Background: HMAs improve survival of pts with higher-risk MDS; however, the role of HMAs is less clear in pts with lower-risk MDS. These pts have a heterogeneous prognosis, and some may benefit from early HMA therapy. To test the hypothesis that low-dose HMA therapy would be safe and effective in pts with lower-risk MDS, we treated pts with International Prognostic Scoring System (IPSS) low- or intermediate-1-risk MDS with low-dose HMA regimens using 3 days of either 5-azacytidine (AZA) or decitabine (DAC). Methods: Adult pts with de novo or secondary low- or intermediate-1-risk MDS, CMML or MDS/MPN were eligible for this study. Pts were treated with AZA 75 mg/m2 IV/SC daily or DAC 20 mg/m2 IV daily for 3 consecutive days on a 28-day cycle. The primary efficacy outcome was the overall improvement rate (OIR) defined as the composite of complete remission (CR), CR with insufficient hematologic recovery (CRi) and hematologic improvement (HI). Secondary outcomes included safety profile, duration of response, conversion to transfusion independence, event-free survival (EFS), and overall survival (OS). EFS was defined as the time to HMA failure, progressive disease, transformation to acute myelogenous leukemia (AML) or death from any cause. Chi-square test was performed to evaluate differences in response rates. EFS and OS were calculated using Kaplan-Meier estimates and compared using the log-rank test. Results: Between 11/2012 and 6/2015, 88 pts with lower-risk MDS were treated; 83 of them are currently evaluable for response assessment (65 MDS, 15 CMML and 3 MDS/MPN). Thirty pts received AZA (36%) and 53 pts (64%) received DAC. Median time from diagnosis to treatment was 5 weeks (range 1-272 weeks). Median age was 71 years (range 44-85 years). Sixteen pts (19%) had therapy-related MDS. Thirty-eight pts (46%) were transfusion-dependent for RBCs and/or platelets at baseline, and 17 pts (20%) had received prior growth factor support with erythropoietin-stimulating agents or G-CSF. By IPSS, 13 pts (16%) had low-risk and 70 pts (84%) had intermediate-1-risk disease. By the MDACC lower-risk scoring system, 38 pts (46%) had high-risk, 38 pts (46%) had intermediate-risk and 7 pts (8%) had low-risk disease. Twenty-seven pts (33%) had ≥5% bone marrow blasts. By IPSS, cytogenetics were good-risk in 55 pts (66%), intermediate-risk in 20 pts (24%) and poor-risk in 8 pts (10%). Mutation analysis was performed in 76 pts at the time of enrollment, 43 (57%) of whom had at least one molecular mutation. TET2 mutation was identified in 17 pts (22%), RUNX1 in 8 pts (11%), TP53 in 6 pts (8%), ASXL1 in 5 pts (7%), IDH1/2 in 5 pts (7%) and DNMT3A in 4 pts (5%). The median follow-up was 13 months (range 2-30 months) and median number of cycles received was 9 (range 2-29 cycles). The OIR for the entire cohort was 61%; 32 pts (39%) achieved CR, 11 (13%) achieved CRi and 8 (10%) achieved HI. Of the 38 transfusion-dependent pts at baseline, 9 (24%) became transfusion-independent. The median time to best response was 2.2 months (range 0.8 to 19.6 months). Median duration of response has not been reached with 71% of responders still on study. Low-dose HMA therapy was well-tolerated with only 6 pts (7%) requiring dose reduction and 19 pts (23%) requiring dose delay. AML developed in 4 pts (5%), and 17 pts (20%) have died. For the entire cohort, the 1-year EFS rate was 67%, and the 1-year OS rate was 86%. The median EFS and OS have not been reached. When stratified by IPSS and the MDACC lower-risk scoring systems, there was not a significant difference in OIR, EFS or OS among various risk groups (Table 1). Conclusions: Among pts with low- and intermediate-1-risk MDS, low-dose HMA therapy was well-tolerated and resulted in an OIR of 61%. Response rates, EFS and OS did not differ when pts were stratified by IPSS or the MDACC lower-risk scoring system. A randomized trial of low-dose AZA vs. DAC vs. best supportive care in lower-risk MDS is ongoing. Disclosures Sekeres:Celgene Corporation: Membership on an entity9s Board of Directors or advisory committees; TetraLogic: Membership on an entity9s Board of Directors or advisory committees; Amgen: Membership on an entity9s Board of Directors or advisory committees. Steensma:Incyte: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Onconova: Consultancy. DiNardo:Novartis: Research Funding. Estrov:incyte: Consultancy, Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Verstovsek:Incyte Corporation: Research Funding.