Combination Chemotherapy With or Without Gemtuzumab in Treating Young Patients With Newly Diagnosed Acute Myeloid Leukemia

A Phase III Randomized Trial of Gemtuzumab Ozogamicin (Mylotarg) Combined With Conventional Chemotherapy for De Novo Acute Myeloid Leukemia (AML) in Children, Adolescents, and Young Adults

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as gemtuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving combination chemotherapy together with gemtuzumab may kill more cancer cells. It is not yet known whether combination chemotherapy is more effective with or without gemtuzumab in treating patients with newly diagnosed acute myeloid leukemia.

PURPOSE: This randomized phase III trial is studying combination chemotherapy and gemtuzumab to see how well they work compared with combination chemotherapy alone in treating young patients with newly diagnosed acute myeloid leukemia.

Study Overview

• Status: Completed
• Conditions: Leukemia
• Intervention / Treatment: Drug: cytarabine; Drug: asparaginase; Drug: daunorubicin hydrochloride; Drug: etoposide; Drug: mitoxantrone hydrochloride; Drug: gemtuzumab ozogamicin

Detailed Description

OBJECTIVES:

Primary

• Compare the event-free survival (EFS) and overall survival (OS) of young patients with newly diagnosed acute myeloid leukemia (AML) treated with conventional combination chemotherapy with vs without gemtuzumab ozogamicin (GMTZ).

Secondary

• Compare the remission induction rates after two courses of therapy in these patients.
• Compare disease-free survival and OS in patients who are eligible for an human leukocyte antigen (HLA)-matched family donor (MFD) stem cell transplant (SCT) by virtue of their risk classification, with patients assigned to MFD SCT if a MFD is available, or to chemotherapy if a MFD is not available.
• Determine the outcome of patients with Down syndrome who are 4 years of age or older at diagnosis and treated with conventional combination chemotherapy without GMTZ.
• Compare the EFS and OS of patients with de novo AML treated with conventional combination chemotherapy with vs without GMTZ censoring MFD SCT recipients.
• Determine the prevalence and prognostic significance of molecular abnormalities of KIT, CCAAT-enhancer binding protein alpha (CEBPα) and MLL-Partial tandem duplications (PTD) genes in these patients.
• Determine the leukemic involvement of hematopoietic early progenitor and its role in defining response to therapy.
• Assess the ability of a second-generation flow cytometric assay to predict patients at high risk for relapse during periods of clinical remission.
• Examine whether GMTZ significantly improves EFS and OS in patients with higher CD33 concentrations/intensity.
• Examine whether GMTZ significantly improves complete remission, EFS, and OS in each of the cytogenetic risk groups (high-, intermediate-, and low-risk) identified in prior Medical Research Council trials.
• Utilize fluorescence in situ hybridization (FISH) analysis to identify variant patterns among subgroups of patients who demonstrate the same G-banded chromosomal abnormality (e.g., inv[16]/t[16;16], t[8;21], 11q23 abnormality) and determine whether these variant patterns account for the heterogeneity of responses to therapy.
• Examine the impact of complex karyotypes (≥ 3, ≥ 4, and ≥ 5 abnormalities) on OS and EFS in intermediate-risk patients for whom no high-risk or low-risk cytogenetic abnormalities exist.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to relapse risk (high vs intermediate vs low). Patients are randomized to 1 of 2 treatment arms. Patients with Down syndrome are nonrandomly assigned to arm I (but do not undergo allogeneic stem cell transplant [SCT]).

• Arm I (standard therapy):

  • Induction 1: Patients receive cytarabine IT at the time of diagnosis or on day 1*. Patients also receive cytarabine IV on days 1-10, daunorubicin hydrochloride IV over 6 hours on days 1, 3, and 5, and etoposide IV over 4 hours on days 1-5. After 3 weeks of rest, all patients (regardless of remission status) proceed to induction 2.

NOTE: *Patients with Central Nervous System (CNS) disease receive cytarabine IT twice weekly until the cerebrospinal fluid is clear, followed by two additional IT treatments. Patients with refractory CNS leukemia after 6 doses of IT treatment are removed from the study.

