International Randomised Phase III Clinical Trial in Children With Acute Myeloid Leukaemia

Inclusion Criteria: Inclusion criteria for trial entry * Diagnosis of acute myeloid leukaemia (AML) /high risk Myelodysplastic syndrome (MDS) (\>10% blasts in the bone marrow)/isolated myeloid sarcoma (MS) (either de novo or secondary). * Age \<18 years at trial entry. * No prior chemotherapy or biological therapy for AML/high risk MDS/isolated MS other than that permitted in the protocol. * Normal cardiac function defined as fractional shortening ≥28% or ejection fraction ≥55%. * Fit for protocol chemotherapy. * Documented negative pregnancy test for female patients of childbearing potential. * Patient agrees to use effective contraception (patients of child bearing potential). * Written informed consent from the patient and/or parent/legal guardian. Inclusion criteria for participation in the gemtuzumab ozogamicin dose finding study: Centres must be formally activated in order to be take part in the embedded dose escalation study. Please contact the trial office for further information. * Patient meets the inclusion criteria for trial entry. * Age: * ≥12 months for the major dose finding study * ≥ 12 weeks and \<12 months for the minor dose finding study * Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2. * Normal hepatic function defined as total bilirubin ≤2.5 upper limit of normal (ULN) for age unless it is caused by leukaemic involvement or Gilbert's syndrome or similar disorder. * Alanine transaminase (ALT) or aspartate transaminase (AST) ≤10 x ULN for age. * Written informed consent from the patient and/or parent/legal guardian. Inclusion criteria for treatment with gemtuzumab ozogamicin for patients not participating in the gemtuzumab ozogamicin dose finding study or R2. * Patient meets the inclusion criteria for trial entry (section 4.1.1) * Age: * ≥12 months * ≥ 12 weeks * ≥28 days and \<12 weeks (patients will receive a maximum of one dose of gemtuzumab ozogamicin) * Normal renal function, defined as calculated creatinine clearance ≥90 ml/min/1.73m2 * Normal hepatic function, defined as total bilirubin ≤2.5 upper limit of normal (ULN) for age and not due to leukaemic involvement or Gilbert's syndrome or similar disorder * ALT or AST ≤10 x ULN for age * Written informed consent from the patient and/or parent/legal guardian Inclusion criteria for participation in R2.(once open to randomisation in the applicable age group) • Patient meets the inclusion criteria for trial entry Patient age: * ≥12 months * ≥12 weeks (once R2 open in patients aged ≥12 weeks and \<12 months) * Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2. * Normal hepatic function defined as total bilirubin ≤2.5 ULN for age and not due to leukaemic involvement or Gilbert's syndrome or similar disorder. * ALT or AST ≤10 x ULN for age. * Written informed consent from the patient and/or parent/legal guardian. Inclusion criteria for participation in R3. * Patient meets the inclusion criteria for trial entry * Induction treatment as per MyeChild 01 protocol or treated with 2 courses of mitoxantrone \& cytarabine off trial. * Minimal residual disease (MRD) response (performed in MyeChild 01 centralised laboratories, see national MyeChild 01 Laboratory Manual): * Patients with good risk cytogenetics/molecular genetics and a MRD level \<0.1% by flow after course 2, or a decrease in transcript levels of \>3 logs after course 2 for those with an informative molecular marker, but without an informative marker of sufficient sensitivity for flow MRD monitoring or * Patients with intermediate risk cytogenetics/molecular genetics with a MRD level \<0.1% by flow after course 1 and course 2, or a decrease in transcript levels of \>3 logs after course 1 and course 2 for those with an informative molecular marker, but without an informative marker of sufficient sensitivity for flow MRD monitoring. * Written informed consent from the patient and/or parent/legal guardian. Inclusion criteria for participation in R4. * Patient meets the inclusion criteria for trial entry * Induction treatment as per MyeChild 01 protocol or treated with 1 or 2 courses of mitoxantrone \& cytarabine ± treatment intensification with fludarabine, cytarabine \& idarubicin (FLA-Ida) off trial. * Patient is in complete remission (CR) or CR with incomplete blood count recovery (CRi) defined as \<5% blasts confirmed by flow cytometry/ molecular/FISH in a bone marrow aspirate taken within 6 weeks prior to randomisation to R4. * Patient meets one of the following criteria and is a candidate for HSCT as per the protocol: * High risk after course 1 (all patients with poor risk cytogenetics and patients with intermediate risk cytogenetics who fail to achieve CR/CRi). * Intermediate risk cytogenetics with MRD \>0.1% after course 1 and 2 measured by flow. If no flow MRD marker of sufficient sensitivity is identified, a molecular MRD marker with a sensitivity of \>0.1% may be used. * Good risk cytogenetics with flow MRD \>0.1% confirmed by a decrease in molecular MRD of \<3 logs or rising transcript levels after course 3 despite treatment intensification (FLA-Ida) and after discussion with the Clinical Co-ordinators. * Availability of a 9-10/10 human leukocyte antigen (HLA) matched family or unrelated donor or 5-8/8 matched cord blood unit with an adequate cell dose as defined by the protocol section 17.1. * Written informed consent from the patient and/or parent/legal guardian. Exclusion Criteria: Exclusion criteria for all randomisations * Acute Promyelocytic Leukaemia. * Myeloid Leukaemia of Down Syndrome. * Blast crisis of chronic myeloid leukaemia. * Relapsed or refractory AML. * Bone marrow failure syndromes. * Prior anthracycline exposure which would inhibit the delivery of study anthracyclines. * Concurrent treatment or administration of any other experimental drug or with any other biological therapy for AML/high risk MDS/isolated MS. * Pregnant or lactating females.