parisi, Sarah, and Martinelli, Giovanni, and Cavo, Michele, and Luiselli, Donata, and McCubrey, James A., and Suh, Pann-Ghill, and Manzoli, Lucia, and Boultwood, Jacqueline, and Finelli, Carlo, and Cocco, Lucio. "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.), February 2019. September 21, 2020. http://hdl.handle.net/10342/8321.
Follo, Matilde Y. and Pellagatt, Andrea and Armstrong, Richard N. and Ratti, Stefano and Mongiorgi, Sara and Fanti, Sara De and Bochicchio, Maria Teresa and Russo, Domenico and Gobbi, Marco and Miglino, Maurizio and Parisi, Sarah and Martinelli, Giovanni and Cavo, Michele and Luiselli, Donata and McCubrey, James A. and Suh, Pann-Ghill and Manzoli, Lucia and Boultwood, Jacqueline and Finelli, Carlo and Cocco, Lucio, "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, no. 9 (February 2019), http://hdl.handle.net/10342/8321 (accessed September 21, 2020).
Follo, Matilde Y., Pellagatt, Andrea, Armstrong, Richard N., Ratti, Stefano, Mongiorgi, Sara, Fanti, Sara De, Bochicchio, Maria Teresa, Russo, Domenico, Gobbi, Marco, Miglino, Maurizio, Parisi, Sarah, Martinelli, Giovanni, Cavo, Michele, Luiselli, Donata, McCubrey, James A., Suh, Pann-Ghill, Manzoli, Lucia, Boultwood, Jacqueline, Finelli, Carlo, Cocco, Lucio. 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. February 2019; 33(9) 2276-2290. http://hdl.handle.net/10342/8321. Accessed September 21, 2020.