• Induction 2: Patients receive cytarabine IT on day 1, cytarabine IV on days 1-8, daunorubicin hydrochloride IV over 6 hours on days 1, 3, and 5, and etoposide IV over 4 hours on days 1-5. After 3 weeks of rest, patients in complete remission (CR) proceed to intensification 1. Patients with refractory disease are removed from protocol therapy.
• Intensification 1: Patients receive cytarabine IT on day 1, high-dose cytarabine IV over 1 hour on days 1-5, and etoposide IV over 1 hour on days 1-5. After 3 weeks of rest, patients in remission proceed to intensification 2, followed by intensification 3. Patients in remission proceed to allogeneic SCT 2-8 weeks after blood counts recover. Patients with high-risk disease with an alternative donor proceed to intensification 2 and 3, followed by allogeneic SCT. Patients not in remission are removed from protocol therapy.
• Intensification 2: Patients receive cytarabine IT on day 1, high-dose cytarabine IV over 2 hours on days 1-4, and mitoxantrone hydrochloride IV over 1 hour on days 3-6. After 3 weeks of rest, patients proceed to intensification 3.

• Intensification 3: Patients receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9 and asparaginase intramuscularly on days 2 and 9.

  • Arm II:
• Induction 1: Patients receive treatment as in induction 1 of arm I. Patients also receive gemtuzumab ozogamicin (GMTZ) IV over 2 hours on day 6.
• Induction 2: Patients receive treatment as in induction 2 of arm I.
• Intensification 1: Patients receive treatment as in intensification 1 of arm I.
• Intensification 2: Patients receive treatment as in intensification 2 of arm I. Patients also receive GMTZ IV over 2 hours on day 7.

• Intensification 3: Patients receive treatment as in intensification 3 of arm I.

  • Allogeneic SCT (for patients with intermediate- or high-risk disease):
• MFD: Patients receive a conditioning regimen comprising busulfan IV over 2 hours every 6 hours on days -9 to -6 and cyclophosphamide IV over 1 hour on days -5 to -2. Patients undergo allogeneic SCT on day 0. Patients receive cyclosporine IV or orally twice daily on days -1 to 180 and methotrexate IV on days 1, 3, 6, and 11. Patients receive graft-vs-host disease (GVHD) prophylaxis comprising cyclosporine IV over 1-4 hours or orally twice daily on days -1 to 180 and methotrexate IV on days 1, 3, 6, and 11.
• Matched alternative donor: Patients receive a conditioning regimen comprising busulfan and cyclophosphamide as above. Patients also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1. Patients then undergo allogeneic SCT and receive GVHD prophylaxis as above.

After completion of study treatment, patients are followed periodically for 3 years and then annually thereafter.

