Fludarabine and Busulfan Followed by Allogeneic Stem Cell Transplant in Treating Older Patients With Acute Myeloid Leukemia in First Complete Remission

Study Overview
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Brief Summary
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This phase II trial studies how well fludarabine and busulfan followed by a donor (allogeneic) stem cell transplant work in treating older patients with acute myeloid leukemia that is in first complete remission. Giving low doses of chemotherapy, such as fludarabine and busulfan, before a donor peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stops the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Giving tacrolimus, methotrexate, and rabbit antithymocyte globulin before or after the transplant may stop this from happening.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine if allogeneic transplantation from a matched sibling or unrelated donor using a non-myeloablative preparative regimen results in a 2-year disease-free survival (DFS) that is better than historical results using standard chemotherapy. SECONDARY OBJECTIVES: I. Determine 2-year actuarial risks of transplant-related mortality, acute and chronic graft-versus-host (GVHD) disease and relapse among patients with acute myeloid leukemia (AML) in first complete remission (CR1) following a non-myeloablative preparative regimen. II. To examine recovery of T and B cell number and function following non-myeloablative stem cell transplant. III. To examine the time course of T, B and myeloid progenitor chimerism following this preparative regimen. IV. To characterize the pharmacokinetics of intravenous busulfan used in a non-myeloablative preparation regimen in AML patients age >= 60 years. OUTLINE: PREPARATIVE REGIMEN: Patients receive fludarabine intravenously (IV) over 30 minutes on days -7 to -3 and busulfan IV over 2 hours 4 times per day (every 6 hours) on days -4 and -3. GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive tacrolimus orally (PO) or IV twice daily (BID) on days -2 with taper between days 90-120, and stopping by days 150-180. Patients also receive methotrexate IV on days 1, 3, 6, and 11 and rabbit antithymocyte globulin IV over 4-6 hours on days -4 through -2. ALLOGENEIC PERIPHERAL BLOOD STEM CELL TRASNPLANTATION (PBSC): Patients undergo allogeneic PBSC transplant on day 0. Patients then receive filgrastim subcutaneously (SC) daily beginning on day 12 and continuing until blood counts recover. Patients are followed monthly for 1 year, every 3 months for 1 year, and then every 6 months for 3 years.

Official Title
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A Phase II Study Of Allogeneic Transplant For Older Patients With AML In First Morphologic Complete Remission Using A Non-Myeloablative Preparative Regimen

Conditions
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Adult Acute Myeloid Leukemia in Remission, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome

Intervention / Treatment
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* Biological: filgrastim
* Biological: Anti-Thymocyte Globulin
* Drug: busulfan
* Drug: fludarabine phosphate
* Drug: methotrexate
* Drug: tacrolimus
* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation


Participation Criteria
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Eligibility Criteria
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Eligibility Criteria: Patients with acute myeloid leukemia (AML) (excluding French-American-British [FAB] classification system M3) who have achieved a first morphologic complete remission and who meet the criteria below; patients with preceding myelodysplastic syndrome (MDS) or treatment-related AML are eligible; patients with prior central nervous system (CNS) involvement are eligible as long as disease is in remission at transplant; patients with acute leukemia following blast transformation of prior chronic myeloid leukemia (CML) or other myeloproliferative disease are excluded Complete remission (CR) will be defined according to the revised recommendations of the International Working Group (24) as all of the following: Normal bone marrow morphology with < 5% blasts Absolute neutrophil count (ANC) > 1,000/uL, referring to the count needed to confirm that the patient achieved a CR Platelet count > 100,000/uL No extramedullary leukemia No blasts in peripheral blood CR was achieved after one or two (but no more than two) cycles of induction chemotherapy with standard cytotoxic chemotherapy (e.g., cytarabine and an anthracycline) or after no more than four cycles of a hypomethylating agent containing regimen including either 5-azacytidine or decitabine Patients may have received as many as but no more than two cycles of consolidation therapy prior to transplant; any consolidation regimen that does not require transplant can be used; no more than 6 months can elapse from documentation of morphologic CR to transplant; the platelet count does not need to be > 100,000/uL after consolidation, as long as the bone marrow assessment prior to transplant does not show relapse Identification of hematopoietic cell donor >= 4 weeks since prior chemotherapy, radiation therapy, and surgery Performance status 0-2 Diffusion capacity of carbon monoxide (DLCO) > 40% with no symptomatic pulmonary disease Left ventricular ejection fraction (LVEF) by multi gated acquisition scan (MUGA) or echocardiogram (ECHO) >= 30% No uncontrolled diabetes mellitus or active serious infection requiring antibiotics No known hypersensitivity to E. coli-derived products No human immunodeficiency virus (HIV) infection Calculated creatinine clearance >= 40 cc/min Bilirubin < 2 mg/dL * If bilirubin is 2-3 mg/dL, but direct bilirubin is normal then patient will be considered eligible Aspartate aminotransferase (AST) < 3 x upper limit of normal DONOR: HLA-identical sibling (6/6); the donor must be determined to be an human leukocyte antigen (HLA)-identical sibling (6/6) by serologic typing for class (A, B) and low resolution molecular typing for class II (DRB1) DONOR: Matched unrelated donor (10/10); high resolution molecular typing at the following loci is required: HLA-A, -B, -C, -DRB1, and -DQB1 DONOR: the donor must be healthy and must be an acceptable donor as per institutional standards for stem cell donation DONOR: the donor must have no significant cardiopulmonary, renal, endocrine, or hepatic disease DONOR: there is no donor age restriction if the donor is a matched sibling DONOR: syngeneic donors are not eligible

