Long-Term Follow up of a Phase II Study of Guadecitabine (SGI-110) in Patients with Higher-Risk Myelodysplastic Syndrome (MDS)
Authors: Morita Kiyomi , Montalban Bravo Guillermo , Sasaki Koji , Bodden Kristy R. , Wang Feng , Bose Prithviraj , Alvarado Yesid , Daver Naval , Borthakur Gautam , Ravandi Farhad , Takahashi Koichi , Jabbour Elias , DiNardo Courtney D. , Pemmaraju Naveen , Kadia Tapan M. , Ohanian Maro , Pierce Sherry A. , Azab Mohammad , Kantarjian Hagop M. , Garcia-Manero Guillermo 
Published: November 2020

Introduction:
Guadecitabine (SGI-110) is a next-generation hypomethylating agent (HMA) not metabolized by cytidine deaminase, a common pathway of decitabine deactivation. A multicenter phase II study has shown the clinical activity of guadecitabine in patients (pts) with intermediate and high-risk MDS (Lancet Heme 2019). Here we present an update of a single center phase II study of guadecitabine for pts with previously untreated higher risk MDS.
Methods:
100 pts with higher risk MDS or chronic myelomonocytic leukemia (CMML, IPSS INT-2 or high, or bone marrow [BM] blast ≥10%) were treated under a phase II study of guadecitabine monotherapy at a dose of 60 mg/m2 SC daily for 5 days every 4 weeks (NCT02131597). One prior cycle of azacitidine or decitabine was allowed. No prior intensive chemotherapy was allowed. Response was evaluated according to the International Working Group 2006 criteria. Next generation sequencing on whole BM extracted DNA was performed using a 28-gene panel (N=62, 62%) or 81-gene panel (N=36, 36%). Overall survival (OS) is calculated from the start date of treatment to the date of death, or last follow-up. Progression-free survival (PFS) is calculated from the start date of treatment to the date of disease progression, or last follow-up. Cox regression model was used for univariate and multivariate analysis to identify prognostic factors. Allogeneic stem cell transplantation (allo-SCT) was considered as a time-dependent variable. Safety profile events were recorded according to the CTCAE v4.0.
Results:
Pts characteristics are summarized in Table 1. Median age was 69 years (range, 22-90), 93 (93%) were previously untreated, and 82 (82%) had MDS. By IPSS classification, 7 (7%) pts were categorized as INT-1, 77 (77%) as INT-2, 15 (15%) as high. Median BM blast percentage was 9% (range, 0-20). Median hemoglobin, neutrophil, and platelet counts were 9.3 g/dL (range, 5.8-13.8), 0.9 x 109/L (range, 0-23.4), and 56 x 109/L (range, 2-881), respectively. Karyotype was normal in 24 (24%) and complex in 39 (39%) pts. Most commonly detected mutations were in TP53 (33%), followed by ASXL1 (31%), TET2 (27%), SRSF2 (22%), RUNX1 (18%), and DNMT3A (16%, Figure 1). Pts received median 5 (range, 1-45) cycles of guadecitabine in total, with median 3 (range, 1-26) cycles until achieving best response. Overall response rate (ORR) was 62%; 25 (25%) with complete remission (CR), 30 (30%) with marrow CR (mCR) with hematologic improvement (HI), 7 (7%) with HI. Two pts (2%) had stable disease, and 33 (33%) showed no response. With a median follow-up duration of 33.8 months (95% CI: 25.9-38.0), 42 (42%) had disease progression and 66 (66%) died. Twenty-one (21%) pts underwent allo-SCT. Median PFS and OS were 14.1 months (95% CI: 10.7-19.2) and 16.9 months (95% CI: 13.2-24.3), respectively. Pts with TP53 mutations had significantly worse OS compared with those without (median OS 11 months [95% CI: 5-14] vs 27 months [95% CI: 16-33], p &lt;0.001, Figure 2). Allo-SCT was associated with better OS among guadecitabine responders (median OS 46 months [95% CI: 31-NA] vs 18 months [95% CI: 14-24] in allo-SCT vs no allo-SCT, p = 0.001). By univariate analysis, complex karyotype (HR 2.78, p &lt;0.001), TET2 mutation (HR 0.44, p = 0.015), TP53 mutation (HR 2.48, p &lt;0.001), overall response (CR/mCR/HI vs others, HR 0.46, p = 0.002), early response within 2 cycles (HR 0.54, p = 0.013), and allo-SCT (HR 0.25, p &lt;0.001) were predictive of OS. Multivariate analysis showed that TP53 mutation (HR 2.25, p = 0.019), overall response (HR 0.42, p = 0.003), early response (HR 0.56, p = 0.039), and allo-SCT (HR 0.36, p = 0.021) were significant prognostic factors for OS (Table 2). Common toxicities regardless of causality included infection (62%), fatigue (46%), nausea (26%), injection site reaction (18%), dyspnea/mucositis/constipation (all 17%), thrombocytopenia/diarrhea (12%), and vomiting (11%).
Conclusions:
Guadecitabine was well tolerated with durable response in previously untreated higher risk MDS and CMML pts. Guadecitabine therapy followed by allo-SCT may confer a long-term survival to higher risk MDS and CMML pts.

Disclosures
Sasaki: Pfizer Japan: Consultancy; Otsuka: Honoraria; Daiichi Sankyo: Consultancy; Novartis: Consultancy, Research Funding. Bose:Kartos Therapeutics: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; NS Pharma: Research Funding; Promedior, Inc.: Research Funding. Alvarado:Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding; BerGenBio ASA: Research Funding; Sun Pharma: Research Funding; Tolero Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding. Daver:Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Borthakur:Curio Science LLC: Consultancy; FTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; Abbvie: Research Funding; Novartis: Research Funding; PTC Therapeutics: Research Funding; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; BMS: Research Funding; BioLine Rx: Research Funding; AstraZeneca: Research Funding; Polaris: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Cyclacel: Research Funding; Incyte: Research Funding; GSK: Research Funding; Jannsen: Research Funding; BioTherix: Consultancy. Ravandi:Orsenix: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria. Jabbour:Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding. DiNardo:Takeda: Honoraria; Calithera: Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; MedImmune: Honoraria; ImmuneOnc: Honoraria; Novartis: Consultancy; Jazz: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding. Pemmaraju:Cellectis: Research Funding; Roche Diagnostics: Honoraria; Celgene: Honoraria; Pacylex Pharmaceuticals: Consultancy; SagerStrong Foundation: Other: Grant Support; Affymetrix: Other: Grant Support, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Blueprint Medicines: Honoraria; Plexxikon: Research Funding; LFB Biotechnologies: Honoraria; MustangBio: Honoraria; DAVA Oncology: Honoraria; Samus Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Incyte Corporation: Honoraria. Kadia:Incyte: Research Funding; Novartis: Honoraria; Cyclacel: Research Funding; Ascentage: Research Funding; Cellenkos: Research Funding; Pfizer: Honoraria, Research Funding; Celgene: Research Funding; Astellas: Research Funding; BMS: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Astra Zeneca: Research Funding; Pulmotec: Research Funding; Amgen: Research Funding; JAZZ: Honoraria, Research Funding. Azab:Astex Pharmaceuticals: Current Employment. Kantarjian:Ascentage: Research Funding; Immunogen: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Abbvie: Honoraria, Research Funding; BMS: Research Funding; Jazz: Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding. Garcia-Manero:Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; H3 Biomedicine: Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Onconova: Research Funding.