The main purpose of this study is to determine the safety of combining selinexor with daunorubicin and cytarabine. The maximal tolerated dose (MTD) of selinexor with daunorubicin and cytarabine will also be established.

Induction Therapy - Dose escalation of selinexor with Daunorubicin and cytarabine at fixed doses.

Consolidation Phase - Patients who are in complete remission (CR) or complete remission with incomplete count recovery (CRi) by day ≤70 and have recovered from any previous non- hematologic toxicity to baseline or grade ≤1 by day ≤70 following induction chemotherapy may go on to receive consolidation therapy for up to 2 cycles. The consolidation treatment phase will include up to two courses of therapy (28 day cycles) as follows:

Daunorubicin 45mg/m^2/day (days 1-2) Cytarabine 100mg/m^2/day (continuous infusion on days 1-5) Selinexor same dose as induction (days 1,3,8,10) unless dose limiting toxicity (DLT) dictates a dose reduction. Selinexor will be given 2 hours prior to daunorubicin on day 1.

A second cycle of consolidation therapy using the same doses as above will be administered, at the investigators discretion, between 28 and 42 days following initiation of the first consolidation treatment, after peripheral blood counts have recovered to CR, CRi levels, and after recovery from any non-hematologic toxicity to baseline or grade ≤1. Dose escalation of Selinexor will not occur during the consolidation phase.

Maintenance Phase - Patients who remain in CR, CRi after up to 2 cycles of consolidation and are not eligible for allogeneic stem cell transplant will be eligible for the maintenance phase of treatment after recovery from any previous non-hematologic toxicity to baseline or grade ≤1. Maintenance therapy will consist of:

Selinexor at the same dose as induction on days 1 and 8 of a 21 day cycle. They will continue for a maximum of 12 months.

Expansion Phase - Once the MTD has been established, there will be an expansion phase to enroll an additional 13 subjects at the MTD to better characterize the safety profile and tolerability.

Inclusion Criteria:

• Potential participants must have newly diagnosed, previously untreated acute myeloid leukemia (AML) (excluding M3); Must have adverse-risk AML defined as poor-risk karyotype (complex, monosomal or other known poor risk cytogenetic abnormality), poor-risk mutations/fusion genes or known history of antecedent hematologic disorder, or treatment related AML, or be ≥60 years of age; Cytogenetics, FISH or mutational analysis confirming adverse risk features must have been done within 90 days prior to enrollment.
• May not have undergone any prior therapy for their AML other than hydroxyurea. However, if patients had an antecedent myelodysplastic syndrome (MDS), prior treatment with a hypomethylating agent or any other therapy (with the exception of allogeneic stem cell transplant) used to treat their MDS is allowed.
• Age ≥18 years
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Life expectancy of greater than 2 months
• Must have normal organ function
• Able and willing to adhere to the study visit schedule and other protocol requirements
• Baseline left ventricular ejection fraction (LVEF) ≥ 50%
• Women of child-bearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 50 milli-international units per milliliter (mIU)mL) within 10 days and again within 24 hours prior to beginning study treatment. Participants of childbearing potential must practice recommended contraception. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Breastfeeding mothers must agree to discontinue nursing if the mother is treated with selinexor.
• Ability to understand and the willingness to sign a written informed consent document
• Able to swallow capsules and have no evidence of GI tract abnormality that would alter the absorption of oral medications
• Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5 x upper limit of normal (ULN)

Exclusion Criteria:

• May not be receiving any other investigational agents
• Documented central nervous system (CNS) involvement of AML
• AML with favorable risk cytogenetic abnormalities including t(15;17), t(8;21) or inv(16)
• Potential participants who are in the blast phase of chronic myeloid leukemia
• Major surgery within 2 weeks of first dose of study drug; must have recovered from the effects of any surgery performed greater than 2 weeks prior
• White blood cell (WBC) count ≥50,000 on hydroxyurea
• Predicted inability to tolerate standard induction chemotherapy with daunorubicin and cytarabine
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• HIV-positive, receiving combination anti-retroviral therapy
• No other malignancies in addition to AML that are currently requiring treatment with the exception of basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast
• History of allogeneic stem cell transplant for MDS or any other antecedent hematologic disorder.