Background: Hypomethylating agents (HMAs) are the preferred treatment for untreated patients (pts) with higher-risk MDS, but the survival of pts after HMAs treatment is poor. It has been demonstrated that the PD-1/PD-L1 expression was upregulated by HMAs in MDS pts, providing a strong rationale for combining HMAs with PD-1 antibody for MDS treatment. Therefore, this single-arm, open-label, clinical trial was performed to evaluate safety and efficacy of Sintilimab plus decitabine for pts with higher-risk MDS (ChiCTR2100044393). Methods: Adult pts with higher-risk MDS by the IPSS-R were enrolled. Patients received decitabine 20mg/m² intravenously daily for 5 days and sintilimab 200mg IV starting on the first and 22nd day of a cycle every 42 days until unacceptable toxicity, relapse, or progression, for a maximum of 8 cycles. The primary endpoint was overall response rate (CR+PR+mCR). Simon’s optimal two-stage design was employed.If five or more pts in stage I (13 pts) achieved ORR, the study would enroll 34 additional pts in stage II (47 pts). Secondary endpoints included safety, and survival outcomes. The relationship between expression levels of immune-checkpoint and efficacy of the combination therapy, as well as other potential biomarkers were also explored via genomic profiling. Results: At data cut-off (January 31, 2022), 21 pts were enrolled with a median follow-up time of 5.8 months. The median age of pts was 64 years (range 30-83), and the other characteristics are summarised in Table.The ORR was 62%,with six pts reaching complete response (CR),four pts reaching marrow CR and three pts achieved marrow CR+ hematologic improvement (HI). In addition,four pts reaching HI. The most common grade 3 TEAEs( > 10%) were febrile neutropenia (76.2%) and pulmonary infection (38.1%). No grade 4 TEAEs and treatment-related deaths occurred. A total of 12 pts （57.1%）experienced immune-related adverse event, including rash (28.6%), pneumonia (9.5%), hypothyroidism (9.5%), elevated serum bilirubin (4.8%) and transpeptidase (4.8%), which were all resolved by glucocorticoid. In these 21 pts, the most frequently mutated genes are ASXL1（28.6%）, RUNX1 (14.3%) and TET2(14.3%). Updated biomarker data will be presented during the ASCO meeting. Conclusions: To the best of our knowledge, this is the first study to evaluate the efficacy and safety of sintilimab plus decitabine in pts with untreated higher-risk MDS. The preliminary results demonstrate that the combination therapy is relatively safe with anti-tumor activity. Clinical trial information: ChiCTR2100044393.