Abstract 2952: Determinants of hypomethylation and clinical responses in relapsed/refractory AML patients treated with SGI-110, a novel hypomethylating agent in a phase 1/2 study
Authors: Woonbok Chung, Pietro Taverna, John Lyons, Yong Hao, Mohammad Azab, Hagop Kantarjian, Patricia Kropf, Jean-Pierre Issa
Journal: Cancer Research (2015)

Abstract Introduction: SGI-110 is a dinucleotide of decitabine and deoxyguanosine and a novel subcutaneous (SQ) hypomethylating agent. In a previous Phase 1 (dose escalation) study, we found in relapsed/refractory (r/r) AML patients who were treated with SGI-110 (36 mg/m2-125 mg/m2) subcutaneously (SQ) daily for 5 days a correlation between low LINE-1 demethylation induction, a three gene expression classifier score (low CDA, low P15 and high DNMT3B) and resistance to SGI-110. Here, we analyzed r/r AML patients (n = 122) from Phase 1/2 studies treated at pharmacologically effective doses of SGI-110 looking for determinants of hypomethylation and response. Methods: Phase 1 patients with r/r AML (n = 27) who were treated at a therapeutic dose range of SGI-110 (35 mg/m2 - 125 mg/m2) by SQ daily for 5 days. Phase 2 study r/r AML patients received 60 mg/m2 SQ daily for 5 days (n = 22), 90 mg/m2 SQ daily for 5 days (n = 25) and 60 mg/m2 SQ daily for 10 days (n = 48). Global DNA methylation at pre/post treatment was estimated by bisulfite-pyrosequencing for the LINE-1 repetitive sequence. We also examined expression of a panel of genes (CDA, P15, P21, DNMT3B, DNMT3A, DNMT1, and CTCF) at baseline by quantitative RT-PCR. Results: We analyzed samples from 122 patients with r/r AML. Median age was 59.6 (range, 23-86), 75 were males (61.5%). Overall, peak LINE-1 demethylation generally occurred on day 8 after daily x 5 treatment, or on day 8 or 15 after daily x 10 treatment. In individual patients, peak LINE-1 demethylation ranged from +4.9% to -56.3%. In 122 r/r AML patients, 28 showed overall remission (23.0%, 15 CR and 13 CRi/CRp). Unsupervised clustering by expression of a panel of genes at baseline grouped the patients into two clusters: A (N = 95, response rate = 29.5%) and B (N = 27, response rate = 0%). Cluster B is characterized by high DNMT3b expression, low P15 expression, low CDA expression (average Z-score 1.44 ± 0.26 in cluster B compared to -1.26 ± 0.14 in clusters A, p&amp;lt;0.0001) and reduced demethylation (demethylation average -14.2 ± 1.90% in cluster B compared to -26.1 ± 1.38% in clusters A, p&amp;lt;0.0001). Peak LINE-1 demethylation was significantly higher in responders than non-responders (average demethylation -32.33 ± 1.91% in responders compared to -21.25 ± 1.42% in non-responders, p = 0.0001). A three gene classifier score (low CDA, low P15 and high DNMT3B) was associated with low LINE-1 demethylation (R = 0.27, p = 0.0034) as well as resistance to SGI-110 (mean Z-score -0.75 in non-responders compared to -1.67 in responders, p = 0.014). Conclusions: In a phase 1/2 study of SGI-110, we identified in r/r AML patients a gene expression signature (high DNMT3B, low P15, and low CDA) associated with reduced demethylation and resistance to SGI-110 and we found strong trends for associations between demethylation and response. Citation Format: Woonbok Chung, Pietro Taverna, John Lyons, Yong Hao, Mohammad Azab, Hagop Kantarjian, Patricia Kropf, Jean-Pierre Issa. Determinants of hypomethylation and clinical responses in relapsed/refractory AML patients treated with SGI-110, a novel hypomethylating agent in a phase 1/2 study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2952. doi:10.1158/1538-7445.AM2015-2952