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
|Phase III||Treatment||Closed||under 15 at diagnosis||MRC-LEUK-AML10-CHILD|
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.
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
No prior cytotoxic treatment for AML
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
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.
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).
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.
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]
Trial Contact Information
Trial Lead Organizations
Medical Research Council's Working Party on Leukemia in Adults and Children
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.