The goal of this clinical research study is to learn if 5-azacitidine and sorafenib can help to control the disease in patients with Acute Myeloid Leukemia (AML) and high risk Myelodisplastic Syndrome (MDS) with FLT3-ITD mutation. The safety of this drug combination will also be studied.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive 5-azacitidine either as an injection under the skin or by vein on Days 1-7 of each 28-day cycle. If by vein, the infusion will take about 10-40 minutes.

You will take sorafenib by mouth 2 times a day about 12 hours apart, with at least 1 cup (8 ounces) of water on an empty stomach, every day. If you vomit a dose, do not make it up. You should wait and take your next scheduled dose.

Each study cycle may last a little longer than 28 days, depending on how you are doing.

Study Visits:

Each week, blood (about 1 tablespoon) will be drawn for routine tests.

Each week for the first 6 weeks, and then as often as your doctor thinks it is needed, you will have your blood pressure measured.

Before each cycle, you will have a physical exam.

Before every 2-4 cycles, you will have a bone marrow aspirate to check the status of the disease.

Length of Study:

You may continue taking the study drugs for as long as your doctor thinks it is in your best interest. You will no longer be able to take the study drugs if the disease gets worse or intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

End-of-Study Visit:

After you have stopped taking the study drugs, the following tests and procedures will be performed:

• You will have a physical exam.
• You will have a bone marrow aspirate to check the status of disease.
• Blood (about 2 tablespoons) will be drawn for routine tests.

Follow-Up Visits:

After your end-of-study visit, you will return to the clinic every 3 months and have the following tests and procedures:

• You will have a physical exam.
• Blood (about 2 tablespoons) will be drawn for routine tests.

This is an investigational study. Sorafenib is FDA approved and commercially available for the treatment of kidney cancer and liver cancer. 5-azacitidine is FDA approved for the treatment of MDS, but combining it with sorafenib is investigational. The study doctor can tell you how the study drugs are designed to work.

Up to 52 participants will be enrolled in this study. All will take part at MD Anderson.

Inclusion Criteria:

1. Patients with untreated AML (> or equal to 20% blasts in bone marrow and/or peripheral blood) or high risk MDS (> or equal to 10% blasts in bone marrow). A. Patients with AML and history of MDS who have received prior therapy with a hypomethylating agent (including azacytidine) and/or with lenalidomide for prior MDS are eligible if the treating physician feels that participation in the study is in the patients' best interest. B. Patients should have molecular evidence of the presence of FLT3-ITD mutation with a molecular burden of at least 10%.
2. Age > or equal to 60 years; patients younger than 60 who are unsuitable for or unwilling to receive standard cytotoxic chemotherapy are also eligible to be enrolled.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status < or equal 2.
4. Adequate liver (bilirubin < or equal to 1.5 x ULN, Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) < or equal to 2.5 x ULN and Alkaline phosphatase < or equal to 4 x ULN if not related to leukemic disease) and renal (creatinine < or equal to 1.5 x ULN) function.
5. Patients must provide written informed consent.
6. Patients must have been off therapy for MDS for 2 weeks prior to entering this study, and must have recovered from the toxic effects of that therapy to at least grade 1, unless there is evidence of rapidly progressive disease. Use of hydroxyurea (any dose) or ara-C (up to 1 g/m^2 X 2 doses) for patients with rapidly proliferative disease is allowed before the start of study therapy; these should be stopped for 24 hours prior to the initiation of azacitidine and sorafenib.
7. Women of childbearing potential should be advised to avoid becoming pregnant with an adequate method of contraception (barrier or hormonal methods) and men should be advised to not father a child while receiving treatment with azacitidine. All men and women of childbearing potential must use acceptable methods of birth control throughout the study as described below: Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment. Men should use adequate birth control for at least 30 days after the last administration of sorafenib. Post-menopausal women (defined as no menses for at least one year) and surgically sterilized women are not required to undergo a pregnancy test. Females of childbearing potential: Recommendation is for 2 effective contraceptive methods during the study.
8. 7. Continued: Adequate forms of contraception are double-barrier methods (condoms with spermicidal jelly or foam and diaphragm with spermicidal jelly or foam), oral, depo provera, or injectable contraceptives, intrauterine devices, and tubal ligation. Male patients with female partners who are of childbearing potential: Recommendation is for male and partner to use at least 2 effective contraceptive methods, as described above, during the study.
9. Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.
10. International Normalized Ratio (INR) < or equal to 1.5. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored weekly, or as defined by the local standard of care, until INR is stable.

Exclusion Criteria:

1. Nursing and pregnant females.
2. Patients with acute promyelocytic leukemia are excluded.
3. Patients with known allergy to sorafenib or azacitidine, mannitol or any of their components.
4. Patients with known severe impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of sorafenib.
5. Patients with any other known disease (except carcinoma in-situ) or concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, cardiovascular disease including congestive heart failure, myocardial infarction within 6 months and uncontrolled hypertension, chronic renal disease (creatinine clearance < 20 ml/min using the Cockcroft and Gault formula), or active uncontrolled infection) which could compromise participation in the study.
6. Patients with a known confirmed diagnosis of HIV infection or active viral hepatitis (B or C).
7. Patients who have had any major surgical procedure within 28 days prior to Day 1.
8. Patients unwilling or unable to comply with the protocol.
9. Cardiac disease: Congestive heart failure > class II New York Heart Association (NYHA). Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months.
10. Uncontrolled hypertension defined as systolic blood pressure > 150? mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.
11. Active clinically serious infection > CTCAE v4, Grade 2 not controlled with antibiotics.
12. Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
13. Pulmonary hemorrhage/bleeding event > or equal to CTCAE v4. Grade 2 within 4 weeks of first dose of study drug.
14. Any other hemorrhage/bleeding event > or equal to CTCAE v4. Grade 3 within 4 weeks of first dose of study drug.
15. Serious non-healing wound, ulcer, or bone fracture.
16. Evidence of bleeding diathesis or coagulopathy within the past 6 months.
17. Known or suspected allergy to sorafenib or any agent given in the course of this trial.
18. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results including known non-compliance issues on study trials.
19. Use of strong CYP3A4 inducer.