• Overall survival [ Designated as safety issue: No ]
• Complete remission rates [ Designated as safety issue: No ]
• Impact of allogeneic stem cell transplantation [ Designated as safety issue: No ]
• Effect of gemtuzumab ozogamicin on in vivo purging using pathologic and molecular correlates [ Designated as safety issue: No ]
• Safety [ Designated as safety issue: Yes ]

• Overall survival
• Complete remission rates
• Impact of allogeneic stem cell transplantation
• Effect of gemtuzumab ozogamicin on in vivo purging using pathologic and molecular correlates
• Safety

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.

OBJECTIVES:

• Compare disease-free and overall survival of patients with acute myeloid leukemia treated with daunorubicin and cytarabine with or without gemtuzumab ozogamicin followed by autologous hematopoietic stem cell transplantation (autologous transplantation arm II closed to accrual as of 10/4/2007).
• Compare response rates in patients treated with these regimens.
• Determine the impact of allogeneic transplantation on patients who have unfavorable prognostic factors.
• Determine the effect of gemtuzumab ozogamicin on in vivo purging using both pathologic and molecular correlates before autologous transplantation in these patients.
• Determine the safety of these regimens in these patients.

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.

  • Arm I: Patients receive standard-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7.
  • Arm II: 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.

PROJECTED ACCRUAL: A total of 830 patients will be accrued for this study within 5 years.

• Biological: filgrastim
  Given IV or as an injection
• Biological: sargramostim
  Given IV or as an injection
• Drug: busulfan
  Given IV
• Drug: cyclophosphamide
  Given IV
• Drug: cytarabine
  Given as a continuous infusion
• Drug: daunorubicin hydrochloride
  Given IV
• Drug: gemtuzumab ozogamicin
  Given IV

• Arm I (induction therapy): Active Comparator

  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.

  Interventions:

  • Drug: cytarabine
  • Drug: daunorubicin hydrochloride
• Arm II (induction therapy): Experimental
  Patients receive high-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine as in arm I. Patients may receive a second course of induction therapy if CR is not achieved after the first course. The second course is administered as in arm I.
  Interventions:

  • Drug: cytarabine
  • Drug: daunorubicin hydrochloride
• Arm I (conditioning/transplant): Active Comparator
  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 peripheral blood stem cell (PBSC) transplantation on day 0. Patients receive sargramostim (GM-CSF) or filgrastim (G-CSF) IV or subcutaneously (SC) beginning on day 0 and continuing until blood counts recover.
  Interventions:

  • Biological: filgrastim
  • Biological: sargramostim
  • Drug: busulfan
  • Drug: cyclophosphamide
• Arm II (conditioning/transplant): Experimental
  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.
  Interventions:

  • Biological: filgrastim
  • Biological: sargramostim
  • Drug: busulfan
  • Drug: cyclophosphamide
  • Drug: gemtuzumab ozogamicin

• 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.
• 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. 2006 Sep 20; [Epub ahead of print]

DISEASE CHARACTERISTICS:

• 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

• The following types of AML are excluded:

  • 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
• No blastic transformation of chronic myelogenous leukemia
• No secondary AML (chemotherapy-induced or evolved from MDS)
• CNS disease allowed
• Patients undergoing allogeneic transplantation must have a sibling donor match defined as HLA match or haplotype match with one locus mismatch on other haplotype

PATIENT CHARACTERISTICS:

Age

• 16 to 60

Performance status

• ECOG 0-4

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics

Hepatic

• Bilirubin no greater than 2.0 mg/dL (unless related to Gilbert's syndrome or hemolysis)
• AST less than 4 times upper limit of normal (ULN)
• Alkaline phosphatase less than 4 times ULN

Renal

• Creatinine no greater than 2.0 mg/dL
• Creatinine clearance at least 50 mL/min

Cardiovascular

• LVEF at least 45% by post-induction MUGA
• No significant cardiac disease requiring active therapy (e.g., digoxin, diuretics, antiarrhythmics, or antianginal medications)

Other

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

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior biologic therapy

Chemotherapy

• No prior cytotoxic chemotherapy for any malignancy
• Prior hydroxyurea allowed

Endocrine therapy

• Prior corticosteroids allowed

Radiotherapy

• No prior radiotherapy for any malignancy

Surgery

• Not specified