Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy With or Without Filgrastim and/or Tretinoin in Treating Patients With Acute Myeloid Leukemia

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	Any age	Other	MRC-LEUK-AML-HR EU-20008, NCT00005863

Objectives

1. 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.
2. Determine if the use of filgrastim (G-CSF) or tretinoin administered during and following chemotherapy improves outcome in this patient population.
3. Determine the impact of these treatment regimens on quality of life in these patients.

Entry 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

Prior/Concurrent Therapy:

Biologic therapy

• Not specified

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

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

Expected Enrollment

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

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.

Milligan DW, Wheatley K, Littlewood T, et al.: Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial. Blood 107 (12): 4614-22, 2006.[PUBMED Abstract]

Burnett AK, Milligan D, Hills RK, et al.: Does all-transretinoic acid (ATRA) have a role in non-APL acute myeloid leukaemia? Results from 1666 patients in three MRC trials. [Abstract] Blood 104 (11): A-1794, 2004.

Trial Contact Information

Trial Lead Organizations

Medical Research Council's Working Party on Leukemia in Adults and Children

D. W. Milligan, MD, Protocol chair		Ph: 44-121-424-3699 Email: d.w.milligan@bham.ac.uk

Registry Information
Official Title		Protocol for Patients with High Risk (Resistant, Refractory, Relapsed or Adverse Cytogenetic) AML
Trial Start Date		1998-08-01
Registered in ClinicalTrials.gov		NCT00005863
Date Submitted to PDQ		2000-04-21
Information Last Verified		2006-01-23

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