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

Alternate Title

Combination Chemotherapy Regimens Followed by CNS Radiation Therapy, Thioguanine, and Cytarabine in Treating Young Patients With Standard-Risk or High-Risk Acute Myeloid Leukemia

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III, Phase II Treatment Active 18 and under Other UCHM-AML-BFM-2004 UCHM-BfArM 4022064, NCT00111345, UCHM-DKH 50-2728, EU-20723, AML-BFM 2004

Objectives

Primary

1. Compare the improvement of prognosis in pediatric patients with acute myeloid leukemia treated with intensified cytostatic induction therapy comprising cytarabine, etoposide phosphate, and liposomal daunorubicin citrate vs standard induction therapy comprising cytarabine, etoposide phosphate, and idarubicin.
2. Compare the improvement of prognosis in high-risk patients treated with consolidation therapy comprising cytarabine and idarubicin with vs without cladribine.
3. Determine the efficacy of 2 different doses of prophylactic CNS irradiation in these patients.
4. Compare the incidence of cardiotoxicity in patients treated with these regimens.

Secondary

1. Compare the incidence of infection-caused deaths in patients treated with these regimens.
2. Determine the prognostic relevance of minimal residual disease, in terms of recognizing recurrence risk early, in patients treated with these regimens.

Entry Criteria

Disease Characteristics:

• Diagnosis of de novo acute myeloid leukemia (AML), including isolated myelosarcoma or acute mixed lineage leukemia/biphenotypic leukemia (predominantly myeloid)



• Patients with Down syndrome are eligible



• No secondary AML



• No preexisting syndromes (e.g., Fanconi's anemia)



• Diagnosis falls into 1 of the following risk groups:
  • Standard risk
    • AML FAB M3 [t(15;17)]
    • AML with Down syndrome
    • AML FAB M1 or M2 with auer rods*
    • AML FAB M4 eosinophil*
    • AML with t(8;21)*
    • AML with inv(16)*
  • High risk
    • AML FAB M0
    • AML FAB M1 or M2 without auer rods
    • AML FAB M4 with > 5% blasts on day 15 (after 1 induction therapy)
    • AML FAB M5
    • AML FAB M6
    • AML FAB M7

     [Note: * Reassigned to high-risk group if FLT-3 ITD mutation is demonstrated]

Prior/Concurrent Therapy:

• More than 14 days since prior intensive induction therapy

Patient Characteristics:

• No other concurrent disease that would preclude study treatment
• Not pregnant
• Negative pregnancy test

Expected Enrollment

A total of 550 patients will be accrued for this study.

Outcomes

Event-free and overall survival
Disease-free survival

Cardiotoxicity

Outline

This is a controlled, open-label, parallel-group, randomized, multicenter study. Patients are stratified according to risk (standard vs high) and disease. Patients may be randomized at 3 different time points during the study.

Patients with large leukemia cell mass (primary WBC > 50,000/mm³) or substantial organ enlargement receive oral thioguanine and cytarabine IV or subcutaneously (SC) for 3-7 days as preliminary cytoreduction before beginning induction therapy.

Patients with acute myeloid leukemia (AML) FAB M3 receive oral tretinoin on days 3-11 for the first course and then on days 1-14 (except during intrathecal [IT] treatment) for all other courses. Treatment repeats every 3 weeks for at least 3 courses (during induction, consolidation, and intensification therapies).

• Induction therapy 1: Patients are randomized to 1 of 2 induction therapy arms.
  • Arm I (ADxE): Patients receive cytarabine IV over 48 hours on days 1 and 2 and then IV over 2 hours twice daily on days 3-8; liposomal daunorubicin citrate IV over 2 hours on days 3, 5, and 7; etoposide phosphate IV over 1 hour on days 6-8; and cytarabine IT on days 1 and 8.
  
  
  
  • Arm II (AIE): Patients receive cytarabine IV and IT and etoposide phosphate as in arm I. Patients also receive idarubicin IV over 4 hours on days 3, 5, and 7.
  
  
  

  Beginning 4 weeks after completion of induction therapy 1, patients with standard-risk disease proceed to consolidation therapy block 1. Patients with high-risk disease proceed to induction therapy 2.




• Induction therapy 2 (HAM): Patients receive induction therapy 2 comprising high-dose cytarabine IV over 3 hours twice daily on days 1-3; mitoxantrone IV over 30 minutes on day 3; and cytarabine IT on day 1.

