Azacitidine With or Without Nivolumab or Midostaurin, or Decitabine and Cytarabine Alone in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Inclusion Criteria:

   - REGISTRATION STEP 1-SPECIMEN SUBMISSION

   - Patients must be suspected to have previously untreated acute myelogenous leukemia
   (AML) or myelodysplastic syndrome with excess blasts-2 (MDS-EB-2)

   - Patients must not be known to have AML in the central nervous system (CNS)

   - Patients must have specimens submitted for FLT3 testing for randomization
   stratification; collection of pretreatment specimens must be completed within 1 day of
   registration to Step 1; specimens must be submitted via the Southwest Oncology Group
   (SWOG) Specimen Tracking System; FLT3 results will be used for stratification purposes
   at the time of randomization; E-mail notification of randomization assignment must be
   received prior to Step 2 registration

   - Patients must be offered participation in specimen banking; with patient consent,
   pretreatment specimens must be collected and submitted via the SWOG Specimen Tracking
   System

   - Patients who have received prior therapy with midostaurin, any anti-PD-1 or anti-PD-L1
   therapy, any deoxyribonucleic acid (DNA)-methyltransferase inhibitor (including
   hypomethylating agents such as azacitidine, decitabine, or other investigational agent
   that acts by inhibiting DNA or ribonucleic acid [RNA] methylation) for any condition,
   or prior intensive cytotoxic therapy for myelodysplastic syndrome (MDS), are not
   eligible

   - Patients must be able to swallow oral medications without crushing or chewing

   - Prior malignancy is allowed providing it does not require concurrent therapy

      - Exception: active hormonal therapy is allowed

   - Patients must not be pregnant or nursing; women/men of reproductive potential must
   have agreed to use an effective contraceptive method; a woman is considered to be of
   "reproductive potential" if she has had menses at any time in the preceding 12
   consecutive months; in addition to routine contraceptive methods, "effective
   contraception also includes (but is not limited to) heterosexual celibacy and surgery
   intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined
   as a hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or vasectomy;
   however, if at any point a previously celibate patient chooses to become
   heterosexually active during the time period for use of contraceptive measures
   outlined in the protocol, he/she is responsible for beginning contraceptive measures

      - Women must agree to avoid breast-feeding and women of child-bearing potential
      (WOCBP) must agree to use highly effective contraception while receiving study
      drug and for a period of 31 weeks after the last dose of study drug;
      sexually-active men must agree to use a condom while receiving study drug and for
      31 weeks after the last dose of study drug; vasectomized men must also agree to
      use a condom to avoid delivering drug in the seminal fluid

   - Patients must be informed of the investigational nature of this study and must sign
   and give written informed consent in accordance with institutional and federal
   guidelines

   - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
   treating institution's identity is provided in order to ensure that the current
   (within 365 days) date of institutional review board approval for this study has been
   entered in the system

   - REGISTRATION STEP 2-RANDOMIZATION: Patients must be registered to Step 2 no more than
   42 days after registration to Step 1 and no more than 42 days after collection of
   specimens for FLT3 testing

   - REGISTRATION STEP 2-RANDOMIZATION: Patients must have morphologically confirmed,
   previously untreated acute myeloid leukemia (AML) or MDS with excess blasts-2
   (MDS-EB-2)

      - Patients with acute promyelocytic leukemia (APL), biphenotypic leukemia, blastic
      transformation of chronic myelogenous leukemia (CML or BCR/ABL), are not eligible

      - Patients must have disease present in the blood or bone marrow; patients with
      only extramedullary disease in the absence of bone marrow or blood involvement
      are not eligible

      - All tests for establishing baseline disease status eligibility must be based on
      blood and/or bone marrow examination performed within 42 days prior to
      randomization (registration Step 2)

   - REGISTRATION STEP 2-RANDOMIZATION: Patients must not be known to have AML in the CNS

   - REGISTRATION STEP 2-RANDOMIZATION: Patients must be deemed, in the judgment of the
   treating physician, to be ineligible for intensive induction therapy, or must have
   refused intensive induction therapy; rationale for clinical determination or notation
   of patient decision must be made

