The goal of this clinical research study is to learn if clofarabine when given in combination with cytarabine can help to control myelodysplastic syndrome (MDS) after the disease could not be controlled with standard therapy. The safety of this treatment will also be studied.

Clofarabine is designed to interfere with the growth and development of cancer cells.

Cytarabine is designed to insert itself into DNA (the genetic material of cells) of cancer cells and stop the DNA from repairing itself.

Induction Cycles:

If you are found to be eligible to take part in the study, on Days 1-5 of each cycle , you will receive clofarabine by vein over 1-2 hours.

On Days 1-7 of each cycle, you will receive cytarabine by injection under the skin over several seconds 2 times a day.

You may receive up to 3 cycles at this dose and schedule (also called "induction cycles"). There are 7 treatment days in each cycle but the total length of one cycle (including rest and recovery period) is usually between 4 and 8 weeks.

Consolidation Cycles:

After you have completed the Induction Cycles, if you show a response to treatment, you can then continue with up to a total of 12 more cycles of therapy, which will be called "consolidation cycles". Not every participant may be able to receive all 12 consolidation cycles. The actual number that you will receive depends on whether or not you maintain the response and how you are able to tolerate ongoing therapy. There will be 4-8 weeks between each consolidation cycle depending on any side effects you may be having and your blood counts.

During consolidation cycles you will receive clofarabine on Days 1-3 by vein over 1-2 hours. You will receive cytarabine by injection under the skin over several seconds 2 times a day .

Induction and Consolidation Cycles:

On the days when you receive clofarabine and cytarabine (Days 1-5 during induction and Days 1-3 during consolidation), the clofarabine will be given about 3-6 hours before the cytarabine injections. You can be taught to give cytarabine injections to yourself. In this case, you can leave the clinic after receiving clofarabine. You will be required to record the injections of cytarabine in a diary unless you receive the treatments while you are in the hospital.

Study Visits:

On Day 1 of every cycle (+/- 7 days):

• You will have a physical exam, including measurements of your weight and vital signs.
• Your performance status will be recorded.
• Blood (about 1-2 teaspoons) will be drawn for routine tests.

About 4 weeks after you started your first cycle, you may have a bone marrow aspirate to check the status of the disease. After that, you may have repeat bone marrow aspirates when the doctor thinks it is needed.

It is recommended that you stay in Houston for up to the first 4 weeks of treatment. After that, you will need to return to Houston before each induction cycle. If you continue with the consolidation you can receive these treatments by your local oncologist. However, you have to return to Houston at least every 3 months for your study visits.

Length of Study:

You may continue taking the study drugs for up to 15 cycles. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

This is an investigational study. Clofarabine is FDA approved and commercially available for use in pediatric patients with acute lymphoblastic leukemia. Its use in adults and in patients with MDS is investigational.

Cytarabine is FDA approved and commercially available for use in patients with acute myeloid leukemia (AML).

Up to 80 patients will take part in this study. All be enrolled at MD Anderson.

Inclusion Criteria:

1. Age >/= 18 years.
2. Diagnosis of MDS confirmed within 10 weeks prior to study entry according to World Health Organization (WHO) or French-American-British (FAB) criteria. Patients are either not eligible for or choose not to proceed with a stem cell transplant.
3. MDS classified as follows: refractory anemia with excess blasts (RAEB-1) (5%-9% BM blasts); RAEB-2 (10%-19% BM Blasts); chronic myelomonocytic leukemia (CMML) (5%-19% Bone Marrow (BM) blasts); RAEB-t (20%-29% BM blasts) AND/OR by International Prostate Symptom Score (IPSS): intermediate-2 and high risk patients.
4. No response, progression, or relapse (according to 2006 International Working Group (IWG) criteria; see section 8 for details) following at least 4 cycles of either azacitidine or decitabine, or following at least 2 cycles of SGI-110, which were completed within the last 2 years - AND/OR - intolerance to azacitidine, decitabine, or SGI-110 defined as drug-related >/= grade 3 hepatic or renal toxicity leading to treatment discontinuation during the preceding 2 years.
5. Eastern Cooperative Oncology Group (ECOG) performance status of </= 2.
6. Willing to adhere to and comply with all prohibitions and restrictions specified in the protocol.
7. Patient (or patient's legally authorized representative) must have signed an informed consent document indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study.

Exclusion Criteria:

1. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
2. Active infection not adequately responding to appropriate antibiotics (i.e. ongoing temperatures of >/= 38 degree Celsius).
3. Total bilirubin >/= 1.5 mg/dL and not related to hemolysis or Gilbert's disease. Patients with total bilirubin >/= 1.5 mg/dL to 3 mg/dL are eligible if at least 75% of the bilirubin is indirect.
4. Alanine transaminase (ALT/SGPT) or aspartate transaminase (AST/SGOT) >/= 2.5 x the upper limit of normal.
5. Serum creatinine > 1.5 mg/dL.
6. Female patients who are pregnant or lactating.
7. Patients with reproductive potential who are unwilling to following contraception requirements (including condom use for males with sexual partners, and for females: prescription oral contraceptives [birth control pills], contraceptive injections, intrauterine devices (IUD), double-barrier method [spermicidal jelly or foam with condoms or diaphragm], contraceptive patch, or surgical sterilization) throughout the study.
8. Female patients with reproductive potential who do not have a negative urine or blood beta-human chorionic gonadotropin (beta HCG) pregnancy test at screening.
9. Patients receiving any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy.
10. No prior treatment with cytarabine or clofarabine. Prior hydroxyurea for control of leukocytosis or use of hematopoietic growth factors (eg, G-CSF, Granulocyte-macrophage colony-stimulating factor (GM-CSF), procrit, aranesp, thrombopoietins) is allowed at any time prior to or during study if considered to be in the best interest of the patient.
11. Psychiatric illness or social situation that would limit the patient's ability to comply with study requirements.

Adverse events captured from the time of participant consent until 30 days after the last dose of drug. AE's can be collected for up to 15 cycles.