Introduction: Guadecitabine is a dinucleotide of decitabine which has shown high response rates in higher-risk myelodysplastic syndrome. In this update we seek to evaluate the performance of the International Working Group (IWG) 2023 criteria in a prospective, systematically annotated clinical trial.

Methods: Patients older than 18 years old with higher-risk MDS/CMML as defined by the International Prognostic Scoring System - Revised (IPSS-R), or those with more than 10% bone marrow blasts were eligible. Guadecitabine was administered at a dose of 60 mg/m2 subcutaneously daily for 5 days every 28 days. We re-classified patients by World Health Organization 2022, calculated IPSS-Molecular (IPSS-M) scores and clinical responses were reassessed under the IWG-2023 criteria and compared to IWG-2006.

Results: From 2014 to 2018, 82 patients with MDS and 18 patients with CMML were enrolled and treated. Median age was 69 (IQR 62.5 - 75), 62% were male, 38.4% had complex karyotype, 86.6% were categorized as IPSS-M high or very-high risk. Additionally, 33.7% were TP53 mut, 21.4% were TP53 multi-hit. Forty percent of patients were classified as MDS-IB-2, 21.4% as MDS-biTP53, and 17.1% as MDS-IB1. Common mutations were TP53 (38.5%), ASXL1 (22%), DNMT3A (18%) in MDS. ASXL1 (61%), TET2 (61%), NRAS (28%), and SRSF2 (22 %) for CMML patients. Most common treatment-emergent adverse events were fatigue (79% G1-2, 6% G3), nausea (37% G1), injection site reaction (29% G1), and constipation (23% G1). Grade 3 events were febrile neutropenia (32%), infection (25%), and thrombocytopenia (16%). Eight-week mortality was 4%. Ninety-six patients were evaluable for response. The median number of cycles was 5 (IQR:3-8) number of cycles to best response was 3 (IQR:2-5). Median overall survival (mOS) was 16.8 months. Survival was response-dependent with mOS in months being 32, 23.3, 15.5 and 8 for complete remission (CR), mCR (marrow complete remission), HI (hematologic improvement) and NR (no response) by IWG 2006 criteria (Figure 1).

By IWG-2023 overall response rate (ORR) was 52%, with a complete remission (CR) of 29%, 3% with complete remission with bilineage limited hematologic recovery (CRLbi), 11% with CRL with unilineage recovery (CRLuni), 5% complete remission with incomplete hematologic recovery (CRh), and 4% had hematologic improvement (HI). Patients classified as mCR by 2006 criteria (n=30) were reclassified as CR (6.6%), CRLbi (6.6%), CRLuni (33.3%), CRh (16.6%), HI (6.6%), NR (26.6%),and PR (3.3%). Patients in mCR who underwent allogeneic-stem cell transplant (allo-SCT) (n=9) had a mOS of 46 months, compared to 14.4 months to those who did not (log-rank, p < 0.005). Median OS in months was 32.8, 28.6, 17.5, 7.8, 16.8, and 9.2 for CR, CRLbi, CRLuni, CRh, HI, and NR, respectively (log-rank < 0.005). In a multivariate analysis TP53 multi-hitwas the only factor significant in prognosticating response (p = 0.023) and overall survival (p =0.03).

Discussion: In this report we examine the performance of the IWG 2023 criteria in a prospective clinical trial. Patients classified as mCR had significantly heterogenous outcomes which were more precise when re-classified by IWG-2023. Patients in mCR may still benefit from allo-SCT. These criteria also demonstrate response-dependent overall survival outcomes. TP53 multi-hitwas predictive of response and overall survival. This analysis shows the improved accuracy of the IWG 2023 model in stratifying clinical responses and survival. These may serve as future benchmarks for drug development and trial design.

Figure 1. Overall survival by A) IWG 2006 criteria and B) IWG 2023 criteria.

