Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy, Interleukin-2, and Peripheral Stem Cell Transplant in Treating Patients With Acute Myeloid Leukemia

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Active	15 to 60	Other	EORTC-06991 NCT00004128, GIMEMA-EORTC-06991

Objectives

1. Compare the overall survival rate in patients with acute myeloid leukemia treated with high-dose versus standard-dose cytarabine during induction.
2. Compare the disease-free survival rate in patients treated with or without interleukin-2 following consolidation and autologous peripheral blood stem cell or bone marrow transplantation.
3. Compare the feasibility of these regimens in these patients.

Entry Criteria

Disease Characteristics:

• First randomization:
  • Untreated newly diagnosed acute myeloid leukemia (AML)
  • At least 30% blasts in bone marrow
  • All cytological types of AML except acute promyelocytic leukemia (M3)
  • No blast crisis of chronic myelogenous leukemia
  • No leukemias supervening after other myeloproliferative disease
  • No leukemias supervening after overt myelodysplastic disorders (e.g., refractory anemia with excess blasts) for more than 6 months duration

• Second randomization:
  • Must have achieved complete remission with full hematologic recovery following consolidation treatment
  • No HLA identical family donor
  • Not eligible for allograft
  • No high risk patient (under age 40) for whom an unrelated bone marrow donor has been found within 8 weeks of beginning consolidation treatment

Prior/Concurrent Therapy:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior chemotherapy for AML except hydroxyurea
• Less than 7 days of prior hydroxyurea

Endocrine therapy:

• No more than 7 days of prior corticosteroid therapy for AML

Radiotherapy:

• No prior radiotherapy for AML

Surgery:

• Not specified

Patient Characteristics:

Age:

• 15 to 60

Performance status:

• WHO 0-3 (first randomization)
• WHO 0-2 (second randomization)

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Bilirubin no greater than 3 times upper limit of normal (ULN)

Renal:

• Creatinine no greater than 3 times ULN

Cardiovascular:

• No severe heart failure requiring diuretics
• Ejection fraction at least 50%

Other:

• First randomization:
  • No other progressive malignant disease except the following:
    • Secondary acute leukemias following curatively treated Hodgkin's disease (even if treated with anthracyclines)
    • Other curatively treated malignancies
    • Secondary leukemias following other exposure to alkylating agents or radiotherapy for other reason
  • No uncontrolled infection
  • No severe concurrent neurologic or psychiatric disease
  • No psychological, familial, sociological, or geographical condition that could preclude compliance

• Second randomization:
  • No nonmalignant systemic illness that would increase risk of participation in study
  • No uncontrolled infection
  • No other progressive malignant disease

Expected Enrollment

A total of 2,000 patients (1,000 per treatment arm) will be accrued for the first randomization and a total of 577 patients (288 per treatment arm) will be accrued for the second randomization of this study.

Outcomes

Duration of overall survival and disease-free survival after first randomization
Duration of overall survival and disease-free survival after second randomization

Response after induction and consolidation
Toxicity measured by Cancer and Leukemia Group B (CALGB) CTCAE v3.0 after induction and consolidation
Disease-free survival after complete remission (CR)
Disease-free interval from CR
Time to death in CR
Peripheral stem cell harvest after consolidation
Rate of completion of autologous peripheral blood stem cell transplantation (auto-PBSCT) and allogeneic stem cell transplantation (allo-SCT)

Outline

This is a randomized, multicenter study. Patients in the first randomization are stratified according to center, WBC (no greater than 25,000/mm³ vs 25,000-99,000/mm³ vs at least 100,000/mm³), age (15 to 45 vs 46 to 60), and performance status (0-1 vs 2 vs 3). Patients in the second randomization are stratified according to center, first treatment arm (I vs II), number of induction courses to reach complete remission (CR), cytogenic/molecular genetic group at diagnosis (low vs high vs intermediate vs unknown), and autologous peripheral blood stem cell (PBSC) transplantation planned after consolidation (yes vs no).

First randomization

• Induction: Patients are randomized to 1 of 2 treatment arms:
  • Arm I: Patients receive standard-dose cytarabine IV over 24 hours on days 1-10, etoposide IV over 1 hour on days 1-5, and daunorubicin IV over 5 minutes on days 1, 3, and 5.
  
  
  
  • Arm II: Patients receive etoposide and daunorubicin as in arm I and high-dose cytarabine IV over 3 hours every 12 hours on days 1, 3, 5, and 7.
  
  
  



• Consolidation: When CR is reached, patients receive intermediate-dose cytarabine IV over 2 hours every 12 hours on days 1-6 and daunorubicin IV over 5 minutes prior to cytarabine on days 4, 5, and 6.



• Harvest: Patients who achieve CR and are ineligible for allogeneic PBSC transplantation receive filgrastim (G-CSF) subcutaneously (SQ) every 12 hours beginning 20 days after starting consolidation treatment and continuing until autologous PBSC are harvested. Autologous bone marrow is collected from patients with insufficient PBSC. Allogeneic PBSC are harvested for patients who have an HLA identical donor. Allogeneic bone marrow is harvested for high risk patients (under age 40) who have an unrelated bone marrow donor.



• Transplant preparative chemotherapy: It is recommended that patients receive cyclophosphamide on 2 consecutive days and total body irradiation on 3 days OR busulfan on days -8, -7, -6, and -5 followed by cyclophosphamide on days -4 and -3.



• Transplantation: PBSC or bone marrow is infused on day 0.

Second randomization

• Patients who achieve CR with full hematologic recovery but have no HLA identical donor are randomized to 1 of 2 treatment arms no earlier than day 22 after stem cell infusion.
  • Arm I: Patients receive interleukin-2 SQ once daily for 5 days. Treatment repeats every 4 weeks for 1 year in the absence of disease progression or unacceptable toxicity.
  
  
  
  • Arm II: Patients receive no further treatment.
  
  
  

Patients are followed at 1, 4, and 13 months, then every 4 months for 3 years, and then every 6 months thereafter.

Trial Contact Information

Trial Lead Organizations

European Organization for Research and Treatment of Cancer

Roel Willemze, MD, PhD, Study coordinator		Ph: 31-71-526-2267 Email: R.Willemze@lumc.nl

Gruppo Italiano Malattie Ematologiche dell’Adulto

Giovanna Meloni, MD, Protocol chair		Ph: 39-0685-7951

Registry Information
Official Title		The Value of High Dose Versus Standard Dose ARA-C During Induction and of IL-2 After Intensive Consolidation/Autologous Stem Cell Transplantation in Patients (Age 15-60 years) With Acute Myelogenous Leukemia. A Randomized Phase II Trial of the EORTC and the GIMEMA-ALWP
Trial Start Date		1999-09-03
Trial Completion Date		2008-01-11 (estimated)
Registered in ClinicalTrials.gov		NCT00004128
Date Submitted to PDQ		1999-09-21
Information Last Verified		2008-04-13

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