Molecular Signatures That Predict Response to Azacitidine Treatment for Myelodysplastic Syndromes

Abstract

Abstract DNA hypomethylating agents (HMAs) constitute standard therapy for higher-risk myelodysplastic syndromes (MDS). However, the lack of reliable genetic markers predicting response to HMAs precludes an optimal use of these agents. Recently, several groups have reported marked efficacy of decitabine for TP53 -mutated myeloid malignancies. However, since decitabine is not approved for MDS in many nations, it is of great interest whether azacitidine (AZA) has similar effects on TP53 -mutated MDS. Thus, we investigated the clonal dynamics and molecular signatures that correlated with response to AZA in MDS. We enrolled a total of 131 cases of MDS patients treated with azacitidine, of which 107 were registered from a prospective multicenter trial of AZA treatment for high-risk MDS patients, while the remaining 24 cases received AZA in off-trial settings. In all patients, a bone marrow specimen was obtained before (pre-therapy samples) and subjected to targeted-capture sequencing, which was designed to detect mutations in 67 known driver genes implicated in myeloid neoplasms as well as genome-wide copy number alterations (CNAs). Mutations and CNAs was also evaluated in samples obtained during and after AZA therapy (post-AZA samples). Analysis of pre-treatment specimens revealed 408 driver mutations in 124 (95%) patients with a mean of 2.7 mutations/sample in 50 genes. At least one CNA was detected in 103 (79%) cases. Most frequently observed lesions included mutations in TP53, ASXL1, RUNX1, TET2, and SRSF2, and other high-risk CNAs, such as -7/7qLOH, 5qLOH, and 17pLOH. Among these TP53 lesions were found in 39 (38%) cases, of which biallelic lesions were suggested for 33 cases (85%), either by multiple mutations (N=11) or accompanying 17p LOH involving the TP53 locus (N=22). TP53 -mutated cases had a significantly lower number of other driver mutations (1.7 vs. 3.1, p 3 years after receiving consolidation with transplant after AZA. Our study revealed a significant positive association of TP53 mutations with favorable responses to AZA in MDS. However, the response was transient, where the development of effective post-AZA therapy after CR should be warranted, such as allogeneic stem cell transplantation to overcome this otherwise intractable disease. Disclosures Chiba: Nippon Shinyaku: Honoraria, Research Funding. Asou: Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding. Kiyoi: Chugai Pharmaceutical Co., Ltd.: Research Funding; MSD K.K.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Meiji Seika Pharma Co.,Ltd.: Research Funding; Phizer Japan Inc.: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; JCR Pharmaceuticals Co.,Ltd.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Eisai Co., Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; ONO Pharmaceutical Co., Ltd.: Research Funding. Ohyashiki: Nippon Shinyaku: Honoraria, Research Funding, Speakers Bureau; Celegen KK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis pharma KK: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb KK: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb KK: Honoraria, Research Funding, Speakers Bureau; Jansen pharmaceutical KK: Honoraria, Research Funding; Alexion: Honoraria; Fujirebio KK: Honoraria; Celegen KK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis pharma KK: Honoraria, Research Funding, Speakers Bureau; Kyowa Hakko Kirin KK: Honoraria; Phizer KK: Honoraria, Research Funding, Speakers Bureau; Otsuka pharmaceutical KK: Honoraria; Chugai pharmaceutical KK: Research Funding; Phizer KK: Honoraria, Research Funding, Speakers Bureau; MSD KK: Honoraria; Fujirebio KK: Honoraria; Nippon Shinyaku: Honoraria, Research Funding, Speakers Bureau; Dainippon Sumitomo KK: Honoraria, Research Funding, Speakers Bureau; Dainippon Sumitomo KK: Honoraria, Research Funding, Speakers Bureau; Kyowa Hakko Kirin KK: Honoraria; Taiho pharmaceutical KK: Honoraria; Otsuka pharmaceutical KK: Honoraria; Jansen pharmaceutical KK: Honoraria, Research Funding; Taiho pharmaceutical KK: Honoraria; Chugai pharmaceutical KK: Research Funding; Alexion: Honoraria; MSD KK: Honoraria. Miyazaki: Nippon Shinyaku: Honoraria. Naoe: Nippon Shinyaku: Honoraria. Makishima: Yasuda Medical Foundation: Research Funding.