Overview

It is a randomized phase 3 study comparing two conditioning regimens in children with Acute Myeloid Leukemia, AML, undergoing allogenic stem cell transplantation. The primary aim is to investigate if a conditioning regimen containing one alkylator (Bu) combined with two antimetabolites (Clo and Flu) results in superior 2-year acute grade III to IV-free, chronic non-limited GvHD-free, relapse free survival than a conditioning regimen combining three alkylating agents (BuCyMel)

Eligibility

Inclusion criteria for randomization part of the study:

• Age ≤18 years at time of initial AML, age ≤ 21 years at transplantation.
• HCT is performed in a study participating center
• All women of childbearing potential who have to have a negative pregnancy test within 2 weeks prior to the start of treatment.
• Signed informed consent.
• Any relapsed AML after initial treatment according to a defined international AML protocol. (NOPHO-DBH AML 2012/new protocol), or AML in first remission with transplant indications and treatment according to national AML protocol (NOPHO-DBH AML 2012 or new protocol).
• In hematological remission, defined as:

        < 5 % leukemic blasts confirmed by flow cytometry (in patients with an informative leukemia
        associated immunophenotype) in a bone marrow sample taken ≤14 days prior to start of
        conditioning and no evidence of extramedullary disease, including in CNS and no leukemic
        blasts in the peripheral blood (verified by flow cytometry in case immature cells are
        detected in the peripheral blood differential).
        -Patients must have a related or unrelated donor fulfilling any of the following criteria:
        HLA 10/10 allelic matched, identical, sibling BM donor or HLA 10/10 or 9/10 allelic matched
        related/unrelated BM or PBSC donor orHLA 5-6/6 unrelated or 6-7-8/8 unrelated Cord Blood
        (UCB)
        Inclusion criteria for observation/registration only:
          -  Diagnosis of acute myeloid leukemia
          -  Indication for allogeneic stem cell transplantation, as defined by primary treatment
             protocol or treating physician.
          -  Age ≤18 years at time of initial AML, age ≤ 21 years at transplantation.
          -  Not eligible for randomization, either due to lack of consent or not fulfilling
             inclusion criteria for interventional part of the study.
          -  Signed informed consent to prospectively register follow-up data.
        Exclusion criteria for the randomization part of the study :
          -  Diagnosis of myelodysplastic syndrome (MDS).
          -  Diagnosis of juvenile myelomonocytic leukemia (JMML).
          -  History of previous malignancy (AML diagnosed as secondary cancer).
          -  Known diagnosis of Fanconi anemia.
          -  Prior autologous or allogeneic hematopoietic stem cell transplant.
          -  Planned prophylactic DLI or other immunotherapeutic interventions after HCT that are
             not included in the upfront protocol, Planned anti-leukemic medication after HCT that
             are not included in the upfront protocol
          -  Known intolerance to any of the chemotherapeutic drugs in the protocol.
          -  Major organ failure precluding administration of planned chemotherapy.
          -  Patients with uncontrolled bacterial, viral, or fungal infections (currently taking
             medication and with progression or no clinical improvement) at time of enrollment.
          -  Severe concomitant disease that does not allow treatment according to the protocol at
             the investigator's discretion, e.g. malformation syndromes, cardiac malformations,
             metabolic disorders, renal impairment (<30% of normal glomerular filtration rate),
             severe pulmonary, hepatic or cardiac impairment due to toxicity or infection.
          -  Karnofsky / Lansky score < 50%
          -  Females who are pregnant (positive serum or urine βHCG) or breastfeeding.
          -  Females of childbearing potential or men who have sexual contact with females of
             childbearing potential unwilling to use effective forms of birth control or abstinence
             for one year after transplantation.
          -  Subjects unwilling or unable to comply with the study procedures.
        Exclusion criteria for the observational part of the study:
          -  Diagnosis of Myelodysplastic syndrome (MDS).
          -  Diagnosis of Juvenile myelomonocytic leukemia (JMML).
          -  Age above 21 years at time of transplantation
          -  No consent is given to prospectively register outcome data
          -  Prior autologous or allogeneic hematopoietic stem cell transplant.