Background: HMAs are the standard of care for most pts with higher risk MDS. However, the role of the therapy is not well defined in lower risk MDS. Data from our center has indicated that attenuated dose schedules of HMA are safe and active in pts with low risk MDS (Jabbour et al. Blood 2018) but the safety and activity of these therapies is not known in TI pts with low risk MDS. To study this, we performed an analysis of a cohort pts with TI low risk or int-1 risk MDS by IPSS. Methods: Eighty-seven pts with low-risk or int-1 risk MDS treated with HMAs from 2012 to 2017 were analyzed. Pts had been treated in prospective trials of attenuated HMA at a single institution. Therapy could consist of decitabine 20 mg/m2 IV QD x 3 days every 28 days or azacitidine 75 mg/m2 daily x 3 days every 28 days or azacitidine at the same dose and schedule for 5 days. All pts were TI at baseline. Results: The median age was 70 (25-85); 64 pts (74%) were males; 57 pts (66%) were int-1 risk and 30 (34%) were low risk by IPSS. By the MDACC Lower Risk Prognostic Model: 51 pts (59%) were intermediate risk, 23 (26%) high risk and 13 (15%) low-risk. Cytogenetics were good in 59 (68%), intermediate in 22 (25%) and poor in 6 pts (7%). The median time to treatment was 4.13 months and the median number of prior treatments was 0 (0-1). The median total courses of treatment was 14 (1-41). TET2, ASXL1 and RUNX1 mutations occurred in 30%, 9% and 8%, respectively. Of the 87 pts, 80 were evaluable. No deaths were observed during the first 8 weeks of therapy and no severe hematological toxicity. The overall response rate (ORR) was 74% [CR – 40 (50%), mCR with and without HI – 5 (6%), 3 (4%), respectively, HIP – 10 (13%) and HIN – 1 (1%)]. The median OS was not reached and the median event-free survival (EFS) was 35.4 months. Two pts (3%) had progressive disease; 19 (24%) had no response; 6 (8%) progressed to acute myeloid leukemia. Five pts (6%) became transfusion dependent at the time of response evaluation. Conclusions: Early intervention with attenuated doses of HMAs in TI pts with lower risk MDS is safe and active and could potentially alter the natural history of MDS.