Combination Chemotherapy With or Without Monoclonal Antibody Therapy in Treating Patients With AML Leukemia

Study Overview
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Brief Summary
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RATIONALE: Giving combination chemotherapy before a stem cell transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the transplanted stem cells. When the healthy stem cells are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. If the patient's stem cells are to be transplanted, the patient is also treated with a monoclonal antibody, such as gemtuzumab ozogamicin, to kill any remaining cancer cells or deliver cancer-killing substances to them without harming normal cells. It is not yet known whether combination chemotherapy is more effective with or without gemtuzumab ozogamicin followed by stem cell transplant in treating acute myeloid leukemia. PURPOSE: This randomized phase III trial is studying combination chemotherapy, gemtuzumab ozogamicin, and stem cell transplant to see how well they work compared to combination chemotherapy and peripheral stem cell transplant alone in treating patients with acute myeloid leukemia.

Detailed Description
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OBJECTIVES: To compare the overall survival (OS) between two induction regimens (standard versus dose intense daunorubicin and cytarabine) in patients with de novo AML. To compare disease-free survival (DFS) between two consolidation regimens. To compare overall survival between two consolidation regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to induction therapy (standard-dose daunorubicin vs high-dose daunorubicin). Induction therapy: Patients are randomized to 1 of 2 induction arms. Standard: Patients receive standard-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. High dose: Patients receive high-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine as in arm I. Patients in both arms may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. The second course is administered as in arm I to all patients. Patients who don't achieve CR after 2 courses of induction therapy are removed from study. Patients who achieve CR after induction therapy proceed to post-remission therapy with EITHER allogeneic transplantation only (on or off study) OR consolidation therapy and autologous transplantation (on study), according to risk status and donor status. Patients who are considered at intermediate or high risk for relapse (unfavorable cytogenetics/high WBC) and have a suitable related donor undergo an allogeneic transplantation. Patients with intermediate-risk cytogenetics, WBC no greater than 100,000/mm^3, and appropriate donors have the option of undergoing allogeneic transplantation. Allogeneic transplantation: Within 1-3 months after recovery from induction therapy, patients receive busulfan IV every 6 hours on days -7 to -4 and cyclophosphamide IV over 4 hours on days -3 and -2. Allogeneic bone marrow or peripheral blood stem cells (PBSCs) are infused on day 0. Patients receive graft-vs-host disease (GVHD) prophylaxis comprising cyclosporine IV over 1-4 hours beginning on day -1 and then orally (when tolerated) twice daily until day 180. Alternatively, patients may receive tacrolimus IV over 24 hours beginning on day -1 and then orally twice daily until day 180. Patients also receive methotrexate IV on days 1, 3, 6, and 11. Patients who do not meet the criteria for allogeneic transplantation (i.e., are favorable risk or do not have a matching related donor) or who opt not to undergo allogeneic transplantation proceed to consolidation therapy followed by randomization to 1 of 2 autologous transplantation arms. Consolidation therapy: Beginning 2-8 weeks after recovery from induction therapy, patients receive high-dose cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5. A second course is administered 3 weeks after blood recovery. Patients receive filgrastim (G-CSF) subcutaneously (SC) daily for 4 days and then autologous PBSCs are harvested by leukapheresis. Autologous stem cell transplantation: Patients are randomized to 1 of 2 autologous transplantation arms. Arm I: Within 1 month after PBSC collection, patients receive conditioning comprising busulfan IV every 6 hours on days -7 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2. Patients then undergo autologous PBSC transplantation on day 0. Patients receive sargramostim (GM-CSF) or G-CSF IV or SC beginning on day 0 and continuing until blood counts recover. Arm II (closed to accrual as of 10/4/2007): Within 2-4 weeks after PBSC collection, patients receive gemtuzumab ozogamicin IV over 2 hours on day 1 and GM-CSF SC or IV beginning on day 10 and continuing until blood counts recover. Within 2-3 weeks after blood count recovery, patients receive conditioning and undergo autologous PBSC transplantation as in arm I. Patients are followed monthly for 1 year, every 2 months for 1 year, and then every 3 months for up to 7 years. ACTUAL ACCRUAL: A total of 657 patients were accrued for this study.