PROJECTED ACCRUAL: A total of 1,012 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 1070
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Westmead Institute for Cancer Research at Westmead Hospital
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Children's Hospital
  • South Australia
    • North Adelaide, South Australia, Australia, 5006
      • Women's and Children's Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6001
      • Princess Margaret Hospital for Children
• Canada
  • Quebec, Canada, G1V 4G2
    • Centre Hospitalier Universitaire de Quebec
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • Children's & Women's Hospital of British Columbia
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Newfoundland and Labrador
    • Saint John's, Newfoundland and Labrador, Canada, A1B 3V6
      • Janeway Children's Health and Rehabilitation Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 6R8
      • IWK Health Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital at Hamilton Health Sciences
    • Kingston, Ontario, Canada, K7L 5P9
      • Cancer Centre of Southeastern Ontario At Kingston General Hospital
    • London, Ontario, Canada, N6A 5W9
      • Children's Hospital of Western Ontario
    • Ottawa, Ontario, Canada, K1H 8L1
      • Children's Hospital of Eastern Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Hopital Sainte Justine
• New Zealand
  • Christchurch, New Zealand, 8011
    • Christchurch Hospital
  • Grafton, New Zealand, 1145
    • Starship Children's Health
• Puerto Rico
  • Santurce, Puerto Rico, 00912
    • San Jorge Children's Hospital
• Switzerland
  • Bern, Switzerland, 3010
    • Swiss Pediatric Oncology Group Bern
  • Geneva, Switzerland, 1205
    • Swiss Pediatric Oncology Group Geneva
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Uab Comprehensive Cancer Center
    • Mobile, Alabama, United States, 36604
      • University of South Alabama Mitchell Cancer Institute
  • Arizona
    • Mesa, Arizona, United States, 85202
      • Banner Desert Medical Center
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
    • Tucson, Arizona, United States, 85724-5024
      • Arizona Cancer Center at University of Arizona Health Sciences Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
  • California
    • Downey, California, United States, 90242
      • Southern California Permanente Medical Group
    • Duarte, California, United States, 91010-3000
      • City of Hope Comprehensive Cancer Center
    • Loma Linda, California, United States, 92354
      • Loma Linda University Cancer Institute at Loma Linda University Medical Center
    • Los Angeles, California, United States, 90095-1781
      • Jonsson Comprehensive Cancer Center at UCLA
    • Los Angeles, California, United States, 90027
      • Childrens Hospital Los Angeles
    • Los Angeles, California, United States, 90048-1865
      • Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center
    • Madera, California, United States, 93636-8762
      • Children's Hospital Central California
    • Oakland, California, United States, 94611
      • Kaiser Permanente Medical Center - Oakland
    • Oakland, California, United States, 94609
      • Children's Hospital and Research Center Oakland
    • Orange, California, United States, 92868-3874
      • Children's Hospital of Orange County
    • Sacramento, California, United States, 95816
      • Sutter Cancer Center
    • Sacramento, California, United States, 95817
      • University of California Davis Cancer Center
    • San Diego, California, United States, 92123-4282
      • Rady Children's Hospital - San Diego
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
    • Santa Barbara, California, United States, 93105
      • Santa Barbara Cottage Children's Hospital
    • Torrance, California, United States, 90502
      • Jonathan Jaques Children's Cancer Center at Miller Children's Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Center for Cancer and Blood Disorders
  • Connecticut
    • Farmington, Connecticut, United States, 06360-2875
      • Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center
    • New Haven, Connecticut, United States, 06520-8028
      • Yale Cancer Center
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I. DuPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
    • Washington, District of Columbia, United States, 20307-5001
      • Walter Reed Army Medical Center
  • Florida
    • Fort Lauderdale, Florida, United States, 33316
      • Broward General Medical Center Cancer Center
    • Fort Myers, Florida, United States, 33901
      • Lee Cancer Care of Lee Memorial Health System
    • Gainesville, Florida, United States, 32610-0232
      • University of Florida Shands Cancer Center
    • Hollywood, Florida, United States, 33021
      • Memorial Cancer Institute at Memorial Regional Hospital
    • Jacksonville, Florida, United States, 32207-8426
      • Nemours Children's Clinic
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center - Miami
    • Miami, Florida, United States, 33155
      • Miami Children's Hospital
    • Miami, Florida, United States, 33176
      • Baptist-South Miami Regional Cancer Program
    • Orlando, Florida, United States, 32803-1273
      • Florida Hospital Cancer Institute at Florida Hospital Orlando
    • Orlando, Florida, United States, 32806
      • Nemours Children's Clinic - Orlando
    • Orlando, Florida, United States, 32806
      • M.D. Anderson Cancer Center at Orlando
    • Pensacola, Florida, United States, 32504
      • Sacred Heart Cancer Center at Sacred Heart Hospital
    • Saint Petersburg, Florida, United States, 33701
      • All Children's Hospital
    • Tampa, Florida, United States, 33607
      • St. Joseph's Cancer Institute at St. Joseph's Hospital
    • West Palm Beach, Florida, United States, 33407
      • Kaplan Cancer Center at St. Mary's Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
    • Atlanta, Georgia, United States, 30322
      • AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
    • Augusta, Georgia, United States, 30912
      • MBCCOP - Medical College of Georgia Cancer Center
    • Savannah, Georgia, United States, 31403-3089
      • Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Cancer Research Center of Hawaii
    • Tripler AMC, Hawaii, United States, 96859-5000
      • Tripler Army Medical Center
  • Idaho
    • Boise, Idaho, United States, 83712
      • Mountain States Tumor Institute at St. Luke's Regional Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
    • Chicago, Illinois, United States, 60612-7243
      • University of Illinois Cancer Center
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital - Chicago
    • Maywood, Illinois, United States, 60153
      • Cardinal Bernardin Cancer Center at Loyola University Medical Center
    • Oak Lawn, Illinois, United States, 60453-2699
      • Advocate Christ Medical Center
    • Oak Lawn, Illinois, United States, 60453
      • Keyser Family Cancer Center at Advocate Hope Children's Hospital
    • Park Ridge, Illinois, United States, 60068-1174
      • Advocate Lutheran General Cancer Care Center
    • Springfield, Illinois, United States, 62794-9677
      • Simmons Cooper Cancer Institute
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Melvin and Bren Simon Cancer Center
    • Indianapolis, Indiana, United States, 46260
      • St. Vincent Indianapolis Hospital
  • Iowa
    • Des Moines, Iowa, United States, 50309
      • Blank Children's Hospital
    • Iowa City, Iowa, United States, 52242-1002
      • Holden Comprehensive Cancer Center at University of Iowa
  • Kansas
    • Kansas City, Kansas, United States, 66160-7357
      • Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0093
      • Lucille P. Markey Cancer Center at University of Kentucky
    • Louisville, Kentucky, United States, 40232
      • Kosair Children's Hospital
  • Louisiana
    • Alexandria, Louisiana, United States, 71315-3198
      • Tulane Cancer Center Office of Clinical Research
    • New Orleans, Louisiana, United States, 70118
      • Children's Hospital of New Orleans
  • Maine
    • Bangor, Maine, United States, 04401
      • CancerCare of Maine at Eastern Maine Medical Center
    • Portland, Maine, United States, 04102
      • Maine Children's Cancer Program at Barbara Bush Children's Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    • Baltimore, Maryland, United States, 21215
      • Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
    • Baltimore, Maryland, United States, 21201
      • Greenebaum Cancer Center at University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
