Abstract 1548: Genetic biomarkers predict clinical response and survival in myelodysplasia

Background: Hypomethylating agents (HMA) used in higher-risk myelodysplastic syndromes (MDS) improve survival but HMA-failure has a poor prognosis. Abnormal bone marrow (BM) colony-forming units (CFUs) persist in treated MDS patients despite achievement of complete remission, suggesting persistent abnormal stem cell function. We aim to identify genetic biomarkers following treatment with Azacitidine ± Thalidomide or Lenalidomide that predict clinical outcomes in MDS. Methods: BM cells from patients enrolled in ALLG MDS3 and MDS4 clinical trials at baseline and after 4 cycles of treatment (C4) were grown in Methocult for 14 days. CFUs were pooled at baseline; C4 macroscopically normal and abnormal colonies were harvested separately. mRNA expression was quantified using the Nanostring nCounter PanCancer Pathways panel. Clinical outcomes analysed were: (1) clinical benefit at 12 months (haematological improvement or better as per IWG criteria) (2) best response achieved. Genes expressed above background level in ≥25% of samples were included for statistical analyses, resulting in 516 genes across 56 samples from 23 different patients. R limma package was used for differential expression analysis. Patients were weighted using limma's voomWithQualityWeights function. Moderated t-tests with empirical Bayes were done to identify differentially expressed genes. For testing between colonies, a log-fold-change cut-off of 0.5 was used with limma's treat function. P-values were adjusted for multiple hypothesis testing. Results: 98 genes exhibited significantly different expression (p Conclusion: We identified changes in gene expression following treatment in MDS that predict outcomes in response and clinical benefit. These genetic biomarkers require further validation and could define early markers of resistance for investigation of novel therapies. Citation Format: Lynette Chee, David Ritchie, Jessica Chung, Daniel Park, Mandy Ludford-Menting, Jane Ripley, Melita Kenealy, Rachel Koldej. Genetic biomarkers predict clinical response and survival in myelodysplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1548.