Official Title
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A Phase III Trial in Adult Acute Myeloid Leukemia: Daunorubicin Dose-Intensification Prior to Risk-Allocated Autologous Stem Cell Transplantation

Conditions
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Leukemia

Intervention / Treatment
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* Biological: sargramostim
* Drug: busulfan
* Drug: cyclophosphamide
* Drug: cytarabine
* Drug: gemtuzumab ozogamicin (GO)
* Drug: Daunorubicin
* Procedure: Autologous HCT
* Procedure: Allogeneic HCT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Morphologically confirmed acute myeloid leukemia (AML) (greater than 20% blasts in the peripheral blood or marrow) meeting any of the following criteria: Recurrent cytogenetic translocations t(8;21)(q22;q22) Bone marrow eosinophil abnormalities inv(16)(p13;q22) t(16;16)(p13;q22) 11q23 abnormalities Multilineage dysplasia without presence of myelodysplastic syndromes (MDS) Minimally differentiated AML AML without maturation AML with maturation AML not otherwise categorized Acute myelomonocytic leukemia Acute monocytic leukemia Acute erythroid leukemia Acute megakaryocytic leukemia Acute basophilic leukemia Patients undergoing allogeneic transplantation must have a sibling donor match defined as human leukocyte antigen (HLA) match or haplotype match with one locus mismatch on other haplotype Age 16 to 60 Eastern Cooperative Oncology Group (ECOG) performance status 0-4 Aspartate aminotransferase (AST) less than 4 times upper limit of normal (ULN) Alkaline phosphatase less than 4 times ULN Creatinine no greater than 2.0 mg/dL Creatinine clearance at least 50 mL/min Left ventricular ejection fraction (LVEF) at least 45% by post-induction multigated acquisition (MUGA) scan Negative pregnancy test Fertile patients must use effective contraception HIV negative Prior hydroxyurea allowed Prior corticosteroids allowed Exclusion Criteria: Recurrent cytogenetic translocations Acute promyelocytic leukemia (PML) with t(15;17)(q22;q21) Variant acute PML with t(v;17) Multilineage dysplasia with prior MDS Acute panmyelosis with myelofibrosis Blastic transformation of chronic myelogenous leukemia Secondary AML (chemotherapy-induced or evolved from MDS) Pregnant or nursing Bilirubin greater than 2.0 mg/dL (unless related to Gilbert's syndrome or hemolysis) Significant cardiac disease requiring active therapy (e.g., digoxin, diuretics, antiarrhythmics, or antianginal medications) Prior biologic therapy Prior cytotoxic chemotherapy for any malignancy Prior radiotherapy for any malignancy

