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

Prior treatment

• 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.

Other illness

• Myeloid Leukaemia of Down Syndrome.
• Bone marrow failure syndromes.

Other

• Acute Promyelocytic Leukaemia.
• Blast crisis of chronic myeloid leukaemia.
• Relapsed or refractory AML.
• Pregnant or lactating females.

• 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.
• 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.
• 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
• 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.
• 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.
• 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.