    • Boston, Massachusetts, United States, 02111
      • Floating Hospital for Children at Tufts - New England Medical Center
    • Springfield, Massachusetts, United States, 01199-0001
      • Baystate Regional Cancer Program at D'Amour Center for Cancer Care
    • Worcester, Massachusetts, United States, 01655
      • UMASS Memorial Cancer Center - University Campus
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0286
      • C.S. Mott Children's Hospital at University of Michigan Medical Center
    • Detroit, Michigan, United States, 48201-1379
      • Barbara Ann Karmanos Cancer Institute
    • Flint, Michigan, United States, 48503
      • Hurley Medical Center
    • Grand Rapids, Michigan, United States, 49503
      • Butterworth Hospital at Spectrum Health
    • Grosse Pointe Woods, Michigan, United States, 48236
      • Van Elslander Cancer Center at St. John Hospital and Medical Center
    • Kalamazoo, Michigan, United States, 49008
      • CCOP - Kalamazoo
    • Lansing, Michigan, United States, 48910
      • Breslin Cancer Center at Ingham Regional Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minnesota - Minneapolis
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center at University of Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Cancer Clinic
  • Missouri
    • Columbia, Missouri, United States, 65203
      • Ellis Fischel Cancer Center at University of Missouri - Columbia
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
    • Saint Louis, Missouri, United States, 63104
      • Cardinal Glennon Children's Hospital
    • Saint Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
  • Nebraska
    • Omaha, Nebraska, United States, 68114-4113
      • Children's Hospital
    • Omaha, Nebraska, United States, 68198-6805
      • UNMC Eppley Cancer Center at the University of Nebraska Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • CCOP - Nevada Cancer Research Foundation
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756-0002
      • Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center Cancer Center
    • New Brunswick, New Jersey, United States, 08903
      • Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
    • Paterson, New Jersey, United States, 07503
      • St. Joseph's Hospital and Medical Center
    • Summit, New Jersey, United States, 07902
      • Overlook Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131-5636
      • University of New Mexico Cancer Center
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center Hospital
    • Bronx, New York, United States, 10461
      • Albert Einstein Cancer Center at Albert Einstein College of Medicine
    • Brooklyn, New York, United States, 11201-5493
      • Brooklyn Hospital Center
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New Hyde Park, New York, United States, 11040
      • Schneider Children's Hospital
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10021
      • New York Weill Cornell Cancer Center at Cornell University
    • New York, New York, United States, 10016
      • NYU Cancer Institute at New York University Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Center at University of Rochester Medical Center
    • Stony Brook, New York, United States, 11794-9446
      • Stony Brook University Cancer Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospitals - Memorial Campus
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
    • Charlotte, North Carolina, United States, 28232-2861
      • Blumenthal Cancer Center at Carolinas Medical Center
    • Charlotte, North Carolina, United States, 28233-3549
      • Presbyterian Cancer Center at Presbyterian Hospital
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center
    • Greenville, North Carolina, United States, 27834
      • Leo W. Jenkins Cancer Center at ECU Medical School
    • Winston-Salem, North Carolina, United States, 27157-1096
      • Wake Forest University Comprehensive Cancer Center
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • CCOP - MeritCare Hospital
  • Ohio
    • Akron, Ohio, United States, 44308-1062
      • Akron Children's Hospital
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies and Children's Hospital
    • Columbus, Ohio, United States, 43205-2696
      • Nationwide Children's Hospital
    • Dayton, Ohio, United States, 45404
      • Children's Medical Center - Dayton
    • Toledo, Ohio, United States, 43606
      • Toledo Hospital
    • Toledo, Ohio, United States, 43614
      • Medical University of Ohio Cancer Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Cancer Institute
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Knight Cancer Institute At Oregon Health and Science University
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Hospital and Health Center and Children's Hospital
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18017
      • Lehigh Valley Hospital - Muhlenberg
    • 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
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Children's Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19134-1095
      • St. Christopher's Hospital for Children
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital Comprehensive Cancer Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Hollings Cancer Center at Medical University of South Carolina
    • Columbia, South Carolina, United States, 29203
      • Palmetto Health South Carolina Cancer Center
    • Greenville, South Carolina, United States, 29605
      • Greenville Hospital Cancer Center
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57117-5039
      • Sanford Cancer Center at Sanford USD Medical Center
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • T.C. Thompson Children's Hospital
    • Knoxville, Tennessee, United States, 37916
      • East Tennessee Children's Hospital
    • Nashville, Tennessee, United States, 37232-6838
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Amarillo, Texas, United States, 79106
      • Texas Tech University Health Sciences Center School of Medicine - Amarillo
    • Austin, Texas, United States, 78723
      • Dell Children's Medical Center of Central Texas
    • Corpus Christi, Texas, United States, 78411
      • Driscoll Children's Hospital
    • Dallas, Texas, United States, 75230
      • Medical City Dallas Hospital
    • Dallas, Texas, United States, 75390
      • Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center - Fort Worth
    • Houston, Texas, United States, 77030
      • Baylor University Medical Center - Houston
    • Lubbock, Texas, United States, 79410
      • Covenant Children's Hospital
    • San Antonio, Texas, United States, 78229-3993
      • Methodist Children's Hospital of South Texas
    • San Antonio, Texas, United States, 78229-3900
      • University of Texas Health Science Center at San Antonio
    • Temple, Texas, United States, 76508
      • CCOP - Scott and White Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84113-1100
      • Primary Children's Medical Center
  • Vermont
    • Burlington, Vermont, United States, 05401
      • Fletcher Allen Health Care - University Health Center Campus
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Cancer Center
    • Falls Church, Virginia, United States, 22042-3300
      • Inova Fairfax Hospital
    • Norfolk, Virginia, United States, 23507
      • Children's Hospital of The King's Daughters
    • Portsmouth, Virginia, United States, 23708-2197
      • Naval Medical Center - Portsmouth
    • Richmond, Virginia, United States, 23298-0037
      • Virginia Commonwealth University Massey Cancer Center
    • Roanoke, Virginia, United States, 24014
      • Carilion Medical Center for Children at Roanoke Community Hospital
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle
    • Spokane, Washington, United States, 99204
      • Providence Cancer Center at Sacred Heart Medical Center
    • Tacoma, Washington, United States, 98405
      • Mary Bridge Children's Hospital and Health Center - Tacoma
    • Tacoma, Washington, United States, 98431
      • Madigan Army Medical Center - Tacoma
  • West Virginia
    • Charleston, West Virginia, United States, 25302
      • West Virginia University Health Sciences Center - Charleston
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54307-3508
      • St. Vincent Hospital Regional Cancer Center
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic - Marshfield Center
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center at Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 29 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Newly diagnosed acute myeloid leukemia (AML)

