Pembrolizumab and Decitabine With or Without Venetoclax in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome That Is Newly-Diagnosed, Recurrent, or Refractory

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorizedrepresentative

• Agreement to allow the use of archival blood samples and marrow from diagnostictumor biopsies. If unavailable, exceptions may be granted with study principalinvestigator (PI) approval

• Eastern Cooperative Oncology Group (ECOG) status =< 1

• Histologically confirmed AML (not including acute promyelocytic leukemia) or MDS

• Patients with the following diagnoses

• Refractory/relapsed AML by World Health Organization (WHO) classification, whoare not candidates for allogeneic stem cell transplantation or potentiallycurative chemotherapy (Extramedullary disease is allowed).

• MDS by WHO Classification who have failed to respond or relapsed after previoustherapies

• Must have a life expectancy of >= 3 months

• Fully recovered (=< grade 1) from the acute toxic effects (except alopecia) orcomplications of prior anti-cancer therapy, including surgery

• Cannot be a candidate for allogeneic hematopoietic cell transplantation (alloHCT)within 90 days of starting treatment on the protocol and should be off pembrolizumabfor at least 30 days to become eligible for alloHCT post-protocol therapy

• White blood cells (WBC) =< 25 x 10^9/L prior to initiation of venetoclax.Cytoreduction with hydroxyurea prior to treatment and/or during cycles 1 and/or 2may be required

• Total bilirubin =< 2 x upper limit of normal (ULN) (unless has Gilbert's disease)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN

• Creatinine clearance of > 30 mL/min per 24-hour urine test or the Cockcroft-Gaultformula

• International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN

• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN

• Left ventricular ejection fraction (LVEF) >= 50%

• Pulmonary function tests diffusion capacity of the lung for carbon monoxide (DLCO) (adjusted for hemoglobin) > 50% predicted

• Corrected QT (QTc) =< 480 ms, Note: electrocardiogram (ECG) (single-read) to beperformed within 14 days prior to day 1 of protocol therapy

• Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab)combo, hepatitis C virus (HCV), and active hepatitis B virus (HBV) (surface antigennegative)

• If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed

• Meets other institutional and federal requirements for infectious disease titerrequirements

• Note: Infectious disease testing to be performed within 28 days prior to day 1of protocol therapy

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

• Agreement by males and females of childbearing potential to use an effective birthcontrol method of low user dependency or abstain from heterosexual activity from 4weeks prior to first dose of treatment throughout the study treatment period and 3 (males) to 4 (females) months from the last dose of treatment

• Childbearing potential is defined as not being surgically sterilized (men andwomen) or have not been free from menses for > 1 year (women only)

• Also, male subjects should refrain from sperm donation from the start of treatmentthroughout the study treatment period and for 6 months following the last dose oftreatment

Exclusion Criteria:

• Previous allogeneic cell transplantation

• Previous treatment with pembrolizumab

• Previously refractory to treatment with decitabine + venetoclax (i.e. progressedthrough therapy without first attaining at least a partial response)

• Systemic steroid therapy or any other form of immunosuppressive medication

• Received a live-virus or live-attenuated virus vaccination within 30 days of plannedtreatment start. Administration of killed vaccines is allowed

• Prior treatment with any other anti-programmed cell death protein-1 (anti-PD-1), orPD ligand-1 (PD-L1) or PD ligand-2 (PD-L2) agent or an antibody targeting otherimmuno-regulatory receptors or mechanisms

• Prior therapy with an anti-CD137, anti-CTLA-4 antibody (including ipilimumab),denosumab or any other antibody or drug specifically targeting T-cell co-stimulationor checkpoint pathways

• Current or planned use of other investigational agents, antineoplastic, biologicalor chemotherapeutic agents during the study treatment period, or within 4 weeks orfive half-lives, whichever is shorter, prior to day 1 of protocol therapy with thefollowing exception:

• Hydroxyurea is allowed prior to treatment with venetoclax and through cycle 2for control of rapidly progressing leukemia

• Strong or moderate CYP3A4 inducers within 14 days prior to day 1 of venetoclax

• Grapefruit, grapefruit products, Seville oranges (including marmalade containingSeville oranges) or star fruit consumed within 3 days prior to the first dose ofvenetoclax

• Has received prior radiotherapy within 2 weeks of start of study intervention.Participants must have recovered from all radiation-related toxicities, not requirecorticosteroids, and not have had radiation pneumonitis. A 1-week washout ispermitted for palliative radiation (=<2 weeks of radiotherapy) to non-centralnervous system (CNS) disease

• Concurrent use of corticosteroids (exception: nasal or topical corticosteroids orphysiologic levels for steroid replacement are allowed)

• Granulocyte-macrophage colony-stimulating factor (GMCSF) or granulocyte colonystimulating factor (GCSF) within 7 days prior to start of study treatment

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to study agent

• Severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb)

• Active central nervous system (CNS) disease

• The following cardiac conditions:

• Unstable angina

• Congestive heart failure (New York Heart Association [NYHA] class III or IV; orclass II with a recent decompensation requiring hospitalization or referral toa heart failure clinic within 6 months before screening)

• Acute coronary syndrome and/or revascularization (e.g., coronary artery bypassgraft, stent) within 6 months of first dose of study drug Note: Allowed heartconditions are restricted to stable angina, arrhythmia or atrial fibrillationcontrolled by medication, history of controlled coronary artery disease > 6months prior to screening and medically managed

• Pulmonary dysfunction, such as history of non-infectious pneumonitis that requiredsteroids or current pneumonitis or idiopathic pulmonary fibrosis. Note: Allowedpulmonary conditions are restricted to mild chronic obstructive pulmonary disease (COPD), controlled asthma, resolved bacterial or fungal pneumonia, or previouspulmonary embolism (PE) that has been compensated

• Active autoimmune disease that has required systemic treatment in the past 2 years (replacement therapies for hormone deficiencies are allowed)

• Uncontrolled active infection requiring therapy

• Known history of active TB (Bacillus tuberculosis)

• Symptomatic ascites or pleural effusion

• Clinically significant uncontrolled illness

• Females only: Pregnant or breastfeeding

• Any other condition that would, in the investigator's judgment, contraindicate thepatient's participation in the clinical study due to safety concerns with clinicalstudy procedures

• Prospective participants who, in the opinion of the investigator, may not be able tocomply with all study procedures (including compliance issues related tofeasibility/logistics)