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

Alternate Title

Combination Chemotherapy in Treating Children With Acute Myeloid Leukemia

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Closed under 17 GER-GPOH-AML-BFM-93 EU-93008

Objectives

I.  Compare the efficacy of 2 post-remission strategies for preventing relapse 
in children with high-risk acute myeloid leukemia (AML) following remission 
induction with cytarabine/daunorubicin/etoposide (ADE) or 
cytarabine/idarubicin/etoposide (AIE):  a second induction with HAM (high-dose 
cytarabine/mitoxantrone) followed by a 6-week multi-agent consolidation 
regimen followed by intensification with high-dose cytarabine/etoposide vs. 
the same consolidation regimen followed by HAM as a first intensification 
followed by high-dose cytarabine/etoposide as a second intensification.

II.  Compare daunorubicin and idarubicin for the speed of 
blast reduction during remission induction in children with standard-risk and 
poor-risk AML randomized for remission induction to ADE vs. AIE.

III.  Determine whether the treatment strategies that include HAM are more 
advantageous in patients with high-risk disease than the treatment specified 
in AML-BFM-87.

IV.  Evaluate, in standard-risk AML children, whether reduction of the 
intensification phase to 1 from 2 blocks of therapy affects the event-free 
interval.

V.  Compare treatment results in high-risk patients who receive allogeneic 
bone marrow transplants (BMT) from HLA-identical donors with results in a 
non-BMT reference group using matched-pair analysis.

VI.  Investigate the prognostic value of such disease-specific parameters as 
FAB type, immunophenotype, and cytogenetic and molecular genetic 
characteristics.

Entry Criteria

Disease Characteristics:

Newly diagnosed childhood acute myeloid leukemia
  Diagnosis based on morphologic and immunologic criteria

No myelodysplastic syndrome

No secondary leukemia

No Down syndrome

Prior/Concurrent Therapy:

No more than 2 weeks of cytostatic agents

Patient Characteristics:

Age:
  Under 17

Performance status:
  Not specified

Hematopoietic:
  Not specified

Hepatic:
  Not specified

Renal:
  Not specified

Expected Enrollment

About 440 patients will be entered over 4 years.

Outline

Randomized study.  All patients are randomized for Induction on Arms I and II. 
 Standard-risk patients are nonrandomly assigned to Regimen A for 
post-Induction therapy, while high-risk patients are randomized on Arms III 
and IV for post-Induction therapy.  Standard-risk patients are defined as FAB 
M1/M2 with Auer rods, M3, or M4 with eosinophils who have no more than 5% 
blasts in the bone marrow on day 15 (excluding FAB M3); all other patients are 
designated high risk.

Patients with testicular involvement receive additional treatment on Regimen 
C, and those with primary CNS disease receive additional treatment on Regimen 
D.  High-risk patients who achieve CR and who have available identically 
HLA-matched sibling donors are eligible for ABMT on Regimen E following 
Consolidation Phase I.

The following acronyms are used:
     ABM         Allogeneic Bone Marrow
     ABMT        ABM Transplantation
     ARA-C       Cytarabine, NSC-63878
     BU          Busulfan, NSC-750
     CTX         Cyclophosphamide, NSC-26271
     DHAD        Mitoxantrone, NSC-301739
     DOX         Doxorubicin, NSC-123127
     DNR         Daunorubicin, NSC-82151
     HD ARA-C    High-Dose Cytarabine
     IDA         Idarubicin, NSC-256439
     IT ARA-C    Intrathecal Cytarabine
     PRED        Prednisone, NSC-10023
     TG          Thioguanine, NSC-752
     VCR         Vincristine, NSC-67574
     VP-16       Etoposide, NSC-141540

INDUCTION (All Patients).

Arm I:  3-Drug Combination Systemic Chemotherapy plus Single-Agent Intrathecal 
Chemotherapy.  ADE:  ARA-C/DNR/VP-16; plus IT ARA-C.

Arm II:  3-Drug Combination Systemic Chemotherapy plus Single-Agent 
Intrathecal Chemotherapy.  AIE:  ARA-C/IDA/VP-16; plus IT ARA-C.

POST-INDUCTION REGIMENS.

REGIMEN A (Standard-Risk Patients).

Consolidation Phase I:  5-Drug Combination Systemic Chemotherapy plus 
Single-Agent Intrathecal Chemotherapy.    PRED/TG/VCR/DOX/ARA-C; plus IT ARA-C.

Consolidation Phase II:  3-Drug Combination Systemic Chemotherapy plus 
Single-Agent Intrathecal Chemotherapy.  TG/ARA-C/CTX; plus IT ARA-C.

Intensification:  2-Drug Combination Systemic Chemotherapy. HD ARA-C/VP-16.

CNS Prophylaxis:  Single-Agent Intrathecal Chemotherapy plus Radiotherapy.  IT 
ARA-C; plus whole-brain irradiation using megavoltage equipment.

Maintenance:  2-Drug Combination Systemic Chemotherapy.  TG/ARA-C.