  • Meets customary criteria for AML with ≥ 20% bone marrow blasts (by WHO classification)

    • Patients with < 20% bone marrow blasts and cytopenia or myelodysplastic syndromes (e.g., chronic myelomonocytic leukemia, refractory anemia (RA), RA with excess blasts, RA with ringed sideroblasts) are eligible provided 1 of the following criteria is met:

      • Karyotypic abnormality characteristic of de novo AML (t[8;21][q22;q22], inv[16][p13q22], t[16;16][p13;q22], or 11q23 abnormalities)
      • Unequivocal presence of megakaryoblasts (by WHO classification)
  • Isolated myeloid sarcoma (i.e., myeloblastoma or chloroma) allowed regardless of bone marrow results
• Infants < 1 month of age with progressive disease* are eligible NOTE: *Infants < 1 month of age with AML may be given supportive care until it is clear that the leukemia is not regressing (i.e., the disappearance of peripheral blasts and the normalization of peripheral blood counts)
• Patients with Down syndrome ≥ 4 years of age are eligible
• No juvenile myelomonocytic leukemia
• No Fanconi's anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome
• No promyelocytic leukemia (M3)
• No secondary or treatment-related AML

• Matched family donor criteria (for patients with intermediate-risk or high-risk disease):

  • HLA-A, -B, -C, and beta chain (-DRB1), identical or 1 antigen or allele mismatched by molecular high resolution technique
  • All available first-degree family members (parents and siblings) must be HLA typed
  • No syngeneic donors

• Matched alternative donor criteria (for patients with high-risk disease):

  • HLA-A, -B, -C, and -DRB1, identical or 1 antigen or allele mismatched donor
  • HLA-A, -B, and -DRB1 4 of 6 antigen matched unrelated cord blood donor
  • Mismatched family member donor with ≥ 1 haplotype match or 5 of 6 antigen phenotypic match