Ages Eligible for Study
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Minimum Age: 60 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 (fludarabine, busulfan, allogeneic PBSC)<br>PREPARATIVE REGIMEN: Patients receive fludarabine IV over 30 minutes on days -7 to -3 and busulfan IV over 2 hours 4 times per day (every 6 hours) on days -4 and -3. GVHD PROPHYLAXIS: Patients receive tacrolimus PO or IV BID on days -2 with taper between days 90-120, and stopping by days 150-180. Patients also receive methotrexate IV on days 1, 3, 6, and 11 and rabbit antithymocyte globulin IV over 4-6 hours on days -4 through -2. ALLOGENEIC PBSC: Patients undergo allogeneic PBSC transplant on day 0. Patients then receive filgrastim SC daily beginning on day 12 and continuing until blood counts recover. | Biological: filgrastim<br>* Given SC<br>Biological: Anti-Thymocyte Globulin<br>* Given IV<br>Drug: busulfan<br>* Given IV<br>Drug: fludarabine phosphate<br>* Given IV<br>Drug: methotrexate<br>* Given IV<br>Drug: tacrolimus<br>* Given PO or IV<br>Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic PBSC transplantation<br>* Other names: HSC, HSCT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2 Year Disease Free Survival In Unrelated Donor Recipient Group | Percentage of participants who were alive and relapse free at 2 years for patients who were matched with an unrelated donor for transplant. The 2 year disease free survival, with 95% confidence interval, was estimated using the Kaplan Meier method. A relapse is defined as any of the following: Reappearance of leukemia blasts cells in peripheral blood >5% blasts in the marrow, not attributable to another cause (e.g., bone marrow regeneration) If there are no circulating blasts, but the marrow contains 5-20% blasts, a repeat bone marrow ≥ 1 week later with >5% blasts is necessary to meet the criteria for relapse The development of extramedullary leukemia or leukemic cells in the cerebral spinal fluid | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2 Year DFS for All Patients | Percentage of participants who were alive and relapse free at 2 years for all patients. The 2 year disease free survival, with 95% confidence interval, was estimated using the Kaplan Meier method. | Up to 2 years | 
| Non-relapse Mortality (NRM) | Percentage of patients who died due to causes other than relapse | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult acute myeloid leukemia in remission, secondary acute myeloid leukemia, adult acute monocytic leukemia (M5b), adult acute erythroid leukemia (M6), adult acute megakaryoblastic leukemia (M7), adult acute minimally differentiated myeloid leukemia (M0), adult acute myeloblastic leukemia with maturation (M2), adult acute myeloblastic leukemia without maturation (M1), adult acute myelomonocytic leukemia (M4), adult acute monoblastic leukemia (M5a), adult acute myeloid leukemia with t(8;21)(q22;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with 11q23 (MLL) abnormalities