Fludarabine Phosphate, Clofarabine, and Busulfan With Vorinostat in Treating Patients With Acute Leukemia in Remission or Relapse Undergoing Donor Stem Cell Transplant

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