Background: Hypomethylating agents (HMA), such as azacitidine (AZA), are the standard of care for patients (pts) with higher-risk myelodysplastic syndromes (MDS). However, overall response rate (ORR=CR+PR) with HMA alone is approximately 30%, with a 2-year overall survival (OS) rate of 50.8%. Preclinical studies show that pracinostat (PRAN), an oral histone deacetylase inhibitor, synergizes with HMA. A study in pts with untreated IPSS intermediate-2/high-risk MDS receiving 60 mg PRAN plus AZA resulted in early discontinuations, mainly due to adverse events (AE), potentially leading to diminished clinical benefit. This follow-up phase II study evaluates a lower dose of PRAN (25% reduction) in combination with AZA in order to reduce toxicity, decrease early discontinuations, and improve outcomes. An interim analysis showed low discontinuation rate and promising efficacy, allowing trial expansion. Herein, we report preliminary safety and efficacy in the overall population. Methods: Open-label, II-stage, phase II trial (NCT03151304) in pts (≥18 years) naive to HMA therapy and with IPSS-R of high/very high-risk MDS. Planned enrollment was 60 pts. Pts received 45 mg PRAN 3 days/week for 3 consecutive weeks plus standard AZA dose for 7 days of each 28-day cycle. Primary objectives were to define the safety/tolerability of the combination and to assess the ORR (CR+PR). OS was a secondary endpoint. Results: Sixty-four pts were enrolled and received ≥1 dose of treatment. Most pts were male (67%), median age was 68 years (range 47–89), and the proportion of pts with high/very high-risk MDS was similar. After 17.6 months’ median follow-up, 31% of pts remain on treatment; 69% of pts discontinued treatment due to stem cell transplant (25%), disease progression (17%), AEs (11%), consent withdrawal (3%), pt noncompliance (3%), death (3%), lost to follow-up (2%), and other (5%). Most common nonhematologic AEs were constipation (55%), nausea (52%), fatigue (45%), decreased appetite (39%), peripheral edema (36%), diarrhea, and dyspnea (31% each). Frequent hematologic AEs were decreased neutrophil count (50%), anemia (39%), decreased platelet count (38%), febrile neutropenia (36%), and thrombocytopenia (30%). ORR was 33% (95% CI 22-46), with 33% achieving CR; 34% of pts had marrow CR. Median OS was 23.5 months (95% CI 16.4-nc), with an estimated 1-year OS of 77%. Conclusions: In pts with high/very high-risk MDS, a lower dose of pracinostat in combination with AZA demonstrated a tolerable safety profile and promising efficacy. Clinical trial information: NCT03151304.