The goal of this clinical research study is to find out if decitabine, given with or without valproic acid, can help to control AML or MDS. The safety of both treatments will also be studied.

Decitabine and valproic acid are both designed to cause changes in different groups of proteins that are attached to DNA (the genetic material of cells), which may cause cancer cells to die. Researchers want to see if a combination of valproic acid with decitabine can help improve disease response as well as how long responses last in treating MDS and AML.

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the toss of a coin) to 1 of 2 groups. Participants in one group will receive decitabine. Participants in the other group will receive decitabine and valproic acid. You will have an equal chance of being assigned to either group at first. After 20 participants are enrolled in each group, you will have a greater chance of being assigned to the group that is showing better results.

Participants in both groups will receive decitabine on Day 1 through a central venous catheter (CVC) in a vein over 1 hour each day for 5 days. A central venous catheter is a sterile flexible tube that will be placed into a large vein while you are under local anesthesia. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form for this procedure. Participants who are assigned to also get valproic acid will take the drug by mouth on Days 1-7 (7 days in a row).

On Day 0 (the day before treatment begins) or on Day 1, you will have a physical exam, including measurement of your vital signs. Blood (about 2 teaspoons) will be drawn on or about Days 0 or 1, 5, and 10 (if your routine blood tests were found to be abnormal) to learn the status of the disease.

Routine blood draws (about 4 teaspoons) will be done 1-2 times weekly for the first cycle and then every 2-4 weeks in further cycles. You will have another bone marrow aspiration to check disease response to treatment, and then you will have one every 1-3 cycles. One (1) cycle of treatment is 4-8 weeks long.

You may remain on this study as long as you are benefitting or up to 2 years after you first achieve a complete response. Your dose level may be decreased depending on the side effects you may experience. However, if the disease gets worse or you experience any intolerable side effects, you will be taken off this study.

This is an investigational study. Decitabine is FDA approved and commercially available for the treatment of MDS. Valproic acid is FDA approved and commercially available for the treatment of seizure disorders. Up to 150 patients will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Patients with MDS and > 5% blasts or IPSS risk intermediate or high; patients with CMML; patients with AML who are age 60 or older. No prior intensive chemotherapy or high-dose ara-C (> 1g/m2). No prior azacytidine for 3 cycles or more or prior decitabine for 2 cycles or more. Prior biologic therapies, targeted therapies, or single agent chemotherapy allowed.Patients must have been off chemotherapy for 2 weeks prior to entering this study and recovered from the toxic effects of that therapy, unless there is evidence of rapidly progressive disease.
2. Continued from #1: Hydroxyurea is permitted for control of counts prior to treatment. Procrit, granulocyte colony-stimulating factor (GCSF) are allowed before therapy. Procrit, GCSF or other growth factors are permitted on therapy. Use of hydroxyurea with rapidly proliferative disease is allowed for the first two weeks on therapy.
3. Performance 0-2 (ECOG). Adequate liver function (bilirubin of < 2mg/dl) and renal function (creatinine < 2mg/dl). Adequate cardiac functions (NYHA cardiac III-IV excluded). ALT < 2.5x institutional upper limit of normal.
4. Signed informed consent.

Exclusion Criteria:

1. Nursing and pregnant females. Patients of childbearing potential should practice effective methods of contraception. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
2. Active and uncontrolled infections.
3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements.
4. Known ornithine transcarbamylase disorder.
5. Patients requiring continuous valproic acid treatment for the control of seizure disorders.

Adverse events reported during each treatment course every 4-8 weeks and extending 30 days beyond the last day of active treatment. Overall period: 12/2006 to 07/2011.