Registration Criteria: 

• Any patient undergoing bone marrow biopsy with suspicion of or known diagnosis of acute myeloid leukemia (AML) will be asked to sign a Prescreening Consent to allow for centralized testing of bone marrow/peripheral blood samples.

Eligibility Criteria: 

• Patient must have previously untreated FLT3 mutated Non M3 AML (FLT3-TKD or FLT3-ITD allowed).

  • NOTE: Standard of care induction 7+3 chemotherapy may start prior to randomization using same regimen and doses as defined in Section 5.2.1 while awaiting prescreening test results.

• Patient must have had no prior systemic therapy for AML, except as noted below:
  • Hydroxyurea and emergent leukapheresis or preemptive treatment with retinoic acid prior to exclusion of Acute Promyelocytic Leukemia (APL) allowed. 
  • Prior therapy for myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN) (e.g., thalidomide or lenalidomide, interferon, jakafi, cytokines, 5-azacytidine or decitabine, histone deacetylase inhibitors). 

  • Initiation of standard of care 7+3 induction chemotherapy using same regimen and doses as defined in protocol (Section 5.2.1) while awaiting prescreening test results.

• Patient may not have hypomethylating agent within 21 days. 
• Patient may not have M3 AML. 
• Patient may not have AML with known Core Binding Factor -t(8;21), inv(16), t(16;16). 

  • NOTE: If results return with known Core Binding Factor –t(8;21), inv(16), t(16;16) after patient is registered, patient may be allowed to remain on-study per investigator’s discretion after discussion with PrECOG.

• Patient may not have known active Central Nervous System (CNS) leukemia. 

  • NOTE: -Prophylaxis with intrathecal chemotherapy is allowed prior to or during induction/consolidation.

    - If prophylactic lumbar puncture is performed, recommend scheduling so results are available prior to Day 8 or wait until Day 21 to perform.

• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3. 
• Patient must be age ≥ 18 years to ≤ 70 years. 
• Patient must be able to understand and willing to sign Institutional Review Board (IRB)-approved informed consent. 
• Patient must be willing to provide mandatory bone marrow and blood samples for research. 
• Patient must have adequate organ function as measured by the following criteria, obtained ≤ 48 hours prior to randomization except ECG and left ventricular ejection fraction (LVEF) which can be done ≤ 2 weeks prior to randomization: 
• Serum creatinine ≤ 1.5x institutional upper limit of normal (ULN), or if serum creatinine outside normal range, then glomerular filtration rate (GFR) > 40 mL/min as measured by Cockcroft-Gault formula. 
• Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 3x ULN, unless secondary to leukemia. 
• Serum total or direct bilirubin <2 mg/dL, unless due to Gilbert's, hemolysis or leukemic infiltration. 
• Fridericia-Corrected QT Interval (QTcF) interval ≤ 500 msec (using Friderica's correction). 
• Left Ventricular Ejection Fraction > 45%.
• The patient may not be known to have hypokalemia and/or hypomagnesemia that does not respond to supplementation.
• A female patient is eligible to participate if she is not pregnant and at least one of the following conditions apply: 
  • Not a woman of childbearing potential (WOCBP); or
  • WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for at least 180 days after the final study drug administration.
• Female patient must agree not to breastfeed or donate ova starting at treatment and throughout the study period, and for at least 180 days after the final study drug administration. 
• A male patient must agree not to donate sperm starting at treatment and throughout the study period, and for at least 120 days after the final study drug administration. 
• A male patient with female partner(s) of child-bearing potential must agree to use contraception during the treatment period, and for at least 120 days after the final study drug administration. 
• Male patient with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the treatment period, and for at least 120 days after the final study drug administration. 
• Patient may not have another malignancy that could interfere with the evaluation of safety or efficacy of this combination. 
• Patient may not have a history of Long QT Syndrome. 
• Patient may not have evidence of uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia, or congestive heart failure (CHF) New York Heart Association (NYHA) Class 3 or 4. Patient may also not have a history of CHF NYHA Class 3 or 4 in the past, unless a prescreening echocardiogram (ECHO) or multigated acquisition scan (MUGA) performed within 2 weeks prior to study entry with results of left ventricular ejection fraction > 45%.
• Patient may not have had major surgery or radiation therapy within 4 weeks of registration. 
• Patient may not require treatment with concomitant drugs that are strong inducers of CYP3A. 
• Patient with a known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent are not eligible. 
• Patient with known gastrointestinal (GI) disease or prior GI procedure that could interfere with the oral absorption or tolerance of gilteritinib or midostaurin including difficulty swallowing are not eligible. 
• Patient with any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of the treatment according to the protocol are not eligible. 
• Patient may not participate in any other therapeutic clinical trials, including those with other investigational agents not included in this trial during treatment on this study without prior approval from PrECOG.