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.