REGIMEN B (High-Risk Patients).

ARM III (HAM as Second Induction).

Induction II:  2-Drug Combination Systemic Chemotherapy.  HAM:  HD ARA-C/DHAD.

Consolidation Phase I:  5-Drug Combination Systemic Chemotherapy plus 
Single-Agent Intrathecal Chemotherapy.   PRED/TG/VCR/DOX/ARA-C; plus IT ARA-C.

Consolidation Phase II:  3-Drug Combination Systemic Chemotherapy plus 
Single-Agent Intrathecal Chemotherapy.  TG/ARA-C/CTX; plus IT ARA-C.

Intensification:  2-Drug Combination Systemic Chemotherapy.  HD ARA-C/VP-16.

CNS Prophylaxis:  Single-Agent Intrathecal Chemotherapy plus Radiotherapy.  As 
in Regimen A.

Maintenance:  2-Drug Combination Chemotherapy.  TG/ARA-C.

ARM IV (HAM as Post-Consolidation Intensification).

Consolidation Phase I:  5-Drug Combination Systemic Chemotherapy plus 
Single-Agent Intrathecal Chemotherapy.  PRED/TG/VCR/DOX/ARA-C; plus IT ARA-C.

Consolidation Phase II:  3-Drug Combination Systemic Chemotherapy plus 
Single-Agent Intrathecal Chemotherapy.  TG/ARA-C/CTX; plus IT ARA-C.

Intensification I:  2-Drug Combination Chemotherapy.  HAM:  HD ARA-C/DHAD.

Intensification II:  2-Drug Combination Systemic Chemotherapy. HD ARA-C/VP-16.

CNS Prophylaxis:  Single-Agent Intrathecal Chemotherapy plus Radiotherapy.  As 
in Regimen A.

Maintenance:  2-Drug Combination Chemotherapy.  TG/ARA-C.

REGIMEN C (Testicular Leukemia):  Radiotherapy.  Bilateral testicular 
irradiation using megavoltage equipment.

REGIMEN D (CNS Leukemia at Presentation):  Single-Agent Intrathecal 
Chemotherapy plus Radiotherapy.  IT ARA-C; plus whole-brain irradiation using 
megavoltage equipment.

REGIMEN E:  2-Drug Combination High-Dose Marrow-Ablative Chemotherapy followed 
by ABMT.  BU/CTX; followed by ABM.

Lehrnbecher T, Kaiser J, Varwig D, et al.: Antifungal usage in children undergoing intensive treatment for acute myeloid leukemia: analysis of the multicenter clinical trial AML-BFM 93. Eur J Clin Microbiol Infect Dis 26 (10): 735-8, 2007.[PUBMED Abstract]

Lehrnbecher T, Varwig D, Kaiser J, et al.: Infectious complications in pediatric acute myeloid leukemia: analysis of the prospective multi-institutional clinical trial AML-BFM 93. Leukemia 18 (1): 72-7, 2004.[PUBMED Abstract]

Mann G, Reinhardt D, Ritter J, et al.: Treatment with all-trans retinoic acid in acute promyelocytic leukemia reduces early deaths in children. Ann Hematol 80 (7): 417-22, 2001.[PUBMED Abstract]

Reinhardt D, Pekrun A, Lakomek M, et al.: Primary myelosarcomas are associated with a high rate of relapse: report on 34 children from the acute myeloid leukaemia-Berlin-Frankfurt-Münster studies. Br J Haematol 110 (4): 863-6, 2000.[PUBMED Abstract]

Creutzig U, Hermann J, Gadner H, et al.: Comparison of equipotential doses of daunorubicin and idarubicin during induction: first results of the randomized trial BFM 93 in children with AML. [Abstract] Blood 90 (10 suppl 1): A-2597, 584a, 1997.

Creutzig U, Büchner T, Sauerland MC, et al.: Significance of age in acute myeloid leukemia patients younger than 30 years: a common analysis of the pediatric trials AML-BFM 93/98 and the adult trials AMLCG 92/99 and AMLSG HD93/98A. Cancer 112 (3): 562-71, 2008.[PUBMED Abstract]

Creutzig U, Reinhardt D, Zimmermann M, et al.: Prognostic relevance of risk groups in the pediatric AML-BFM trials 93 and 98. Ann Hematol 83 (Suppl 1): S112-6, 2004.[PUBMED Abstract]

Creutzig U, Zimmermann M, Reinhardt D, et al.: Early deaths and treatment-related mortality in children undergoing therapy for acute myeloid leukemia: analysis of the multicenter clinical trials AML-BFM 93 and AML-BFM 98. J Clin Oncol 22 (21): 4384-93, 2004.[PUBMED Abstract]

Vormoor J, Boos J, Stahnke K, et al.: Therapy of childhood acute myelogenous leukemias. Ann Hematol 73 (1): 11-24, 1996.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster

Jorg Ritter, MD, Protocol chair		Ph: 49-251-834-7742 Email: ritterj@uni-muenster.de