This phase II trial studies how well tislelizumab combined with DNA hypomethylation agent +/- CAG regimen (cytarabine, idarubicin / Aclarithromycin, rhG-CSF/ PEG-rhG-CSF) work in treating patients with high-risk acute myeloid leukemia (AML) or AML patients older than 60 years of age who are unfit for standard-dose chemotherapy. The expressions of PD-1 and PD-L1 are increased in AML cells. However, blocking the immune checkpoint alone has limited efficacy as a single agent in highly proliferative leukemia cells. During the recovery period after cytotoxic chemotherapy, the activation of PD-1/PD-L1 pathway may be increased and DNA hypomethylation agents can also up-regulate PD-1, PD-L1 and PD-L2 in AML patients. The up-regulation and activation of above immune checkpoint molecules are related to chemotherapy resistance. Therefore, adding chemotherapy and epigenetic regulation agents to Immune checkpoint blockade therapy may work better through overcoming drug resistance in AML treatment.

Inclusion Criteria:

1. Patients or their legally authorized representative must provide written informed consent.
2. Meet the diagnostic criteria for acute myeloid leukemia (AML) with positive minimal residual disease (MRD), excluding those patients who are MRD-positive or MRD recurrence after allogeneic hematopoietic stem cell transplantation (HSCT); or meet the diagnostic criteria for relapsed AML, excluding those experience relapsed within 2 months after HSCT from matched sibling donor or within 3 months after HSCT from alternative donor; or meet the diagnostic criteria for refractory AML, excluding those patients within 2 months after HSCT from matched sibling donor or those patients within 3 months after HSCT from alternative donor.
3. Bone marrow (BM) or peripheral blood (PB) leukemia cells were measured to express PD-L1 within 3 months of entering the study.
4. The toxic side effects of the last treatment should be restored.
5. Eastern Cooperative Oncology Group (ECOG) performance status =< 2.
6. Creatinine =< 1.5 x upper limit of normal (ULN). Serum bilirubin =< 1.5 x ULN. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN.
7. Karnofsky Performance Scale Index => 70.
8. The expected survival period is at least 12 weeks.
9. Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (b-hCG) pregnancy test result within 24 hours prior to the first dose of treatment and must agree to use an effective contraception method during the study and for 23 weeks after the last dose of the study drug; females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy. Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 31 weeks following the last dose of study drug.

Exclusion Criteria:

1. Patients with positive minimal residual disease (MRD) or MRD recurrence after HSCT; or patients who relapse or refractory within 2 months after HSCT from matched sibling donor or within 3 months after HSCT from alternative donor.
2. History of another primary invasive malignancy that has not been definitively treated or in remission for at least 2 years.
3. Any major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy, experimental therapy within 2 weeks prior to the first dose of the study drugs.
4. Patients with any other known concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes; cardiovascular disease including congestive heart failure New York Heart Association [NYHA] class III or IV, myocardial infarction within 6 months, and poorly controlled hypertension; chronic renal failure; or active uncontrolled infection) which, in the opinion of the investigator could compromise participation in the study.
5. Patients unwilling or unable to comply with the protocol.
6. Patients who are on steroids (> 10 mg/day or equivalent) or immune suppression medications.
7. Patients with autoimmune diseases (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's granulomatosis]).
8. Patients with a history of inflammatory bowel disease such as Crohn's disease and ulcerative colitis.
9. Patients known to be positive for hepatitis B surface antigen expression or with active hepatitis C infection (positive by polymerase chain reaction or on antiviral therapy for hepatitis C within the last 6 months), or with known human immunodeficiency virus (HIV) infection.
10. Current therapy with other systemic anti-neoplastic or anti-neoplastic investigational agents.
11. Females who are pregnant or lactating.
12. Any grade of not controlled graft versus host disease.