Decitabine and Total-Body Irradiation Followed By Donor Bone Marrow Transplant and Cyclophosphamide in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine overall survival at 100 days after transplantation following decitabine and a
bone marrow transplant using a donor that is at least partially-matched and a myeloablative
preparative regimen with post-transplantation cyclophosphamide for graft-versus-host disease
(GVHD) prophylaxis.

SECONDARY OBJECTIVES:

I. Patients enrolled in this study will also be followed for the following endpoints:
neutrophil and platelet recovery, graft failure, acute graft-versus-host disease (GVHD),
chronic GVHD, incidence of infection, treatment-related mortality, time to
relapse/progression, overall survival, and progression-free survival.

OUTLINE:

Beginning between days -29 and -22, patients receive decitabine intravenously (IV) over 1
hour daily for 10 days, fludarabine phosphate IV over 30 minutes on days -5 to -2, and
busulfan IV over 3 hours on days -5 to -2.

PREPARATIVE REGIMEN: Patients undergo total-body irradiation twice daily (BID) on day -1.

TRANSPLANT: Patients undergo allogeneic bone marrow transplant on day 0.

GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 2 hours on days 3 and 4,
tacrolimus orally (PO) BID or IV continuously on days 5-180, mycophenolate mofetil PO three
times daily (TID) on days 5-35 and filgrastim subcutaneously (SC) beginning day 5 until
absolute neutrophil count (ANC) >= 1,000/mm^3 for 3 consecutive days.

After completion of study treatment, patients are followed up at 6 months and 1 year.

Inclusion Criteria:

- Patients must meet one of two disease criteria:

- Acute myelogenous leukemia within one of the following categories:

- Primary induction failure (PIF): patients who have not achieved a complete
remission following initial diagnosis and after at least two induction
cycles of chemotherapy consisting of cytarabine and an anthracycline or
high-dose cytarabine

- Relapsed AML: Patients are defined as having relapsed disease if they
entered a complete remission confirmed with a bone marrow biopsy following
initial treatment, and then were found to have morphological or cytogenetic
evidence of recurrent disease on a subsequent bone marrow exam

- Any complete remission (CR)2 or greater: CR must be defined using a bone
marrow exam taken at least 21 days since the last chemotherapy (including a
methyltransferase inhibitor), and may include CRp (morphologic CR without
peripheral platelet recovery)

- CR1 with high-risk features: includes patients with treatment-related AML,
secondary AML (following myelodysplastic syndrome [MDS] or
myeloproliferative neoplasms [MPN]), high-risk cytogenetic or molecular
phenotype (by National Comprehensive Cancer Network [NCCN] criteria)

- Untreated AML (> 20% blasts on a bone marrow) arising from a previous
confirmed diagnosis of MDS or MPN (excluding BCR-ABL positive diseases).

- Myelodysplastic syndromes within one of the following categories:

- High-risk MDS at diagnosis as defined by the International Prognostic
Scoring System (IPSS) or World Health Organization (WHO) classification
based Prognostic Scoring System (WPSS)

- Transfusion dependent MDS (either red blood cells [RBC] or platelet
dependent) without a hematologic response to at least 4 months of MTI
therapy; hematological response is defined as transfusion independence for
two or more months

- Progressive MDS following at least 4 months of MTI therapy; progression is
defined as resumption of transfusion dependence after at least two months of
transfusion independence OR increase of marrow blasts by 50% from
pretreatment OR overall blasts over 10% of marrow cells at any time after
treatment

- Available related donor that is at least an allele level haplotype-match at human
leukocyte antigen (HLA)- A, B, C, DRB1 and DPB1 loci (DPB1 matching according to the
"permissive - non-permissive" dichotomy as stated by University of Wisconsin [UW]
Histocompatibility Laboratory); a minimum match of 5/10 loci is required; an unrelated
donor search is not required for a patient to be eligible for this protocol

- Karnofsky score of 60% or better (requires occasional assistance, but is able to care
for most of his/her needs)

- Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for hemoglobin >
40%; and forced expiratory volume in one second (FEV1) > 50%

- Ejection fraction (EF) >= 50% and no uncontrolled angina, symptomatic ventricular
arrhythmias, or electrocardiogram (ECG) evidence of active ischemia

- Serum creatinine within normal range for age, or if serum creatinine outside normal
range, then renal function (estimated glomerular filtration rate [GFR] by modification
of diet in renal disease [MDRD] formula) > 40 mL/min/1.73 m^2

- Women of child bearing potential must have a negative pregnancy test within 14 days
prior to study registration and agree to use adequate birth control during study
treatment

- Voluntary written consent

- Patients must be 28 days from the end of the last induction course or at least 14 days
from completion of previous methyltransferase inhibitor therapy (azacitidine or
decitabine) at the time of registration

- DONOR: Donors must be at least HLA-haploidentical first degree relatives of the
patients; eligible donors include biological parents, siblings, half-siblings or
children

- DONOR: Age >= 18 years and =< 60 years

- DONOR: Donors must meet the selection criteria prior to the start of the recipient's
pre-transplant conditioning regimen as defined by the Foundation for the Accreditation
of Cell Therapy (FACT) and will be screened according to the American Association of
Blood Banks (AABB) guidelines and UW Bone Marrow Transplant (BMT) program standard
operating procedure (SOP)

Exclusion Criteria:

- Active central nervous system (CNS) leukemia within two weeks of registration;
patients with a history of CNS leukemia must have adequate treatment as defined by at
least two negative spinal fluid assessments separated by at least one week; patients
who have received cranial radiation therapy (XRT) must still be eligible to receive
total body irradiation to 4 Gy

- New or active infection as determined by fever, unexplained pulmonary infiltrate or
sinusitis on radiographic assessment; infections diagnosed within 4 weeks of
registration must be determined to be controlled or resolving prior to treatment

- Active human immunodeficiency virus (HIV), hepatitis A, B or C infection

- Allergy or hypersensitivity to agents used within the treatment protocol

- DONOR: Recipient derived anti-donor high-titer (> 3000 MFI) HLA antibody as determined
by Luminex assay

- DONOR: Not suitable for donation according to UW BMT program donor selection SOP