Abstract 1920: Response to hypomethylating agents based on cytidine deaminase expression, genetic polymorphisms, and NPM1 mutation status in acute myeloid leukemia
2020
Response to hypomethylating agents (HMAs) in patients (pts) with acute myeloid leukemia (AML) is variable. Data on biological predictors of response is limited. Cytidine deaminase (CDA) inactivates HMAs. Increased CDA activity may lead to HMA resistance. Using core pathway analysis, we identified nucleophosmin 1 (NPM1) indirectly influences CDA expression. We hypothesized that responses to HMAs occur in the setting of decreased CDA expression regulated by NPM1 and investigated the relationship between NPM1 status, CDA expression, single nucleotide polymorphisms (SNPs) in CDA, and HMA response in pts with AML. AML pts with banked samples who received HMA-based therapy between 1/2014 to 12/2018 were reviewed. Responses following at least 2 cycles of HMA were categorized as responders (R) or non-responders (NR). Pt, disease, NPM1 status, and treatment characteristics were summarized. CDA gene and protein expression was examined in bone marrow and peripheral blood samples at diagnosis using qRT-PCR and CDA sandwich ELISA, respectively. CDA gene expression levels were normalized to the housekeeping gene, 18s, and the comparative CT method was used to assess expression. Comparisons based on response and NPM1 mutation status were performed using the Mann-Whitney U test. 17 SNPs previously shown to alter CDA activity were selected for analysis. SNPs were determined using real-time PCR with allele specific probes; longer insertions/deletions were identified by sanger sequencing. Univariate logistic regression analysis was performed to discern the association between SNPs in CDA and response to HMAs. 54 pts had available blood, marrow, or buccal samples available for analysis. 33 pts provided blood or marrow samples for gene and protein analysis prior to HMA. 22 pts (67%) were classified as R in this cohort. 35 pts had available buccal swabs for genotyping, and 28 pts (80%) were classified as R. Median OS was 21 months (mo) for all pts, 23 mo among R, and 18 mo in NR. CDA expression was significantly decreased in NPM1 wild type pts compared to NPM1 mutant pts (p=0.02) but did not differ in R compared to NR. No significant differences were identified in CDA protein expression based on NPM1 status or response. No SNPs were significantly associated with response. Baseline CDA gene expression in bulk tumor cells was significantly lower in NPM1 wild type pts compared to NPM1 mutant pts but no different between pts responding to HMAs compared to NR. There was no clear correlation between CDA protein expression and NPM1 status or response. None of the CDA SNPs were predictive of response to HMAs. This analysis reveals feasibility of assessing CDA activity in this population. Our small sample size limits our ability to determine CDA activity as a biological predictor of response, and ongoing pt accrual will allow for further exploration of the role of CDA in HMA response. Citation Format: Brittany Knick Ragon, Issam S. Hamadeh, C Greer Vestal, Alicia Hamilton, Mathew L. Smith, Danielle Boselli, Jing Ai, Thomas G. Knight, Michael R. Grunwald, Jonathan M. Gerber, Edward A. Copelan, Lawrence J. Druhan, Belinda R. Avalos, Nury M. Steuerwald, Jai N. Patel. Response to hypomethylating agents based on cytidine deaminase expression, genetic polymorphisms, and NPM1 mutation status in acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1920.
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