RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Colony-stimulating factors such as filgrastim may increase the number of immune cells found in bone marrow or peripheral blood and may help a person's immune system recover from the side effects of chemotherapy. It is not yet known whether combination chemotherapy with filgrastim and/or tretinoin is more effective than combination chemotherapy alone for acute myeloid leukemia.

PURPOSE: This randomized phase III trial is studying combination chemotherapy with filgrastim and/or tretinoin to see how well they work compared to combination chemotherapy alone in treating patients with acute myeloid leukemia.

Condition	Treatment or Intervention	Phase
Acute Myeloid Leukemia adult acute monoblastic and acute monocytic leukemia atypical chronic myeloid leukemia childhood acute monocytic leukemia myelodysplastic and myeloproliferative disease	Drug: cytarabine  Drug: daunorubicin  Drug: etoposide  Drug: filgrastim  Drug: fludarabine  Drug: tretinoin  Procedure: biological response modifier therapy  Procedure: chemotherapy  Procedure: colony-stimulating factor therapy  Procedure: cytokine therapy	Phase III

Further Study Details: 

OBJECTIVES:

• Compare standard induction chemotherapy with cytarabine, daunorubicin, and etoposide vs fludarabine and cytarabine in terms of achievement of remission, reasons for remission failure, duration of remission, survival, toxicity, and supportive care needs in patients with high risk acute myeloid leukemia.
• Determine if the use of filgrastim (G-CSF) or tretinoin administered during and following chemotherapy improves outcome in this patient population.
• Determine the impact of these treatment regimens on quality of life in these patients.

OUTLINE: This is a randomized, controlled, multicenter study. Patients are stratified according to type of disease (resistant vs refractory vs relapsed vs adverse cytogenetic), age (under 15 vs 15 to 29, vs 30 to 49 vs 50-59 vs 60-69 vs 70 and over), performance status, and de novo and secondary leukemia. Patients with relapsed disease are further stratified according to duration of first remission (less than 6 months vs 6 to 12 months vs 12 months and over), and prior transplantation (yes vs no).

Patients are randomized into one of two treatment arms for induction chemotherapy.

• Arm I: Patients receive induction chemotherapy consisting of cytarabine IV every 12 hours on days 1-10, daunorubicin IV on days 1, 3, and 5 and etoposide IV over 1 hour on days 1-5. Patients receive a second course of therapy with cytarabine IV every 12 hours on days 1-8 and daunorubicin and etoposide as in course 1.
• Arm II: Patients receive 2 courses of induction chemotherapy consisting of fludarabine IV over 30 minutes followed by cytarabine IV over 4 hours on days 1-5. Patients are further randomized into one of two treatment arms for colony stimulating factor therapy.
• Arm I: Patients receive filgrastim (G-CSF) subcutaneously or IV daily beginning on day 1 of each course of induction chemotherapy and continuing until blood counts recover, for up to a maximum of 28 days.
• Arm II: Patients receive no G-CSF during and following induction chemotherapy. Patients are further randomized into one of two treatment arms for retinoid therapy.
• Arm I: Patients receive oral tretinoin daily beginning on day 1 of induction chemotherapy and continuing for up to a maximum of 90 days.
• Arm II: Patients receive no retinoid therapy during and following induction chemotherapy. Following completion of induction chemotherapy, patients achieving complete remission and blood count recovery may receive subsequent therapy consisting of consolidation chemotherapy and/or autologous or allogeneic transplantation.

Quality of life is assessed at 3 months.

PROJECTED ACCRUAL: Approximately 800-1,000 patients will be accrued for this study within 4-5 years.

Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of acute myeloid leukemia (AML) including de novo or secondary AML, or a preexisting myelodysplastic syndrome
• Overt resistant disease with more than 15% bone marrow blasts after induction course
• Primary refractory disease
• Failure to achieve first complete remission after at least 2 induction courses
• Relapse from first remission with more than 5% bone marrow blasts
• Complete or partial remission following 1 induction course with adverse cytogenetic abnormalities at diagnosis
• No acute promyelocytic leukemia
• No chronic myeloid leukemia in blast transformation
• No prior relapse from a second or greater remission

PATIENT CHARACTERISTICS: Age:

• Any age

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Not specified

Renal:

• Creatinine clearance at least 30 mL/min

Other:

• No other active malignancy
• Not pregnant or nursing
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY: Biologic therapy

• Not specified

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

United Kingdom, England
      Birmingham Heartlands and Solihull NHS Trust -Teaching, Birmingham,  England,  B9 5SS,  United Kingdom; Recruiting

Study chairs or principal investigators

D.W. Milligan, MD,  Study Chair,  Birmingham Heartlands and Solihull NHS Trust -Teaching   

Study ID Numbers:  CDR0000067895; MRC-LEUK-AML-HR; EU-20008; NCT00005863
Record last reviewed:  June 2000
Last Updated:  February 7, 2005
Record first received:  June 2, 2000
ClinicalTrials.gov Identifier:  NCT00005863
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08