Abstract Introduction: Historically, clinical outcome of patients with myelodysplastic syndrome (MDS), progressing on hypomethylating agents (HMA; azacitidine or decitabine) has been dismal with median overall survival (OS) of less than 6 months (Jabbour et al. Cancer 2010). With recent approval of venetoclax based combinations for acute myeloid leukemia (AML) and CPX-351 for AML with MDS related changes (primary or secondary), clinical outcome has improved in sub-set of high-risk patients compared to historical cohorts. Hence, we analyzed clinical outcome of MDS patients progressing on HMA, in the current era of novel therapies. Methods: We retrospectively analyzed clinical outcome of 43 MDS patients who progressed on HMA-based therapy and treated at the Mayo Clinic between February 2015 and February 2021. We describe clinical characteristics of these patients, therapies received after progressing on HMA-based therapy, duration of response attained after 1st line therapy post HMA-based therapy and OS from time of HMA failure till death or last follow up. We also performed Cox regression multivariate analysis for OS after progression on HMA-based therapy. Results: Baseline characteristics are summarized in Table 1.The median age of the patients were 69 years (range [R], 48-93). R-IPSS score in this cohort of patients was very low (2[5%]), low (5[12%]), intermediate (5 [12%]), high (11[26%]) and very high (20 [46.5%]). Forty-nine percent of patients had complex cytogenetics. Most commonly occurring mutations (≥ 5%) were TP53 (42%), splicing mutation (SRSF2/SF3B1/ or U2AF1) (16%), ASXL1 (12%), RUNX1 (7%), DNMT3A (5%) and IDH1/ or IDH2 (5%). The HMA-based therapy patients received were azacitidine (40%), decitabine (30%) and HMA plus venetoclax (30%). The median time to progression from time of initiation of HMA-based therapy was 5 months (R= 1-30). Sixty-three percent (n= 27) of patients progressed to AML after HMA-based therapy. The most common 1 st line therapies post HMA was venetoclax-based (12 [28%]), CPX-351 (12 [28%]), and allogeneic stem cell transplantation (SCT) (4 [9%]). Fifteen (45.5%) patients achieved CR/CRi, 17 (51.5%) patients progressed and 1 (3%) patient had stable disease. The percentage of patients received venetoclax with HMA, 1 st and 2 nd line therapy post HMA were 26%, 28% and 10%, respectively. Overall, 11 (25%) patients received SCT in this cohort of patients. The median duration of response after 1 st line therapy post HMA was not reached (NR; 66% progression free at 1 year) (Figure 1A). The median OS after HMA failure was 12.7 months (95% CI: 3.1-22.2) (Figure 1B). In the univariate analysis for OS after HMA failure, SCT at any time point (p = 0.01) and achieving CR/CRi after 1 st line therapy post HMA (p= <0.001) showed favorable significance for OS. Whereas, R-IPSS high/very high (p= 0.35), treatment with CPX-351 on AML progression (p=0.33), venetoclax-based therapy (p= 0.59) did not show statistical significance. Subsequently, in multivariate analysis, only achievement of CR/CRi after 1 st line therapy post HMA retained significance for favorable OS (HR: 0.19, 95% CI: 0.04-0.86, p= 0.03). Conclusions: To the best of our knowledge, this is the first report analyzing outcome of MDS patients progressing on HMA in the recent era. Acknowledging the limitations of retrospective analysis, our report suggests improved outcome of these high-risk patients compared to historical data. Utilizing venetoclax plus HMA combination earlier in patients with high-risk MDS as being evaluated in VERONA trial and consolidation therapy with SCT in eligible patients have potential to improve long term outcome of this group of high-risk patients. Figure 1 Figure 1. Disclosures Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Palmer: PharmaEssentia: Research Funding; Incyte: Research Funding; Protagonist: Consultancy, Research Funding; CTI BioPharma: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding. Murthy: CRISPR Therapeutics: Research Funding. Litzow: Pluristem: Research Funding; Actinium: Research Funding; AbbVie: Research Funding; Omeros: Other: Advisory Board; Jazz: Other: Advisory Board; Amgen: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Foran: pfizer: Honoraria; takeda: Research Funding; trillium: Research Funding; boehringer ingelheim: Research Funding; syros: Honoraria; sanofi aventis: Honoraria; revolution medicine: Honoraria; servier: Honoraria; bms: Honoraria; certara: Honoraria; abbvie: Research Funding; OncLive: Honoraria; gamida: Honoraria; taiho: Honoraria; novartis: Honoraria; aptose: Research Funding; actinium: Research Funding; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees.