Midostaurin and Decitabine in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia and FLT3 Mutation

Inclusion Criteria:

* Unfit for chemotherapy based on investigator assessment or patient not willing to receive intensive induction as advised by investigator
* Untreated, histological confirmed acute myeloid leukemia (AML) based on World Health Organization (WHO) 2008 criteria with either/or both:

  * FLT3 ITD mutation
  * FLT3 TKD mutation
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2 or 3
* Serum amylase and lipase =\< 1.5 x upper limit of normal (ULN)
* Total bilirubin =\< 1.5 x ULN (does not apply to patients with isolated hyperbilirubinemia \[e.g., Gilbert's disease\], in that case direct bilirubin should be =\< 2 x ULN)
* Alkaline phosphatase =\< 3 x ULN
* Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 2.5 x ULN
* Creatinine =\< 2 x ULN
* Negative pregnancy test done =\< 7 days prior to registration, for women of childbearing potential only
* Provide informed written consent
* Willing to return to consenting Mayo Clinic (Mayo Clinic's campus in Rochester), for follow-up during the Active Monitoring Phase of the study
* Willing to provide bone marrow aspirate and blood samples for correlative research purposes

Exclusion Criteria:

* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 3 months after treatment completion
* Highly effective contraception methods include:

  * Total abstinence (when this is in line with the preferred and usual lifestyle of the subject; NOTE: periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception)
  * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
  * Male sterilization (at least 6 months prior to screening); NOTE: for female subjects on the study the vasectomized male partner should be the sole partner for that subject
  * Combination of any two of the following (a+b or a+c, or b+c):

    * a) Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate \< 1%), for example hormone vaginal ring or transdermal hormone contraception
    * b) Placement of an intrauterine device (IUD) or intrauterine system (IUS)
    * c) Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
  * NOTE:

    * In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment
    * Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) OR
  * Sexually active males unless they use a condom during intercourse while taking drug and for 5 months after stopping midostaurin medication
  * NOTE:

    * They should not father a child in this period
    * A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid
* Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
* Immunocompromised patients (other than that related to the use of corticosteroids) including patients confirmed to be human immunodeficiency virus (HIV) positive or have active viral hepatitis
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements; patients with any other known concurrent severe and/or uncontrolled medical condition (except carcinoma in-situ), which could compromise participation in the study (e.g. uncontrolled infection, uncontrolled diabetes, chronic active pancreatitis)
* Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
* Other active malignancy =\< 1 year prior to registration; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix
* Previous treatment with specific chemotherapy (cytarabine, idarubicin, daunorubicin) or hypomethylating drug (decitabine or azacitidine) for a hematological disorder; EXCEPTIONS: prior hydroxyurea allowed; secondary AML is allowed
* Impaired cardiac function including any of the following:

  * Inability to monitor the QT interval on electrocardiogram (ECG)
  * Congenital long QT syndrome or a known family history of long QT syndrome
  * Clinically significant resting brachycardia (\< 50 beats per minute)
  * Corrected QT (QTc) \> 450 msec on baseline ECG; NOTE: if the ECG shows a QTc interval greater than 450 msecs at screening triplicates should be performed, one minute apart to confirm the finding (after replacement of any electrolyte imbalance); if 2/3 or 3/3 of the ECGs confirm the QT prolongation (i.e. QTc interval \> 450 msecs) the patient must not be included into the trial
  * Myocardial infarction =\< 3 months prior to starting study
  * Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension)
  * History of or presence of clinically significant ventricular, atrial tachyarrhythmias or ejection fraction cutoff
  * Left ventricle ejection fraction \< 45%
  * History of congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
* Patients currently receiving treatment with strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors and treatment that cannot be either discontinued or switched to a different medication prior to starting study drug; patients receiving any medications or substances that are strong inhibitors of CYP3A4; all azoles but fluconazole are discouraged to be used in patients requiring treatment with antifungal antibiotics; use of the following strong inhibitors is prohibited =\< 7 days prior to registration

  * Strong inhibitors of CYP3A4/5; \> 5-fold increase in the plasma area under the curve (AUC) values or more than 80% decrease in clearance

    * Boceprevir (Victrelis)
    * Clarithromycin (Biaxin, Biaxin XL)
    * Conivaptan (Vaprisol)
    * Indinavir (Crixivan)
    * Itraconazole (Sporanox)
    * Ketoconazole (Nizoral)
    * Lopinavir/Ritonavir (Kaletra)
    * Mibefradil
    * Nefazodone (Serzone)
    * Nelfinavir (Viracept)
    * Posaconazole (Noxafil)
    * Ritonavir (Novir®, Kaletra)
    * Saquinivir (Fortovase, Invirase)
    * Telaprevir (Incivek)
    * Telithromycin (Ketek)
    * Voriconazole (Vfend)
    * Troleandomycin
    * Cobicistat
    * Tipranavir
* Receiving any medications or substances that are inducers of CYP3A4; use of the following inducers are prohibited =\< 7 days prior to registration

  * Strong inducers of CYP3A4/5; \> 80% decrease in AUC

    * Avasimibe
    * Carbamazepine (Carbatrol, Epitol, Equetro, Tegretol, Tegretol-XR)
    * Phenytoin (Dilantin, Phenytek)
    * Rifampin (Rifadin)
    * St. John's wort
    * Mitotane
    * Rifabutin
    * Phenobarbital
  * Moderate inducers of CYP3A4/5; 50-80% decrease in AUC

    * Bosentan (Tracleer)
    * Efavirenz (Sustiva)
    * Etravirine (Intelence)
    * Modafinil (Provigil)
    * Nafcillin
    * Genistein
    * Ritonavir
    * Talyiraline
    * Thioridazine
    * Tipranavir
    * Nevirapine (Viramune)
    * Phenobarbital (Luminal)
    * Rifabutin (Mycobutin)
    * Troglitazone
* Patients currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug; NOTE: prohibited medications contains drugs that should be used with caution due to possible or conditional risk of Torsades de Pointes
* Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery)
* Acute or chronic pancreatic disease
* Known cytopathologically confirmed central nervous system (CNS) infiltration
* Acute or chronic liver disease or severe renal disease considered unrelated to the cancer
* History of significant congenital or acquired bleeding disorder unrelated to cancer
* Major surgery =\< 4 weeks prior to registration of the study or who have not recovered from prior surgery regardless of time since surgery
* Treatment with other investigational agents =\< 30 days or 5 half-lives of registration
* Diagnosis of AML-M3 (or acute promyelocytic leukemia)