An Open Label Complex Clinical Trial in Newly Diagnosed Pediatric de Novo AML Patients - a Study by the NOPHO-DB-SHIP Consortium, Master Protocol

This is a master protocol comprising a complex clinical trial with a stratification approach to allocate patients to randomized studies described in the master protocol or linked trials.

The overarching objective of the CHIP-AML22 study is to improve event-free survival (EFS) in children and adolescents with AML, as compared to NOPHO-DBH 2012.

The consortium strives to achieve the overarching aim by:

1. Avoiding unnecessary toxicity. This will be investigated in a randomized setting (non-inferiority) by omitting a third standard-of-care consolidation course for standard-risk patients (4 versus 5 courses of chemotherapy).
2. Introducing quizartinib as FLT3-inhibitor in addition to the first three sequential chemotherapy courses for all patients with FLT3-ITD/NPM1wt, and as post-SCT continuation treatment for the subset of patients that have MRD ≥0.1% after course 1 or at any time-point later on (historical comparison, higher efficacy).
3. Refining risk-group adapted treatment, by classifying patients with KMT2A-rearrangement (except KMT2A/MLLT3) and MRD≥0.1% in BM after course 1 as high-risk (historical comparison, higher efficacy), as well as patients with the RAM-phenotype and/or CBFA2T3::GLIS2 fusion (historical comparison, higher efficacy). High-risk (non-FLT3-ITD/NPM1wt patients) will also be concluded for patients having ≥15% leukemic cells in BM after course 1, or ≥0.1-5% after course 2. Refractory disease will be defined as ≥5% leukemic cells in bone marrow after 2 courses of induction treatment, or disease elsewhere, or both.
4. Recommending the use of the cardioprotective drug dexrazoxane in all courses incorporating an anthracycline or mitoxantrone (exploratory objective, no statistical design), with the aim to prevent cardiotoxicity.
5. To assess if adding gemtuzumab ozogamicin to the first induction course results in better anti-leukemic efficacy in CD33-positive AML patients. Children with FLT3-ITD/NPM1wt are not eligible for this randomization.
6. To explore health-related Quality of Life during and after completion of treatment by using short questionnaires (exploratory objective, no statistical design).