PATIENT CHARACTERISTICS:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy, radiation therapy, or any antileukemic therapy

  • Topical or inhalation steroids for other conditions allowed
  • Intrathecal cytarabine given at diagnosis allowed
• No other prior treatment for AML
• No concurrent peripheral blood stem cell transplantation in patients with matched family donor

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A: Standard Arm - No GMTZ, AML Pts w/out Down Syndrome; Patients receive intrathecal (IT) cytarabine (ARA-C) at diagnosis or on day 1 of treatment or twice a week for up to 6 doses. They also receive an infusion of ARA-C on days 1-10; a 6-hour infusion of daunorubicin hydrochloride on days 1, 3, and 5; and a 4-hr infusion of etoposide on days 1-5. After 3 weeks of rest, patients receive IT ARA-C on day 1. They also receive an infusion of ARA-C on days 1-8; a 6-hr infusion of daunorubicin on days 1, 3, and 5; and a 4-hr infusion of etoposide on days 1-5. After 3 weeks of rest, some patients receive IT ARA-C on day 1 and 1-hr infusions of ARA-C and etoposide on days 1-5. After 3 weeks of rest, some patients receive IT ARA-C on day 1; a 2-hr infusion of ARA-C on days 1-4; and a 1-hour infusion of mitoxantrone on days 3-6. After 3 weeks of rest, they receive a 3-hr infusion of ARA-C on days 1, 2, 8, and 9 and an injection of asparaginase on days 2 and 9.	Drug: cytarabine; Given IV; Other Names: Ara-C; Cytosar; Cytosine arabinoside; NSC # 63878; Drug: asparaginase; Given intramuscularly; Other Names: Elspar; Kidrolase; Leunase; Crasnitin; E.coli; E.coli L-asparaginase; EC 3.5.2.2; colaspase; L-asnase; NSC 109229; Drug: daunorubicin hydrochloride; Given IV over 6 hours; Other Names: Cerubidine; NSC #82151; Daunomycin; rubidomycin; Drug: etoposide; Given IV over 1-4 hours; Other Names: VP-16; Etopophos; VePesid; NSC #141540; Drug: mitoxantrone hydrochloride; Given IV over 1 hour; Other Names: Mitozantrone; CL 232315; DHAD; Novantrone; DAD; NSC #301739
Experimental: Arm B: Experimental - with GMTZ, AML Pts w/out Down Syndrome; Pts receive IT ARA-C at diagnosis or on day 1 of treatment or twice a week for up to six doses. They also receive an infusion of ARA-C on days 1-10; a 6-hr infusion of daunorubicin on days 1, 3, & 5; a 4-hr infusion of etoposide on days 1-5; and a 2-hr infusion of GMTZ - gemtuzumab ozogamicin (Mylotarg) on day 6. After 3 wks of rest, patients receive IT ARA-C on day 1. They also receive an infusion of ARA-C on days 1-8; a 6-hr infusion of daunorubicin on days 1, 3, and 5; and a 4-hr infusion of etoposide on days 1-5. After 3 weeks of rest, some patients receive IT ARA-C on day 1 and 1-hr infusions of ARA-C and etoposide on days 1-5. After 3 wks of rest, some patients receive IT ARA-C on day 1; a 2-hr infusion of ARA-C on days 1-4; and a 1-hr infusion of mitoxantrone hydrochloride on days 3-6. They also receive a 2-hr infusion of gemtuzumab on day 7. After 3 weeks of rest, they receive a 3-hr infusion of ARA-C on days 1, 2, 8, and 9 and an injection of asparaginase on days 2 and 9.	Drug: cytarabine; Given IV; Other Names: Ara-C; Cytosar; Cytosine arabinoside; NSC # 63878; Drug: asparaginase; Given intramuscularly; Other Names: Elspar; Kidrolase; Leunase; Crasnitin; E.coli; E.coli L-asparaginase; EC 3.5.2.2; colaspase; L-asnase; NSC 109229; Drug: daunorubicin hydrochloride; Given IV over 6 hours; Other Names: Cerubidine; NSC #82151; Daunomycin; rubidomycin; Drug: etoposide; Given IV over 1-4 hours; Other Names: VP-16; Etopophos; VePesid; NSC #141540; Drug: mitoxantrone hydrochloride; Given IV over 1 hour; Other Names: Mitozantrone; CL 232315; DHAD; Novantrone; DAD; NSC #301739; Drug: gemtuzumab ozogamicin; Given IV over 2 hours; Other Names: Mylotarg; GMTZ
Active Comparator: Arm A: Standard Arm - No GMTZ, AML Patients with Down Syndrome; Patients receive intrathecal (IT) cytarabine (ARA-C) at diagnosis or on day 1 of treatment or twice a week for up to 6 doses. They also receive an infusion of ARA-C on days 1-10; a 6-hour infusion of daunorubicin hydrochloride on days 1, 3, and 5; and a 4-hr infusion of etoposide on days 1-5. After 3 weeks of rest, patients receive IT ARA-C on day 1. They also receive an infusion of ARA-C on days 1-8; a 6-hr infusion of daunorubicin on days 1, 3, and 5; and a 4-hr infusion of etoposide on days 1-5. After 3 weeks of rest, some patients receive IT ARA-C on day 1 and 1-hr infusions of ARA-C and etoposide on days 1-5. After 3 weeks of rest, some patients receive IT ARA-C on day 1; a 2-hr infusion of ARA-C on days 1-4; and a 1-hour infusion of mitoxantrone on days 3-6. After 3 weeks of rest, they receive a 3-hr infusion of ARA-C on days 1, 2, 8, and 9 and an injection of asparaginase on days 2 and 9.	Drug: cytarabine; Given IV; Other Names: Ara-C; Cytosar; Cytosine arabinoside; NSC # 63878; Drug: asparaginase; Given intramuscularly; Other Names: Elspar; Kidrolase; Leunase; Crasnitin; E.coli; E.coli L-asparaginase; EC 3.5.2.2; colaspase; L-asnase; NSC 109229; Drug: daunorubicin hydrochloride; Given IV over 6 hours; Other Names: Cerubidine; NSC #82151; Daunomycin; rubidomycin; Drug: etoposide; Given IV over 1-4 hours; Other Names: VP-16; Etopophos; VePesid; NSC #141540; Drug: mitoxantrone hydrochloride; Given IV over 1 hour; Other Names: Mitozantrone; CL 232315; DHAD; Novantrone; DAD; NSC #301739

