This phase I trial studies the side effects and the best dose of selinexor when give together with standard chemotherapy, high dose cytarabine and mitoxantrone hydrochloride, in treating patients with acute myeloid leukemia. Selinexor may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and mitoxantrone hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving selinexor together with standard chemotherapy may be a better treatment for patients with acute myeloid leukemia.

Inclusion Criteria:

• Signed, written informed consent in accordance with federal, local, and institutional guidelines
• Patients with newly diagnosed or relapsed/refractory AML, except acute promyelocytic leukemia (APL), requiring intensive induction chemotherapy
• Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
• Creatinine clearance > 30 cc/min calculated using the Cockcroft and Gault (1976) formula or measured
• Total bilirubin =< 2 mg/dl unless high indirect bilirubin is due to a congenital disorder
• Transaminases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) =< 3.0 x upper limit of normal (ULN) unless due to leukemia infiltration
• Prothrombin time (PT) and partial thromboplastin time (PTT) =< 2 x ULN
• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures
• It is important patients understand the need to use birth control while on this study; female patients of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening (< 3 days prior to first dose), male patients with partners of childbearing potential must agree to use effective contraception during the study period and a period of 3 months after the last dose of study drug; for both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose

Exclusion Criteria:

• Treatment with any investigational agent within two weeks prior to first dose in this study; hydroxyurea is allowed to control the AML prior to treatment on the study

• AML central nervous system (CNS) involvement

• Major surgery within 2 weeks of first dose of study drug; patients must have recovered from the effects of any surgery performed greater than 2 weeks previously

• Patient has a concurrent advantage active malignancy under treatment

• Unstable cardiovascular function:

  • Symptomatic ischemia, or
  • Uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on antiarrhythmic agents are excluded; 1st degree atrioventricular [AV] block or asymptomatic left anterior fascicular block/right bundle branch block [left anterior fascicular block (LAFB)/right bundle branch block (RBBB)] will not be excluded), or
  • Congestive heart failure (CHF) New York Heart Association (NYHA) class >= 3, or
  • Myocardial infarction (MI) within 3 months

• Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines is acceptable

• Known active hepatitis B virus (HBV) or C virus (HCV) infection; or known to be positive for HCV ribonucleic acid (RNA) or HBsAg (HBV surface antigen)

• Known human immunodeficiency virus (HIV) infection

• Any medical condition which, in the investigator's opinion, could compromise the patient's safety

• Patients unable to swallow tablets or patients with malabsorption syndrome, or any other disease significantly affecting gastrointestinal function

• Seizure or cerebrovascular accident (CVA) in the last year