International study on the treatment of pediatric relapsed acute myeloid leukemia

INTERVENTION: The aim of this study is to answer a randomized study question: can the response to the first reinduction chemotherapy block be improved by the addition of GO to the standard therapy? Standard Arm: DX‐FLA (Triple IT: Cytarabine, Methotraxate, Prednisolone i.th in age related dosis on day 0, liposomal daunorubicine dosis: 60 mg/m2/day, day 1,3,5; Fludarabine dosis: 30 mg/m2/day, day 1‐5; Cytarabine dosis: 2000 mg/m2/day, day 1‐5) Experimental Arm: DX‐FLA + GO (Triple IT: Cytarabine, Methotraxate, Prednisolone i.th in age related dosis on day 0, liposomal daunorubicine dosis: 60 mg/m2/day, day 1,3,5; Fludarabine dosis: 30 mg/m2/day, day 1‐5; Cytarabine dosis: 2000 mg/m2/day, day 1‐5; Gemtuzumab ozogomicin dosis: 4.5 mg/m2, day 6) Subsequent therapy depends on the response to the first block: >20% blasts off protocol =20% blasts Second Reinduction: FLA (Triple IT: Cytarabine, Methotraxate, Prednisolone i.th in age related dosis on day 1, Fludarabine dosis: 30mg/m2/day, day 1‐5; Cytarabine dosis: 2000mg/m2/day, day 1‐5) Consolidation high intensity (Triple IT: Cytarabine, Methotraxate, Prednisolone i.th in age related dosis on day 1; Cytarabine dosis: 500 mg/m2/day, day 1‐4; Etoposide dosis: 100 mg/m2/day, day 1‐5) or Consolidation low intensity (Triple IT: Cytarabine, Methotraxate, Prednisolone i.th in age related dosis on day 1; Cytarabine dosis: 75 mg/m2/day, day 1‐4 and 15‐18 s.c.; Thioguanine dosis: 100 mg/m2/day, max. 4 weeks oral dose) Stem cell transplantation (SCT) Total duration of therapy will be up to three months. Follow‐up duration will be five years. CONDITION: Pediatric relapsed or refractory acute myeloid leukemia (AML) ; Cancer ; Myeloid leukemia PRIMARY OUTCOME: The early treatment response will be determined by morphological and flow cytometric examination of the BM sampled at day 28 (in practice anytime between day 28 and 42 after start of first reinduction chemotherapy). If the BM shows 20% of leukemic blasts or less, the response is good. If the BM shows > 20% leukemic blasts, the response is poor. Event‐free, disease‐free and overall survival and AML toxicity rates will be evaluated. SECONDARY OUTCOME: 1. Determination of the incidence of refractory disease, CR/CRi rates after two courses and long‐term efficacy (cumulative incidence of relapse, event‐free survival, and overall survival) in the different study arms; 2. Determination of the toxicity of GO (Mylotarg®) when added to DX‐FLA in terms of BM aplasia, liver toxicity including VOD, cardiotoxicity, mucosal toxicity and other adverse reactions according to CTCAEv4 which are considered to be relevant in relapsed AML and the proposed therapy when compared to treatment with DX‐FLA only; 3. Identification of additional prognostic factors in pediatric relapsed AML, other than early treatment response, cytogenetics and duration of first remission; 4. Providing of individual biological characterization of leukemia (morphology, immunophenotype, cytogenetics, molecular genetics and activated signalling pathways), for future individualized stratification to targeted therapy INCLUSION CRITERIA: 1. Children and adolescents < 18 years of age at start of initial chemotherapy and < 21 years of age at start of this relapsed AML treatment 2. Patients with first relapsed (including relapse after SCT) or primary refractory AML 3. Signed written informed consent from patients and/or from parents or legal guardians for minor patients, according to local law and regulations 4. In female patients of childbearing potential pregnancy must be excluded 5. Sexually active patients must be using two reliable contraception methods from the time of screening/baseline and during the study for a minimum of 3 months after the last administration of study medication. This includes every combination of a hormonal contraceptive (such as injection, transdermal patch, implant, cervical ring) or of an intrauterine device (IUD) with a barrier method (e.g. diaphragm, cervical cap, or condom) or with a spermicide.