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free Survival at 3 Years	The Kaplan-Meier method will be used to calculate estimates of Event Free Survival (EFS). The log-rank test will be used to compare survival between treatment groups. Analysis of EFS of Down syndrome patients will be performed separately. Monitoring for efficacy of GMTZ with respect to Overall Survival (OS) and EFS will utilize monitoring based on the Lan-DeMets criterion with α-spending function αt^2 (truncated at 3 standard deviations) and 2.5% type I error.	Time from study entry to time of induction failure, relapse, or death, assessed at 3 years
Overall Survival at 3 Years	The Kaplan-Meier method will be used to calculate estimates of OS. Analysis of OS of Down syndrome patients will be performed separately. Monitoring for efficacy of GMTZ with respect to OS and EFS will utilize monitoring based on the Lan-DeMets criterion with α-spending function αt^2 (truncated at 3 standard deviations) and 2.5% type I error.	Time from study entry, assessed at 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Remission Induction Rate After 2 Courses of Induction Therapy	Patients without an evaluable bone marrow at the end of Induction I will be excluded from the calculation of remission rate after 2 courses of therapy because their responses are not evaluable. The following patients will be considered to not be in complete remission (CR) after 2 courses of therapy: (1) patients who die during Induction I and II; (2) patients with ≥ 5% blasts or extramedullary disease at the end of Induction II.	After 2 courses of induction (I and II) therapy, assessed for up to 10 years
Disease-free Survival (DFS)	Time from end of Intensification I to relapse, death or last contact	At 3 years from end of Intensification I
Mortality	Number of participants who died during the first three courses of therapy.	During the first three courses of therapy
Time to Marrow Recovery	Mean time to ANC recovery - defined as ANC greater than 500/MicroLiter for 3 consecutive days.	At 25 days after treatment with Induction I, Induction II, and Intensification I
Toxicities, Including Infectious Complications	Number of participants with at least one grade 3 or higher adverse event during therapy.	From the time therapy is initiated, assessed up to 10 years

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Alan S. Gamis, MD, MPH, Children's Mercy Hospital Kansas City; Study Chair: Richard Aplenc, MD, MSCE, Children's Hospital of Philadelphia