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 60 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Standard Daunorubicin Then Autologous HCT<br>Induction: Patients receive standard-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Before initiating consolidation therapy, patients with CR were randomized to a standard or an investigational arm. All patients received 2 cycles of high-dose cytarabine therapy (3 g/m2 given IV over a 3-hour period every 12 hours every other day for a total of 6 doses), followed by sargramostim 250 μg/m2 until recovery of blood counts. The patients undergoing autologous hematopoietic cell transplantation (HCT) received intravenous busulfan 0.8 mg/kg every 6 hours for 16 doses (without pharmacokinetic sampling) followed by intravenous cyclophosphamide 60 mg/kg daily for 2 days. | Biological: sargramostim<br>* Given IV or as an injection<br>* Other names: Leukine;Drug: busulfan<br>* Given IV<br>* Other names: Myleran;Drug: cyclophosphamide<br>* Given IV<br>* Other names: cytophosphane;Drug: cytarabine<br>* Given as a continuous infusion<br>* Other names: cytosine arabinoside;Drug: Daunorubicin<br>* Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.<br>* Other names: daunomycin cerubidine;Procedure: Autologous HCT<br>* Autologous hematopoietic cell transplantation<br>* Other names: Autologous hematopoietic cell transplantation;|
| Experimental: High-dose Daunorubicin Then Autologous HCT<br>Induction: Patients receive high-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Before initiating consolidation therapy, patients with CR were randomized to a standard or an investigational arm. All patients received 2 cycles of high-dose cytarabine therapy (3 g/m2 given IV over a 3-hour period every 12 hours every other day for a total of 6 doses), followed by sargramostim 250 μg/m2 until recovery of blood counts. The patients undergoing autologous hematopoietic cell transplantation (HCT) received intravenous busulfan 0.8 mg/kg every 6 hours for 16 doses (without pharmacokinetic sampling) followed by intravenous cyclophosphamide 60 mg/kg daily for 2 days. | Biological: sargramostim<br>* Given IV or as an injection<br>* Other names: Leukine;Drug: busulfan<br>* Given IV<br>* Other names: Myleran;Drug: cyclophosphamide<br>* Given IV<br>* Other names: cytophosphane;Drug: cytarabine<br>* Given as a continuous infusion<br>* Other names: cytosine arabinoside;Drug: Daunorubicin<br>* Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.<br>* Other names: daunomycin cerubidine;Procedure: Autologous HCT<br>* Autologous hematopoietic cell transplantation<br>* Other names: Autologous hematopoietic cell transplantation;|
| Experimental: Standard Daunorubicin Then GO/Autologous HCT<br>Induction: Patients receive standard-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Before initiating consolidation therapy, patients with CR were randomized to a standard or an investigational arm. All patients received 2 cycles of high-dose cytarabine therapy (3 g/m2 given IV over a 3-hour period every 12 hours every other day for a total of 6 doses), followed by sargramostim 250 μg/m2 until recovery of blood counts. patients randomized to the investigational arm received a single dose of Gemtuzumab ozogamicin (GO) at 6 mg/m2 followed by sargramostim 250 μ/m2 until recovery of counts. The patients undergoing autologous HCT received intravenous busulfan 0.8 mg/kg every 6 hours for 16 doses followed by intravenous cyclophosphamide 60 mg/kg daily for 2 days. | Biological: sargramostim<br>* Given IV or as an injection<br>* Other names: Leukine;Drug: busulfan<br>* Given IV<br>* Other names: Myleran;Drug: cyclophosphamide<br>* Given IV<br>* Other names: cytophosphane;Drug: cytarabine<br>* Given as a continuous infusion<br>* Other names: cytosine arabinoside;Drug: gemtuzumab ozogamicin (GO)<br>* Given IV<br>* Other names: Mylotarg;Drug: Daunorubicin<br>* Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.<br>* Other names: daunomycin cerubidine;Procedure: Autologous HCT<br>* Autologous hematopoietic cell transplantation<br>* Other names: Autologous hematopoietic cell transplantation;|
| Experimental: High-dose Daunorubicin Then GO/Autologous HCT<br>Induction: Patients receive high-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Before initiating consolidation therapy, patients with CR were randomized to a standard or an investigational arm. All patients received 2 cycles of high-dose cytarabine therapy (3 g/m2 given IV over a 3-hour period every 12 hours every other day for a total of 6 doses), followed by sargramostim 250 μg/m2 until recovery of blood counts. patients randomized to the investigational arm received a single dose of Gemtuzumab ozogamicin (GO) at 6 mg/m2 followed by sargramostim 250 μ/m2 until recovery of counts. The patients undergoing autologous HCT received intravenous busulfan 0.8 mg/kg every 6 hours for 16 doses followed by intravenous cyclophosphamide 60 mg/kg daily for 2 days. | Biological: sargramostim<br>* Given IV or as an injection<br>* Other names: Leukine;Drug: busulfan<br>* Given IV<br>* Other names: Myleran;Drug: cyclophosphamide<br>* Given IV<br>* Other names: cytophosphane;Drug: cytarabine<br>* Given as a continuous infusion<br>* Other names: cytosine arabinoside;Drug: gemtuzumab ozogamicin (GO)<br>* Given IV<br>* Other names: Mylotarg;Drug: Daunorubicin<br>* Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.<br>* Other names: daunomycin cerubidine;Procedure: Autologous HCT<br>* Autologous hematopoietic cell transplantation<br>* Other names: Autologous hematopoietic cell transplantation;|
| Active Comparator: Standard Daunorubicin Then Allogeneic HCT or no Consolidation<br>Induction: Patients receive standard-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Patients without CR did not receive any consolidation treatment. Patients in CR with an unfavorable cytogenetic profile or an initial white blood cell count > 100,000/μL were to proceed to allogeneic HCT if they had a suitable human leukocyte antigen (HLA)-matched sibling donor available. | Drug: cytarabine<br>* Given as a continuous infusion<br>* Other names: cytosine arabinoside;Drug: Daunorubicin<br>* Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.<br>* Other names: daunomycin cerubidine;Procedure: Allogeneic HCT<br>* Allogeneic hematopoietic cell transplantation<br>* Other names: Allogeneic hematopoietic cell transplantation;|
| Experimental: High-dose Daunorubicin Then Allogeneic HCT or no Consolidation<br>Induction: Patients receive high-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Patients without CR did not receive any consolidation treatment. Patients in CR with an unfavorable cytogenetic profile or an initial white blood cell count > 100,000/μL were to proceed to allogeneic HCT if they had a suitable human leukocyte antigen (HLA)-matched sibling donor available. | Drug: cytarabine<br>* Given as a continuous infusion<br>* Other names: cytosine arabinoside;Drug: Daunorubicin<br>* Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.<br>* Other names: daunomycin cerubidine;Procedure: Allogeneic HCT<br>* Allogeneic hematopoietic cell transplantation<br>* Other names: Allogeneic hematopoietic cell transplantation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (Induction Phase) | Overall survival is defined as the time from randomization in the induction phase to death. | Assessed during the first 4 months, then at least every three months for 2 years. then every six months until 5 years after study entry and every 12 months thereafter. | 
| Disease-free Survival (Consolidation Phase) | Disease-free survival is defined from the time of the confirmation of a complete remission via biopsy to the relapse of the disease. | Assessed during the first 4 months, then at least every three months for 2 years. then every six months until five years after study entry, and every 12 months thereafter. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (Consolidation Phase) | Overall survival is defined as the time from randomization in the consolidation phase to death. | Assessed during the first 4 months, then at least every three months for 2 years. then every six months until five years after study entry, and every 12 months thereafter. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute myeloid leukemia, autologous transplantation, gemtuzumab ozogamicin