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

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

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.

Study Overview

• Status: Completed
• Conditions: Leukemia
• Intervention / Treatment: Drug: cyclophosphamide; Drug: busulfan; Biological: sargramostim; Drug: cytarabine; Drug: Daunorubicin; Procedure: Autologous HCT; Drug: gemtuzumab ozogamicin (GO); Procedure: Allogeneic HCT

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 657
• Phase: Phase 3

Contacts and Locations

Study Locations

• Israel
  • Haifa, Israel, 31096
    • Rambam Medical Center
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
  • Arizona
    • Scottsdale, Arizona, United States, 85259-5499
      • Mayo Clinic Scottsdale
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Aurora Presbyterian Hospital
    • Colorado Springs, Colorado, United States, 80933
      • Penrose Cancer Center at Penrose Hospital
    • Denver, Colorado, United States, 80210
      • Porter Adventist Hospital
    • Denver, Colorado, United States, 80220
      • Rose Medical Center
    • Denver, Colorado, United States, 80218
      • Presbyterian - St. Luke's Medical Center
    • Denver, Colorado, United States, 80204
      • St. Anthony Central Hospital
    • Denver, Colorado, United States, 80218
      • St. Joseph Hospital
    • Denver, Colorado, United States, 80224-2522
      • CCOP - Colorado Cancer Research Program
    • Englewood, Colorado, United States, 80110
      • Swedish Medical Center
    • Grand Junction, Colorado, United States, 81502
      • St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center
    • Greeley, Colorado, United States, 80631
      • North Colorado Medical Center
    • Lone Tree, Colorado, United States, 80124
      • Sky Ridge Medical Center
    • Longmont, Colorado, United States, 80502
      • Hope Cancer Care Center at Longmont United Hospital
    • Loveland, Colorado, United States, 80539
      • McKee Medical Center
    • Pueblo, Colorado, United States, 81004
      • St. Mary - Corwin Regional Medical Center
    • Thornton, Colorado, United States, 80229
      • North Suburban Medical Center
    • Wheat Ridge, Colorado, United States, 80033
      • Exempla Lutheran Medical Center
  • Florida
    • Boca Raton, Florida, United States, 33428
      • Eugene M. and Christine E. Lynn Cancer Institute at Boca Raton Community Hospital - West
    • Boca Raton, Florida, United States, 33486
      • Eugene M. and Christine E. Lynn Cancer Institute at Boca Raton Community Hospital - Main Campus
    • Gainesville, Florida, United States, 32610-0232
      • University of Florida Shands Cancer Center
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center - Miami
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
  • Illinois
    • Chicago, Illinois, United States, 60611-3013
      • Robert H. Lurie Comprehensive Cancer Center at Northwestern University
    • Chicago, Illinois, United States, 60611
      • Hematology and Oncology Associates
    • Evanston, Illinois, United States, 60201-1781
      • Evanston Northwestern Healthcare - Evanston Hospital
    • Joliet, Illinois, United States, 60435
      • Joliet Oncology-Hematology Associates, Limited - West
    • Joliet, Illinois, United States, 60432
      • Midwest Center for Hematology/Oncology
    • Libertyville, Illinois, United States, 60048
      • North Shore Oncology and Hematology Associates, Limited - Libertyville
    • Naperville, Illinois, United States, 60563
      • La Grange Oncology Associates - Geneva
    • Niles, Illinois, United States, 60714
      • Cancer Care and Hematology Specialists of Chicagoland - Niles
    • Park Ridge, Illinois, United States, 60068-1174
      • Advocate Lutheran General Cancer Care Center
    • Skokie, Illinois, United States, 60076
      • Hematology Oncology Associates - Skokie
    • Urbana, Illinois, United States, 61801
      • Carle Cancer Center at Carle Foundation Hospital
    • Urbana, Illinois, United States, 61801
      • CCOP - Carle Cancer Center
  • Indiana
    • Fort Wayne, Indiana, United States, 46815
      • Fort Wayne Medical Oncology and Hematology
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Melvin and Bren Simon Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts-NEMC Cancer Center
  • Michigan
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
    • Kalamazoo, Michigan, United States, 49001
      • Borgess Medical Center
