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

Study Overview
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Brief Summary
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This phase II clinical trial is studying how well giving busulfan, fludarabine phosphate, and anti-thymocyte globulin followed by donor stem cell transplant and azacitidine works in treating patients with high-risk myelodysplastic syndrome and older patients with acute myeloid leukemia. Giving low doses of chemotherapy, such as busulfan and fludarabine phosphate, before a donor stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-vs-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving anti-thymocyte globulin before transplant and giving azacitidine, tacrolimus, and methotrexate after the transplant may stop this from happening.

Detailed Description
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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.

Official Title
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Phase II Study of the Addition of Azacitidine (NSC#102816) to Reduced-Intensity Conditioning Allogeneic Transplantation for Myelodysplasia (MDS) and Older Patients With AML

Conditions
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Acute Myeloid Leukemia, Adult Acute Megakaryoblastic Leukemia, Adult Acute Monoblastic Leukemia, Adult Acute Monocytic Leukemia, Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11, Adult Acute Myeloid Leukemia With Maturation, Adult Acute Myeloid Leukemia With Minimal Differentiation, Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11, Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1, Adult Acute Myeloid Leukemia With t(9;11)(p21.3;q23.3); MLLT3-MLL, Adult Acute Myeloid Leukemia Without Maturation, Adult Acute Myelomonocytic Leukemia, Adult Erythroleukemia, Adult Pure Erythroid Leukemia, Alkylating Agent-Related Acute Myeloid Leukemia, de Novo Myelodysplastic Syndrome, Myelodysplastic Syndrome, Myelodysplastic Syndrome With Excess Blasts, Recurrent Adult Acute Myeloid Leukemia, Secondary Myelodysplastic Syndrome

Intervention / Treatment
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* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Biological: Anti-Thymocyte Globulin
* Drug: Azacitidine
* Drug: Busulfan
* Drug: Fludarabine Phosphate
* Other: Laboratory Biomarker Analysis
* Drug: Methotrexate
* Other: Pharmacological Study
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy and transplant)<br>REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate 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 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 SC or IV on days 1. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic hematopoietic stem cell transplantation<br>* Other names: Stem Cell Transplantation, Allogeneic;Biological: Anti-Thymocyte Globulin<br>* Given IV<br>* Other names: ATS;Drug: Azacitidine<br>* Given SC or IV<br>* Other names: Vidaza;Drug: Busulfan<br>* Given IV<br>* Other names: WR-19508;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Methotrexate<br>* Given IV<br>* Other names: WR-19039;Other: Pharmacological Study<br>* Correlative studies<br>Drug: Tacrolimus<br>* Given PO or IV<br>* Other names: Protopic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival rate (percentage) at 2 and 5 years is defined as the percentage of patients who are alive and progression free at 2 and 5 years from date of transplantation respectively. AML progression is defined as: Reappearance of leukemia blast cells in peripheral blood and > 5% blasts in marrow If no circulating blasts, but the marrow contains 5-20% blasts, a repeat bone marrow >= 1 week later with > 5% blasts Development of extramedullary leukemia MDS progression is defined as For patients with <5% bone marrow blasts: ≥50% increase in blasts to >5% blasts For patients with 5-10% bone marrow blasts: ≥50% increase to >10% blasts Any of the following: Reappearance of prior documented characteristic cytogenetic abnormality or refractory cytopenias with unequivocal evidence of dysplasia on bone marrow biopsy/aspirate | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival rate (percentage) at 2 and 5 years is defined as the percentage of patients who are still alive 2 and 5 years after date of transplantation respectively. Estimated using the Kaplan-Meier product limit estimator. | Up to 5 years | 
| 100-day Mortality | The number of death reported within the first 100 days after transplant. | Up to 100 days post-treatment |