The goal of this clinical research study is to learn if clofarabine given by mouth on a weekly schedule can help to control MDS. The safety of clofarabine given by mouth will also be studied.

Clofarabine is a new chemotherapy drug that is designed to interfere with the growth and development of cancer cells.

If you are found to be eligible, you will be randomly assigned (as in the roll of dice) to one of 2 treatment groups. Participants in Group 1 will take a lower dose of clofarabine than Participants in Group 2. You have an equal chance of being assigned to either of the 2 treatment groups. Neither you nor your study doctor can choose your assignment. Later (after the first 40 patients), the assignment will favor the better treatment arm until one arm is selected as the significantly better one, or until 80 patients are treated in total. When you have been assigned to a treatment group, you will receive clofarabine as tablets once a day for 5 days in a row. This will be repeated every 4-8 weeks. Each 4-8 week period is considered 1 cycle of treatment.

Original patients who are still on study (original patients who received or are still receiving 30 mg/m2) have already been reduced to lower doses on subsequent courses or had treatment discontinued/completed. These patients will be asked to sign a new informed consent document to be made aware of the new developments in this study.

Each dose of clofarabine should be taken with 4 ounces of water in the morning, on an empty stomach. You must not eat or drink anything besides water from midnight the night before you take the study drug until 1 hour after taking the morning dose. You should take clofarabine every morning at about the same time. If vomiting occurs within 15 minutes of taking clofarabine, the dose may be repeated. If vomiting occurs more than 15 minutes after taking clofarabine, the dose cannot be replaced or made up.

Coffee and other caffeinated liquids cannot be taken before dosing and for 1 hour after dosing.

All clofarabine doses should be taken either in the outpatient or inpatient setting by qualified and trained site personnel or given with appropriate instructions to you and/or your care provider to take at home. At the start of each cycle, you will receive enough clofarabine for 1 cycle of therapy. You should store the clofarabine in its original container at room temperature. You should keep the container closed when not in use, and out of the reach of children.

After each cycle of therapy, you will not receive the next cycle of chemotherapy until your blood counts have recovered and any possible side effects have gone away (for around 4 to 8 weeks). You must stay in Houston for the first treatment cycle (about 4 to 8 weeks) and will be required to return to Houston before receiving each additional cycle of chemotherapy (up to 6 days each cycle).

Before every treatment cycle, your doctor will perform a physical exam, including measurement of your weight and vital signs (blood pressure, heart rate, temperature, and breathing rate). You will be asked about the level of your daily activities and how you are feeling. You will have blood samples (about 1-2 teaspoons) collected for routine lab tests 1-2 times a week for the first cycle, then every 2-4 weeks while on therapy. Repeat bone marrow samples will be collected every 1-3 cycles. However, if you complete the study before the third cycle, the bone marrow may be taken then. You may choose to have check-up visits and blood tests with your local doctor.

If you show a response and do not experience any severe side effects, you can receive up to a total of 12 cycles of therapy. During each cycle, clofarabine will be given the same way as during the first cycle. However, the dose of clofarabine may be lowered during later cycles to decrease the risk of side effects that may have occurred in previous cycles. If the disease gets worse or you experience any intolerable side effects, you will be taken off the study and your doctor will discuss other treatment options with you.

This is an investigational study. Clofarabine given by vein is approved by the FDA for treatment of pediatric acute lymphoblastic leukemia. Its use in this study is experimental. Up to 80 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 Chronic myelomonocytic leukemia (CMML).
2. No prior intensive chemotherapy or high-dose ara-C (>/= 1g/m2).
3. Prior biologic therapies, targeted therapies, or single agent chemotherapy allowed.
4. 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.
5. Hydroxyurea is permitted for control of counts prior to treatment.
6. Procrit, GCSF are allowed before therapy.
7. Performance 0-2 (ECOG). Adequate organ function including the following:Adequate liver function (bilirubin of < 2mg/dl), and renal function (creatinine < 2mg/dl), and SGPT (ALT) < 3 X ULN. Adequate cardiac functions (NYHA cardiac III-IV excluded).
8. Signed informed consent.

Exclusion Criteria:

1. Nursing and pregnant females. Patients of childbearing potential should practice effective methods of contraception. Child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization. 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. Prior clofarabine treatment.

Adverse event collection with each 4-8 weeks course, up to a total of 12 courses of therapy. Overall study period, three years and four months.

The first participant of the phase II portion of this study started treatment in August 2009.