Busulfan, Fludarabine Phosphate, and Anti-Thymocyte Globulin Followed By Donor Stem Cell Transplant and Azacitidine in Treating Patients With High-Risk Myelodysplastic Syndrome and Older Patients With Acute Myeloid Leukemia

PRIMARY OBJECTIVE:

I. To determine if this treatment can improve 2-year progression-free survival (PFS) in
patients with high risk myelodysplastic syndrome (MDS) and in patients with acute myeloid
leukemia (AML) >= 60 yrs age

SECONDARY OBJECTIVES:

I. To determine the safety and feasibility of using post-transplantation azacitidine.

II. To determine the ability to use pharmacokinetic-directed busulfan to achieve area under
the curve (AUC) within 20% of target AUC in > 80% of patients.

III. To determine the rate of grade II-IV and III-IV acute graft-vs-host disease (GVHD).

IV. To determine the incidence of extensive chronic GVHD. V. To determine treatment-related
mortality at 100 days and at 1 year. VI. To determine 5-year overall survival.

OUTLINE:

REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV)
over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and
anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or
-6 to -4 (matched unrelated donor [MUD]).

TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0
or on days 0-1.

GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus orally (PO) or IV on days -2
to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6
(MSD), and 11 (MUD).

CONSOLIDATION: Beginning on day 42, patients receive azacitidine subcutaneously (SC) or IV on
days 1-5.

Treatment repeats every 4 weeks for 6 courses. Blood and bone marrow samples may be collected
periodically for correlative and pharmacokinetic studies.

After completion of study treatment, patients are followed up every 6 months for 5 years.

Inclusion Criteria:

- Meets one of the following sets of criteria:

- Myelodysplastic syndromes (MDS):

- Disease with high-risk features (found either at diagnosis or before
initiation of cytotoxic therapy), defined as one of the following:

- International prognostic scoring system (IPSS) risk >= intermediate-2

- Refractory anemia with excess blasts by French-American-British (FAB)
classification

- High-risk cytogenetics (either complex or -7)

- Less than 10% bone marrow blasts as determined by bone marrow biopsy within
the past 4 weeks (reduction in marrow blast percentage may be achieved with
chemotherapy or other therapy)

- Less than 75 years old

- Acute myeloid leukemia (AML):

- No FAB M3

- No acute leukemia following blast transformation of prior chronic
myelogenous leukemia or other myeloproliferative disease

- Patients with preceding MDS or treatment-related AML are eligible

- Prior central nervous system (CNS) involvement is allowed provided the
disease is in remission at transplantation

- Morphologic complete remission (leukemia-free state) is defined as meeting
all of the following criteria:

- Bone marrow blasts < 5% (as determined by bone marrow within the past 4
weeks), but without requirement for normal peripheral blood counts

- No extramedullary leukemia

- No blasts in peripheral blood

- Achieved complete remission (CR) after no more than 2 courses of induction
chemotherapy

- Patients treated with azacitidine or decitabine who achieve a
leukemia-free state are eligible (may have required up to 4 courses of
therapy to reach this status)

- Age 60 to 74 years

- Donors must meet the following criteria:

- One of the following:

- HLA-identical sibling (6/6) by serologic typing for class (A, B) and
low-resolution molecular typing for class II (DRB1)

- Matched unrelated donor (8/8) by high-resolution molecular typing at HLA-A,
-B, -C, and DRB1

- No syngeneic donors

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Calculated creatinine clearance ≥ 40 mL/min

- Bilirubin < 2 mg/dL OR bilirubin 2-3 mg/dL provided direct bilirubin is normal

- Aspartate aminotransferase (AST) < 3 times upper limit of normal

- Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% with no symptomatic
pulmonary disease

- Left ventricle ejection fraction (LVEF) >= 30% by echocardiogram (ECHO) or multigated
acquisition (MUGA)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No uncontrolled diabetes mellitus or active serious infections

- No known hypersensitivity to E. coli-derived products, azacitidine, or mannitol

- No human immunodeficiency virus (HIV) infection or active hepatitis B or C

- Prior azacitidine or decitabine allowed

- No patients who progressed from MDS to AML during treatment with azacitidine or
decitabine

- At least 4 weeks since prior deoxyribonucleic acid (DNA)-hypomethylating chemotherapy,
radiotherapy, and/or surgery

- No more than 2 courses of consolidation therapy before transplantation (for patients
with AML)

- Any consolidation regimen that does not require transplantation can be used

- No more than 6 months from documentation of morphologic CR to transplantation