  Beginning 4 weeks after completion of induction therapy 2, patients proceed to consolidation therapy block 1.




• Consolidation therapy block 1: Standard-risk patients (including those with AML M3) are assigned to arm II; high-risk patients are randomized to arm I or II.
  • Arm I (AI/2-CDA): Patients receive cytarabine IV over 96 hours on days 1-4; cladribine IV over 30 minutes on days 1 and 3; idarubicin IV over 1 hour on days 3 and 5; and cytarabine IT on days 1 and 6.
  
  
  
  • Arm II (AI): Patients receive cytarabine IV over 96 hours on days 1-4; idarubicin IV over 1 hour on days 3 and 5; and cytarabine IT on days 1 and 6.
  
  
  

  Beginning 4 weeks after completion of consolidation therapy block 1, patients in both arms proceed to consolidation therapy block 2.




• Consolidation therapy block 2 (HAM): Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-3; mitoxantrone IV over 30 minutes on days 3 and 4; and cytarabine IT on days 1 and 6.

  Beginning 2-4 weeks after completion of consolidation therapy block 2, patients who do not have a planned allogeneic stem cell transplant (SCT) proceed to intensification therapy. High-risk patients with available sibling donor proceed to matched sibling donor SCT. Other high-risk patients who exhibit a nonresponse or an enduring aplasia without signs of hematologic regeneration (at least 4 weeks after consolidation therapy block 2) proceed to matched family donor SCT or matched unrelated donor SCT.




• Allogeneic SCT: Patients receive conditioning therapy comprising oral busulfan every 6 hours on days -7 to -4 and cyclophosphamide IV on days -3 and -2. Patients undergo allogeneic SCT on day 0.



• Intensification therapy (HAE): Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-3; etoposide phosphate IV over 1 hour on days 2-5; and cytarabine IT on day 1.

  Beginning at least 4 weeks after completion of intensification therapy, patients proceed to CNS treatment/prophylaxis.




• CNS treatment/prophylaxis: Patients with primary CNS involvement receive cytarabine IT weekly for at least 3 weeks until cerebral spinal fluid stabilization and then undergo CNS irradiation* for 2-3 weeks. Patients without CNS involvement are randomized to receive 1 of 2 dose levels of prophylactic CNS irradiation**.
  • Arm I: Patients receive prophylactic CNS irradiation.
  
  
  
  • Arm II: Patients receive prophylactic CNS irradiation at a higher dose.
  
  
  

   [Note: *Patients with Down syndrome or who are less than 1 ¼ years of age do not receive CNS irradiation.]

   [Note: **Patients who have undergone planned allogeneic SCT do not receive prophylactic CNS irradiation.]

  All patients then proceed to maintenance therapy.




• Maintenance therapy: Beginning 4 weeks after completion of intensification therapy and CNS irradiation, patients receive oral thioguanine daily on days 1-28; cytarabine SC on days 1-4; and cytarabine IT* weekly. Treatment repeats every 4 weeks for up to 1 year. Patients with AML M3 also receive oral tretinoin on days 1-14 of the first course and then every 3 months for 14 days for 3 courses.

   [Note: *Patients with Down syndrome do not receive cytarabine IT.]

After completion of study therapy, patients are followed periodically.

Meyer LH, Queudeville M, Eckhoff SM, et al.: Intact apoptosis signaling in myeloid leukemia cells determines treatment outcome in childhood AML. Blood 111 (5): 2899-903, 2008.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Medizinische Klinik und Poliklinik A - Universitaetsklinikum Muenster

Ursula Creutzig, MD, Protocol chair		Ph: 49-511-532-9123 Email: AML-BFM@MH-Hannover.de

Germany
	Hannover
	Medizinische Hochschule Hannover
		Dirk Reinhardt, MD	Ph:  49-511-532-9123
			Email: AML-BFM@MH-Hannover.de
	Muenster
	Medizinische Klinik und Poliklinik A - Universitaetsklinikum Muenster
		Ursula Creutzig, MD	Ph:  49-511-532-9123
			Email: AML-BFM@MH-Hannover.de

Registry Information
Official Title		Multicenter Therapy-Optimization Trial AML-BFM 2004 for the Treatment of Acute Myeloid Leukemias in Children and Adolescents
Trial Start Date		2004-03-01
Trial Completion Date		2014-02-28 (estimated)
Registered in ClinicalTrials.gov		NCT00111345
Date Submitted to PDQ		2007-04-25
Information Last Verified		2008-04-28