    • Kalamazoo, Michigan, United States, 49007-3731
      • West Michigan Cancer Center
  • Minnesota
    • Bemidji, Minnesota, United States, 56601
      • MeritCare Bemidji
    • Burnsville, Minnesota, United States, 55337
      • Fairview Ridges Hospital
    • Coon Rapids, Minnesota, United States, 55433
      • Mercy and Unity Cancer Center at Mercy Hospital
    • Edina, Minnesota, United States, 55435
      • Fairview Southdale Hospital
    • Fridley, Minnesota, United States, 55432
      • Mercy and Unity Cancer Center at Unity Hospital
    • Maplewood, Minnesota, United States, 55109
      • Minnesota Oncology Hematology, PA - Maplewood
    • Minneapolis, Minnesota, United States, 55407
      • Virginia Piper Cancer Institute at Abbott - Northwestern Hospital
    • Robbinsdale, Minnesota, United States, 55422-2900
      • Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
    • Saint Louis Park, Minnesota, United States, 55416
      • CCOP - Metro-Minnesota
    • Saint Louis Park, Minnesota, United States, 55416
      • Park Nicollet Cancer Center
    • Saint Paul, Minnesota, United States, 55102
      • United Hospital
    • Waconia, Minnesota, United States, 55387
      • Ridgeview Medical Center
    • Woodbury, Minnesota, United States, 55125
      • Minnesota Oncology Hematology, PA - Woodbury
  • Montana
    • Billings, Montana, United States, 59101
      • CCOP - Montana Cancer Consortium
    • Billings, Montana, United States, 59101
      • Hematology-Oncology Centers of the Northern Rockies - Billings
    • Billings, Montana, United States, 59101
      • Northern Rockies Radiation Oncology Center
    • Billings, Montana, United States, 59101
      • St. Vincent Healthcare Cancer Care Services
    • Billings, Montana, United States, 59107-7000
      • Billings Clinic - Downtown
    • Bozeman, Montana, United States, 59715
      • Bozeman Deaconess Cancer Center
    • Butte, Montana, United States, 59701
      • St. James Healthcare Cancer Care
    • Great Falls, Montana, United States, 59405
      • Great Falls Clinic
    • Great Falls, Montana, United States, 59405
      • Great Falls Clinic - Main Facility
    • Helena, Montana, United States, 59601
      • St. Peter's Hospital
    • Kalispell, Montana, United States, 59901
      • Kalispell Regional Medical Center
    • Kalispell, Montana, United States, 59901
      • Glacier Oncology, PLLC
    • Kalispell, Montana, United States, 59901
      • Kalispell Medical Oncology at KRMC
    • Missoula, Montana, United States, 59801
      • Community Medical Center
    • Missoula, Montana, United States, 59804
      • Guardian Oncology and Center for Wellness
    • Missoula, Montana, United States, 59807-7877
      • Montana Cancer Specialists at Montana Cancer Center
    • Missoula, Montana, United States, 59807
      • Montana Cancer Center at St. Patrick Hospital and Health Sciences Center
  • New York
    • Bronx, New York, United States, 10461
      • Albert Einstein Cancer Center at Albert Einstein College of Medicine
    • New York, New York, United States, 10016
      • NYU Cancer Institute at New York University Medical Center
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • CCOP - MeritCare Hospital
    • Fargo, North Dakota, United States, 58122
      • MeritCare Broadway
  • Ohio
    • Canton, Ohio, United States, 44710-1799
      • Aultman Cancer Center at Aultman Hospital
    • Canton, Ohio, United States, 44708
      • Mercy Cancer Center at Mercy Medical Center
    • Cincinnati, Ohio, United States, 45236
      • Jewish Hospital Cancer Center
    • Lima, Ohio, United States, 45801
      • St. Rita's Medical Center
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822-0001
      • Geisinger Cancer Institute at Geisinger Health
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Cancer Institute at Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19111-2497
      • Fox Chase Cancer Center - Philadelphia
    • Philadelphia, Pennsylvania, United States, 19104-4283
      • Abramson Cancer Center of the University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Cancer Centers
    • State College, Pennsylvania, United States, 16801
      • Geisinger Medical Group - Scenery Park
    • Wilkes-Barre, Pennsylvania, United States, 18711
      • Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232-6838
      • Vanderbilt-Ingram Cancer Center
  • Virginia
    • Richmond, Virginia, United States, 23298-0037