Chien:Rigel Pharmaceuticals: Consultancy; AbbVie: Consultancy. Borthakur:Pacylex, Novartis, Cytomx, Bio Ascend:: Membership on an entity's Board of Directors or advisory committees; Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Alvarado Valero:MEI Pharma: Research Funding; BerGenBio: Research Funding; FibroGen: Research Funding; Daiichi-Sankyo: Research Funding; CytomX Therapeutics: Consultancy; Astex: Research Funding; Jazz: Research Funding; Sun Pharma: Consultancy, Research Funding. Kadia:Biologix, Cure, Hikma Pharmaceuticals: Speakers Bureau; Iterion: Research Funding; Ascentage Pharma Group: Research Funding; GenFleet Therapeutics: Research Funding; Glycomimetics: Research Funding; Astellas Pharma Global Development: Research Funding; Cyclacel: Research Funding; Amgen, Inc.: Research Funding; AbbVie, Amgen, Inc, Ascentage Pharma Group, Astellas Pharma Global Development, Astex, AstraZeneca, BMS, Celgene, Cellenkos Inc, Cyclacel, Delta-Fly Pharma, Inc, Genentech, Inc., Genfleet, Glycomimetics, Iterion, Janssen Research and Development: Research Funding; Novartis: Consultancy; Genzyme: Honoraria; SELLAS Life Sciences Group: Research Funding; Genentech: Consultancy, Research Funding; Jazz Pharmaceuticals, Pfizer, Pulmotect, Inc, Regeneron Pharmaceuticals, SELLAS Life Sciences Group: Research Funding; Cellenkos Inc.: Research Funding; Cure: Speakers Bureau; Delta-Fly Pharma, Inc.: Research Funding; Janssen Research and Development: Research Funding; Hikma Pharmaceuticals: Speakers Bureau; Liberum: Consultancy; AstraZeneca: Research Funding; Celgene: Research Funding; Sanofi-Aventis: Consultancy; Regeneron Pharmaceuticals: Research Funding; Pulmotect, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo, Genentech, Inc., Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Inc, Pulmotect, Inc, Sanofi-Aventis, Servier: Consultancy; Agios: Consultancy; Servier: Consultancy; Pinotb-Bio: Consultancy; BMS: Consultancy, Research Funding; Astex: Honoraria. Daver:Jazz: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Novartis: Consultancy; Hanmi: Research Funding; Trovagene: Research Funding; Syndax: Consultancy; Pfizer: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Agios: Consultancy; Celgene: Consultancy; Gilead: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding; FATE: Research Funding; AROG: Consultancy; Shattuck Labs: Consultancy; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kite, a Gilead company: Consultancy, Research Funding; Kronos Bio: Research Funding. Ravandi:Syros: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astex/taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomea fusion: Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Xencor: Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Prelude: Research Funding. Bose:GSK, Novartis, Karyopharm, AbbVie, Pharma Essentia, Jubilant, Morphic: Honoraria; Kartos, Telios, Ionis, Disc, Janssen, Geron: Research Funding; Incyte, BMS, CTI, Morphosys, Blueprint, Cogent, Sumitomo: Honoraria, Research Funding. Yilmaz:Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Kantarjian:Abbvie: Consultancy, Honoraria; Astellas Pharma: Honoraria; Ascentage Pharma Group: Honoraria; AstraZeneca/MedImmune: Honoraria; Daiichih-Sankyo (Inst): Honoraria, Research Funding; Immunogen (Inst): Honoraria, Research Funding; Ipsen: Honoraria; Jazz Pharmaceuticals (Inst): Honoraria, Research Funding; KAHR Medical: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Precision Biosciences: Honoraria; Shenzhen Target Rx: Honoraria; Taiho Pharmaceutical: Honoraria; Abbvie (Inst): Research Funding; Amgen (Inst): Research Funding; Ascentage Pharma (Inst): Research Funding; Bristol-Myers Squibb (Inst): Research Funding; Novartis (Inst): Research Funding; Amgen: Honoraria. Garcia-Manero:Bristol Myers Squibb: Other: Medical writing support, Research Funding; Genentech: Research Funding; AbbVie: Research Funding.

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