This phase I trial studies the side effects and best dose of vorinostat when given together with fludarabine phosphate, clofarabine, and busulfan in treating patients with acute leukemia that is under control (remission) or has returned (relapse) undergoing donor stem cell transplant. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate, clofarabine, and busulfan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving vorinostat together with fludarabine phosphate, clofarabine, and busulfan before a donor stem cell transplant may be a better treatment for patients with acute leukemia.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of SAHA (vorinostat) in combination with the preparative regimen fludarabine (fludarabine phosphate), clofarabine, and busulfan followed by allogeneic hematopoietic stem cell transplantation (SCT) for patients with advanced acute leukemia.

SECONDARY OBJECTIVES:

I. To determine the rate of graft versus host disease (GVHD), engraftment, progression-free survival (PFS) and overall survival (OS) for this treatment regimen.

OUTLINE: This is a dose-escalation study of vorinostat.

CONDITIONING REGIMEN: Patients receive vorinostat orally (PO) once daily (QD), fludarabine phosphate intravenously (IV) over 1 hour, clofarabine IV over 1 hour, and busulfan IV over 3 hours on days -6 to -3. Patients receiving a transplant from a human leukocyte antigen (HLA)-matched unrelated donor, receive anti-thymocyte globulin IV over 4 hours on days -3 to -1.

TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell or bone marrow transplant on day 0.

Inclusion Criteria:

• Patients with biopsy-proven acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome in remission or relapse
• Estimated creatinine clearance at least 50 ml/min
• Bilirubin equal or less than 1.5 (unless Gilbert's syndrome)
• Serum glutamate pyruvate transaminase (SGPT) < 3 x upper limit of normal
• Alkaline phosphatase < 2 x upper limit of normal
• Pulmonary function with forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) at least 45% of expected corrected for hemoglobin; children unable to perform pulmonary functions must have an oxygen saturation greater than 92% at room air
• Left ventricular ejection fraction at least 45% on appropriate medical therapy; no uncontrolled arrhythmias or symptomatic cardiac disease
• Zubrod performance status 0-1 or Lansky/Karnofsky performance status (PS) equal or greater to 80%
• Patients must have a related, genotypically HLA identical donor, or they must have an unrelated donor who is 8/8 HLA match by high resolution typing
• Patient or patient's legal representative, parent(s) or guardian should provide written informed consent; assent of a minor if participant's age is at least seven and less than eighteen years
• Negative beta human chorionic gonadotropin (HCG) test in a woman with child bearing potential defined as not post-menopausal for 12 months and no previous surgical sterilization

Exclusion Criteria:

• Patients with active central nervous system (CNS) disease
• Evidence of acute or chronic active hepatitis or cirrhosis
• Uncontrolled infection, including human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV)-1, hepatitis B or hepatitis C viremia
• Prior allogeneic SCT
• Prior autologous SCT in last 12 months
• Patients with acute myeloid leukemia (AML) in first remission after one course of induction and with favorable cytogenetics (t[8;21], inv 16, or t[15;17]) and/or molecular profile (nucleophosmin [NPM]1)
• Prior radiation to liver in form of total body or involved field