      • Virginia Commonwealth University Massey Cancer Center
  • Wisconsin
    • Eau Claire, Wisconsin, United States, 54701
      • Marshfield Clinic Cancer Care at Regional Cancer Center
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
    • Marshfield, Wisconsin, United States, 54449
      • Saint Joseph's Hospital
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic - Marshfield Center
    • Rhinelander, Wisconsin, United States, 54501
      • Ministry Medical Group at Saint Mary's Hospital
    • Weston, Wisconsin, United States, 54476
      • Marshfield Clinic - Weston Center
  • Wyoming
    • Sheridan, Wyoming, United States, 82801
      • Welch Cancer Center at Sheridan Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard Daunorubicin Then Autologous HCT; 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.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; Neosar; Revimmune; Procytox; cytophosphane; Drug: busulfan; Given IV; Other Names: Myleran; Biological: sargramostim; Given IV or as an injection; Other Names: Leukine; Drug: cytarabine; Given as a continuous infusion; Other Names: cytosine arabinoside; Drug: Daunorubicin; Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.; Other Names: daunomycin; daunomycin cerubidine; Procedure: Autologous HCT; Autologous hematopoietic cell transplantation; Other Names: Autologous hematopoietic cell transplantation
Experimental: High-dose Daunorubicin Then Autologous HCT; 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.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; Neosar; Revimmune; Procytox; cytophosphane; Drug: busulfan; Given IV; Other Names: Myleran; Biological: sargramostim; Given IV or as an injection; Other Names: Leukine; Drug: cytarabine; Given as a continuous infusion; Other Names: cytosine arabinoside; Drug: Daunorubicin; Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.; Other Names: daunomycin; daunomycin cerubidine; Procedure: Autologous HCT; Autologous hematopoietic cell transplantation; Other Names: Autologous hematopoietic cell transplantation
Experimental: Standard Daunorubicin Then GO/Autologous HCT; 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.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; Neosar; Revimmune; Procytox; cytophosphane; Drug: busulfan; Given IV; Other Names: Myleran; Biological: sargramostim; Given IV or as an injection; Other Names: Leukine; Drug: cytarabine; Given as a continuous infusion; Other Names: cytosine arabinoside; Drug: Daunorubicin; Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.; Other Names: daunomycin; daunomycin cerubidine; Procedure: Autologous HCT; Autologous hematopoietic cell transplantation; Other Names: Autologous hematopoietic cell transplantation; Drug: gemtuzumab ozogamicin (GO); Given IV; Other Names: Mylotarg
Experimental: High-dose Daunorubicin Then GO/Autologous HCT; 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.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; Neosar; Revimmune; Procytox; cytophosphane; Drug: busulfan; Given IV; Other Names: Myleran; Biological: sargramostim; Given IV or as an injection; Other Names: Leukine; Drug: cytarabine; Given as a continuous infusion; Other Names: cytosine arabinoside; Drug: Daunorubicin; Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.; Other Names: daunomycin; daunomycin cerubidine; Procedure: Autologous HCT; Autologous hematopoietic cell transplantation; Other Names: Autologous hematopoietic cell transplantation; Drug: gemtuzumab ozogamicin (GO); Given IV; Other Names: Mylotarg
Active Comparator: Standard Daunorubicin Then Allogeneic HCT or no Consolidation; 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; Given as a continuous infusion; Other Names: cytosine arabinoside; Drug: Daunorubicin; Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.; Other Names: daunomycin; daunomycin cerubidine; Procedure: Allogeneic HCT; Allogeneic hematopoietic cell transplantation; Other Names: Allogeneic hematopoietic cell transplantation
Experimental: High-dose Daunorubicin Then Allogeneic HCT or no Consolidation; 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; Given as a continuous infusion; Other Names: cytosine arabinoside; Drug: Daunorubicin; Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.; Other Names: daunomycin; daunomycin cerubidine; Procedure: Allogeneic HCT; Allogeneic hematopoietic cell transplantation; Other Names: Allogeneic hematopoietic cell transplantation

