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Clinical Trials (PDQ®)

Phase III Randomized Trial of Remission Induction with DAT (DNR/ARA-C/TG) vs ADE (ARA-C/DNR/VP-16), Consolidation with Sequential MACE (AMSA/ARA-C/VP-16) and MidAC (DHAD/ARA-C), and Early vs Late Autologous Bone Marrow Transplant in Children with AML

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

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentClosedunder 15 at diagnosisMRC-LEUK-AML10-CHILD
EU-92001

Objectives

I.  Assess, in a randomized Phase III trial, the effect of immediate 
postconsolidation marrow ablation with cyclophosphamide (CTX) and total-body 
irradiation followed by autologous bone marrow (ABM) rescue vs. delayed 
ablation with busulfan/CTX and rescue during second remission following 
relapse in children and adolescents with acute myelogenous leukemia.

II.  Compare the efficacy of remission induction with DAT 
(daunorubicin/cytarabine/thioguanine) vs. ADE 
(cytarabine/daunorubicin/etoposide) in children and adolescents with AML.

III.  Determine whether cytogenetic and immunophenotypic analysis of 
autologous bone marrow can predict which patients will relapse.


Entry Criteria

Disease Characteristics:


De novo or secondary acute myelogenous leukemia (AML)

  Patients with pre-existing hematologic disorders must meet
  one of the following conditions:
     At least 30% blast cells (granular and agranular) in
     bone marrow

     MDS that has transformed to a more malignant phase
     (e.g., more severe anemia or thrombocytopenia) with a
     cellular marrow containing greater than 10% blasts
     cells (granular and agranular)

CNS disease (leukemic blast cells greater than 5/cumm on CSF
cytospin) allowed

No CML in blast crisis


Prior/Concurrent Therapy:


No prior cytotoxic treatment for AML


Patient Characteristics:


Age:
  Under 15 at diagnosis (patients over 15 should be entered on
  the MRC-LEUK-AML10-ADULT trial)

Performance status:
  1-4

Hematopoietic:
  See Disease Characteristics

Hepatic:
  Not specified

Renal:
  Not specified

Other:
  No concurrent malignancy

  Patients unwilling to travel to a designated regional
  transplant center are not eligible for postinduction
  randomization


Expected Enrollment

Approximately 300 children will be accrued over 6 years.  If a difference 
between treatments of 3 standard deviations or more is found at any of the 
annual interim analyses, the trial will be stopped; data from this study will 
be analyzed in conjunction with data from MRC-LEUK-AML10-ADULT.

Outline

Randomized study.  All patients are randomized to Arms I and II for remission 
induction, and those who achieve CR proceed to Regimen A for consolidation 
therapy.  Following consolidation, eligible patients without suitable bone 
marrow donors are randomized to immediate marrow ablation/autologous rescue 
(Arm III) vs. delayed marrow/rescue, i.e., during second remission following 
relapse (Arm IV); patients with HLA-matched siblings receive marrow ablation 
and allogeneic rescue on Regimen B.  All patients receive CNS therapy on 
Regimen C.

Induction.

Arm I:  3-Drug Combination Chemotherapy.  DAT:  Daunorubicin, DNR, NSC-812151; 
Cytarabine, ARA-C, NSC-63878; Thioguanine, TG, NSC-752.

Arm II:  3-Drug Combination Chemotherapy.  ADE:  ARA-C; DNR; Etoposide, VP-16, 
NSC-141540.

Regimen A (Consolidation):  3-Drug Combination Chemotherapy followed by 2-Drug 
Combination Chemotherapy.  MACE:  Amsacrine, AMSA, NSC-249992; ARA-C; VP-16; 
followed by MidAC:  Mitoxantrone, DHAD, NSC-301739; ARA-C.

Autologous Bone Marrow Therapy.

Arm III:  Either Single-agent Ablative Chemotherapy with Urothelial Protection 
plus Radiotherapy or 2-Drug Ablative Chemotherapy with Urothelial Protection 
followed by Autologous Bone Marrow Rescue.  Cyclophosphamide, CTX, NSC-26271; 
with Mesna, NSC-113891; plus Total-Body Irradiation, TBI, using megavoltage 
equipment; or CTX; Busulfan, BU, NSC-750; with Mesna; followed by autologous 
bone marrow infusion.  Early ablation/rescue.

Arm IV:  2-Drug Combination Ablative Chemotherapy with Urothelial Protection 
followed by Autologous Bone Marrow Rescue.  BU; CTX; with Mesna; followed by 
autologous bone marrow infusion.  Delayed ablation/rescue.

Regimen B (Allogeneic Bone Marrow Therapy):  Either Single-agent Ablative 
Chemotherapy with Urothelial Protection plus Radiotherapy or 2-Drug Ablative 
Chemotherapy with Urothelial Protection followed by Allogeneic Bone Marrow 
Rescue.  CTX; with Mesna; plus TBI, using equipment as in Arm III; or CTX; BU; 
with Mesna; followed by allogeneic bone marrow infusion.

Regimen C (CNS Therapy/Prophylaxis):  Triple Intrathecal Chemotherapy plus (as 
indicated) Radiotherapy.  IT ARA-C; IT Methotrexate, IT MTX, NSC-740; IT 
Hydrocortisone, IT HC, NSC-10483; plus (as indicated) craniospinal irradiation 
(equipment unspecified).

Published Results

Webb DK, Harrison G, Stevens RF, et al.: Relationships between age at diagnosis, clinical features, and outcome of therapy in children treated in the Medical Research Council AML 10 and 12 trials for acute myeloid leukemia. Blood 98 (6): 1714-20, 2001.[PUBMED Abstract]

Webb DK, Wheatley K, Harrison G, et al.: Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial. MRC Childhood Leukaemia Working Party. Leukemia 13 (1): 25-31, 1999.[PUBMED Abstract]

Burnett AK, Goldstone AH, Stevens RM, et al.: Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. UK Medical Research Council Adult and Children's Leukaemia Working Parties. Lancet 351 (9104): 700-8, 1998.[PUBMED Abstract]

Grimwade D, Walker H, Oliver F, et al.: The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 92 (7): 2322-33, 1998.[PUBMED Abstract]

Stevens R, Hann I, Wheatley K, et al.: Improved outcome in paediatric acute myeloid leukaemia (AML): results of the United Kingdom Medical Research Council (MRC) AML10 trial. [Abstract] Proceedings of the American Society of Clinical Oncology 14: A-1036, 343, 1995.

Related Publications

Horan JT, Alonzo TA, Lyman GH, et al.: Impact of disease risk on efficacy of matched related bone marrow transplantation for pediatric acute myeloid leukemia: the Children's Oncology Group. J Clin Oncol 26 (35): 5797-801, 2008.[PUBMED Abstract]

Rao A, Hills RK, Stiller C, et al.: Treatment for myeloid leukaemia of Down syndrome: population-based experience in the UK and results from the Medical Research Council AML 10 and AML 12 trials. Br J Haematol 132 (5): 576-83, 2006.[PUBMED Abstract]

Gibson BE, Wheatley K, Hann IM, et al.: Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials. Leukemia 19 (12): 2130-8, 2005.[PUBMED Abstract]

Burnett AK, Hills RK, Goldstone AH, et al.: The impact of transplant in AML in 2nd CR: a prospective study of 741 in the MRC AML 10 and 12 trials. [Abstract] Blood 104 (11): A-620, 2004.

Trial Contact Information

Trial Lead Organizations

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

Ian Malcolm Hann, MD, Protocol chair
Ph: 44-20-7829-8831
Email: Ian.Hann@gosh-tr.nthames.nhs.uk

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.

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