   - REGISTRATION STEP 2-RANDOMIZATION: Pretreatment cytogenetics must be performed on all
   patients; collection of pretreatment specimens must be completed within 42 days prior
   to randomization (registration Step 2); reports of the results must be submitted

   - REGISTRATION STEP 2-RANDOMIZATION: FLT3 results will be used for stratification
   purposes at the time of randomization; E-mail notification that FLT3 specimens have
   been processed must be received prior to randomization (registration Step 2)

   - REGISTRATION STEP 2-RANDOMIZATION: Prior treatment with hydroxyurea is permitted;
   prior all-trans retinoic acid (ATRA) for suspected APL and prior intrathecal therapy
   are permitted, but must plan to be discontinued prior to initiating protocol therapy;
   patients with signs/symptoms of hyperleukocytosis or white blood cells (WBC) >=
   50,000/mcL can be treated with leukapheresis prior to randomization (registration to
   Step 2)

   - REGISTRATION STEP 2-RANDOMIZATION: Patients may have received non-intensive therapy
   for antecedent hematologic disorders, including lenalidomide; patients may have
   received prior chemotherapy for prior cancers; these therapies must be discontinued at
   least 5 days prior to randomization (registration to Step 2)

   - REGISTRATION STEP 2-RANDOMIZATION: Patients who are transfusion-dependent and patients
   receiving growth factor support are eligible; patients must discontinue growth factor
   support prior to initiation of protocol therapy

   - REGISTRATION STEP 2-RANDOMIZATION: The following tests must be performed within 14
   days prior to randomization (registration to Step 2) to establish baseline values:

      - Performance status

      - Complete blood count (CBC)/differential/platelets

      - Creatinine clearance (Cockcroft-Gault)

      - Total bilirubin

      - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)

      - Lactate dehydrogenase (LDH)

      - Albumin

      - Glucose

      - Fibrinogen

      - Electrocardiogram (ECG)

   - REGISTRATION STEP 2-RANDOMIZATION: Patients must have complete history and physical
   examination within 28 days prior to randomization (registration to Step 2); history
   must include autoimmune disease status (to determine whether patient is eligible for
   Arm B)

   - REGISTRATION STEP 2-RANDOMIZATION: Patients must not have active infection (systemic
   bacterial, fungal, or viral infection) that is not controlled (defined as exhibiting
   ongoing signs/symptoms related to the infection and without improvement despite
   appropriate antibiotics or other treatment)

   - REGISTRATION STEP 2-RANDOMIZATION: Patients must be eligible for at least one of the
   currently active investigational treatment arms (S1612B or S1612C); if the patient
   does not meet eligibility criteria for at least one active investigational arm, then
   the patient is not eligible for S1612

   - REGISTRATION STEP 2-RANDOMIZATION: Patients must be informed of the investigational
   nature of this study and must sign and give written informed consent in accordance
   with institutional and federal guidelines

   - ARM B (AZACITIDINE + NIVOLUMAB)

   - Patients must not have active autoimmune disease that has required systemic treatment
   in past 2 years (i.e., with use of disease modifying agents, corticosteroids or
   immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or
   physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
   etc.) is not considered a form of systemic treatment

   - Patients must have AST and ALT =< 2.5 x institutional upper limit of normal (IULN)

   - Patients must have total bilirubin =< 1.5 x IULN

   - Patients must have baseline troponin test performed for eligibility; however, no
   associated values must be met in order for the patient to be eligible

   - ARM C (AZACITIDINE + MIDOSTAURIN)

   - Patients must have total bilirubin =< 2.5 x IULN

   - Patients must have creatinine clearance =< 2.5 x IULN

   - Patients must have corrected QT (QTc) interval < 500/msec (by Bazett's formula) on
   baseline ECG

   - Patients must not have any history of hypersensitivity to any drugs or metabolites of
   midostaurin

   - All tests for establishing baseline values must be completed within 14 days prior to
   registration to Step 2 (randomization)