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Eastern Cooperative Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Hugo F. Fernandez, MD, H. Lee Moffitt Cancer Center and Research Institute

Publications and helpful links

General Publications

• Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, Racevskis J, Dewald GW, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Tallman MS. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1249-59. doi: 10.1056/NEJMoa0904544.
• Fernandez HF, Sun Z, Bennett JM, et al.: A single dose of gemtuzumab-ozogamicin (GO) in consolidation prior to autologous transplant for younger patients with newly diagnosed acute myeloid (AML) is safe but has no effect on disease free survival: interim results of Eastern Cooperative Oncology Group study (E1900). [Abstract] Biol Blood Marrow Transplant 14 (2): A-52, 21-2, 2008.
• Vance GH, Kim H, Hicks GA, Cherry AM, Higgins R, Hulshizer RL, Tallman MS, Fernandez HF, Dewald GW. Utility of interphase FISH to stratify patients into cytogenetic risk categories at diagnosis of AML in an Eastern Cooperative Oncology Group (ECOG) clinical trial (E1900). Leuk Res. 2007 May;31(5):605-9. doi: 10.1016/j.leukres.2006.07.026. Epub 2006 Sep 22.
• Fernandez HF, Kim HT, Bennett JM, et al.: Gemtuzumab-ozogamicin (GO; mylotarg®) as part of consolidation therapy for AML before autograft: low incidence of hepatic veno-occlusive disease. [Abstract] Biol Blood Marrow Transplant 11 (2 Suppl 1): A-187, 2005.
• Gonen M, Sun Z, Figueroa ME, Patel JP, Abdel-Wahab O, Racevskis J, Ketterling RP, Fernandez H, Rowe JM, Tallman MS, Melnick A, Levine RL, Paietta E. CD25 expression status improves prognostic risk classification in AML independent of established biomarkers: ECOG phase 3 trial, E1900. Blood. 2012 Sep 13;120(11):2297-306. doi: 10.1182/blood-2012-02-414425. Epub 2012 Aug 1.
• Fernandez HF, Sun Z, Litzow MR, Luger SM, Paietta EM, Racevskis J, Dewald G, Ketterling RP, Rowe JM, Lazarus HM, Tallman MS. Autologous transplantation gives encouraging results for young adults with favorable-risk acute myeloid leukemia, but is not improved with gemtuzumab ozogamicin. Blood. 2011 May 19;117(20):5306-13. doi: 10.1182/blood-2010-09-309229. Epub 2011 Mar 17.
• Luskin MR, Gimotty PA, Smith C, Loren AW, Figueroa ME, Harrison J, Sun Z, Tallman MS, Paietta EM, Litzow MR, Melnick AM, Levine RL, Fernandez HF, Luger SM, Carroll M, Master SR, Wertheim GB. A clinical measure of DNA methylation predicts outcome in de novo acute myeloid leukemia. JCI Insight. 2016 Jun 16;1(9):e87323. doi: 10.1172/jci.insight.87323.
• Luskin MR, Lee JW, Fernandez HF, Abdel-Wahab O, Bennett JM, Ketterling RP, Lazarus HM, Levine RL, Litzow MR, Paietta EM, Patel JP, Racevskis J, Rowe JM, Tallman MS, Sun Z, Luger SM. Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups. Blood. 2016 Mar 24;127(12):1551-8. doi: 10.1182/blood-2015-07-657403. Epub 2016 Jan 11.
• Walter RB, Othus M, Paietta EM, Racevskis J, Fernandez HF, Lee JW, Sun Z, Tallman MS, Patel J, Gonen M, Abdel-Wahab O, Levine RL, Estey EH. Effect of genetic profiling on prediction of therapeutic resistance and survival in adult acute myeloid leukemia. Leukemia. 2015 Oct;29(10):2104-7. doi: 10.1038/leu.2015.76. Epub 2015 Mar 16. No abstract available.

Helpful Links

• Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive.

Study record dates

Study Major Dates

• Study Start (Actual): December 19, 2002
• Primary Completion (Actual): March 1, 2009
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: November 12, 2002
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimated): January 27, 2003

Study Record Updates

• Last Update Posted (Actual): June 15, 2023
• Last Update Submitted That Met QC Criteria: June 13, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: acute myeloid leukemia; autologous transplantation; gemtuzumab ozogamicin
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Immunoconjugates; Immunotoxins; Cyclophosphamide; Cytarabine; Daunorubicin; Busulfan; Sargramostim; Gemtuzumab
• Other Study ID Numbers: CDR0000258113; U10CA021115 (U.S. NIH Grant/Contract); E1900 (Other Identifier: Eastern Cooperative Oncology Group (ECOG))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No