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