Publications and helpful links

General Publications

• Pollard JA, Alonzo TA, Loken M, Gerbing RB, Ho PA, Bernstein ID, Raimondi SC, Hirsch B, Franklin J, Walter RB, Gamis A, Meshinchi S. Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML. Blood. 2012 Apr 19;119(16):3705-11. doi: 10.1182/blood-2011-12-398370. Epub 2012 Feb 29.
• Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children's Oncology Group trial AAML0531. J Clin Oncol. 2014 Sep 20;32(27):3021-32. doi: 10.1200/JCO.2014.55.3628.
• Elgarten CW, Wood AC, Li Y, Alonzo TA, Brodersen LE, Gerbing RB, Getz KD, Huang YV, Loken M, Meshinchi S, Pollard JA, Sung L, Woods WG, Kolb EA, Gamis AS, Aplenc R. Outcomes of intensification of induction chemotherapy for children with high-risk acute myeloid leukemia: A report from the Children's Oncology Group. Pediatr Blood Cancer. 2021 Dec;68(12):e29281. doi: 10.1002/pbc.29281. Epub 2021 Oct 1.
• Brodersen LE, Gerbing RB, Pardo ML, Alonzo TA, Paine D, Fritschle W, Hsu FC, Pollard JA, Aplenc R, Kahwash SB, Hirsch B, Ramondi S, Wells D, Kolb EA, Gamis AS, Meshinchi S, Loken MR. Morphologic remission status is limited compared to DeltaN flow cytometry: a Children's Oncology Group AAML0531 report. Blood Adv. 2020 Oct 27;4(20):5050-5061. doi: 10.1182/bloodadvances.2020002070.
• Voigt AP, Brodersen LE, Alonzo TA, Gerbing RB, Menssen AJ, Wilson ER, Kahwash S, Raimondi SC, Hirsch BA, Gamis AS, Meshinchi S, Wells DA, Loken MR. Phenotype in combination with genotype improves outcome prediction in acute myeloid leukemia: a report from Children's Oncology Group protocol AAML0531. Haematologica. 2017 Dec;102(12):2058-2068. doi: 10.3324/haematol.2017.169029. Epub 2017 Sep 7.
• Eidenschink Brodersen L, Alonzo TA, Menssen AJ, Gerbing RB, Pardo L, Voigt AP, Kahwash SB, Hirsch B, Raimondi S, Gamis AS, Meshinchi S, Loken MR. A recurrent immunophenotype at diagnosis independently identifies high-risk pediatric acute myeloid leukemia: a report from Children's Oncology Group. Leukemia. 2016 Oct;30(10):2077-2080. doi: 10.1038/leu.2016.119. Epub 2016 May 2. No abstract available.
• Sung L, Aplenc R, Alonzo TA, Gerbing RB, Lehrnbecher T, Gamis AS. Effectiveness of supportive care measures to reduce infections in pediatric AML: a report from the Children's Oncology Group. Blood. 2013 May 2;121(18):3573-7. doi: 10.1182/blood-2013-01-476614. Epub 2013 Mar 7.

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: August 1, 2006
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): September 30, 2020

Study Registration Dates

• First Submitted: September 6, 2006
• First Submitted That Met QC Criteria: September 6, 2006
• First Posted (Estimate): September 7, 2006

Study Record Updates

• Last Update Posted (Actual): March 24, 2021
• Last Update Submitted That Met QC Criteria: March 22, 2021
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); untreated adult acute myeloid leukemia; adult acute megakaryoblastic leukemia (M7); adult acute minimally differentiated myeloid leukemia (M0); adult acute monoblastic leukemia (M5a); adult acute monocytic leukemia (M5b); adult acute myeloblastic leukemia with maturation (M2); adult acute myeloblastic leukemia without maturation (M1); adult acute myelomonocytic leukemia (M4); adult acute basophilic leukemia; adult acute eosinophilic leukemia; adult erythroleukemia (M6a); adult pure erythroid leukemia (M6b); childhood acute erythroleukemia (M6); childhood acute megakaryocytic leukemia (M7); childhood acute minimally differentiated myeloid leukemia (M0); childhood acute basophilic leukemia; childhood acute eosinophilic leukemia; untreated childhood acute myeloid leukemia and other myeloid malignancies; childhood acute myeloblastic leukemia without maturation (M1); childhood acute myeloblastic leukemia with maturation (M2); childhood acute myelomonocytic leukemia (M4); childhood acute monoblastic leukemia (M5a); childhood acute monocytic leukemia (M5b)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Etoposide; Cytarabine; Daunorubicin; Asparaginase; Mitoxantrone; Gemtuzumab
• Other Study ID Numbers: AAML0531; COG-AAML0531 (Other Identifier: Children's Oncology Group); CDR0000487497 (Other Identifier: Clinical Trials.gov); NCI-2009-00320 (Registry Identifier: Clinical Trials Reporting Program)