AIEOP-BFM-AML 2020

Primary objectives

All groups

• To collect samples for biological and toxicity studies
• To determine if the event-free-survival of patients with de-novo AML other than APL can be improved though the therapeutic use of CPX351

Group B

• To determine the initial efficacy of Gemtuzumab-Ozogamicin when added to standard chemotherapy backbone in children with relapsed or refractory AML (CBF-AML will receive standard therapy: IDA-FLA)

Group C

To compare GVRDS in patients treated with Treosulfan-based conditioning regimen compared with those treated with BuCyMel.
GVRDS is a composite endpoint. Events included in the composite endpoint GVRDS are:
-Acute GvHD grade 3-4 (G)
-Chronic GvHD (moderate and severe) (G)
-VOD Grad 3 or 4 (V)
-Clinical or Molecular Relapse (R)
-Death from any cause (D)
-Diagnosis of a second malignant neoplasm (S)

Patients will be allocated to the respective treatment group according to a fixed algorithm outlined in the protocol:
Patients with newly diagnosed AML will be allocated to Group A and will be stratified to the respective group A1-A3 according to the risk group after the first randomized course.
Patients with refractory or relapsed AML will be allocated to Group B, regardless of whether or not they were treated in one of the other trial groups before. Patient will be stratified into 2 groups: for AML with core-binding factor, gemtuzumab ozagomicin will be added to the standard re-induction with fludarabine/AraC (FLA) followed by FLA. Children with a t(8;21)- or inv(16)-mutated AML (with core-binding factor) will be treated with Ida-FLA/FLA.
Patients with the indication for a SCT due to AML will be allocated to Group C, irrespective of whether or not they were treated in one of the other trial groups before.

For all groups

• Understand and voluntarily provide written permission of parental/legal representative(s) to the ICF prior to conducting any study related assessments/procedures, also concerning data and biomaterial transfer according to ICH/GCP and national/local regulations
• Able to adhere to the study visit schedule and other protocol requirements
• Negative serum pregnancy tests for females of child-bearing potential within 10 days prior to treatment

Group A

• Diagnosis of an AML (according to WHO classification 2016)
• Acute leukemia of ambiguous lineage (MPAL; according to WHO classification 2016: acute undifferentiated leukemia (AUL, bilineal leukemia; biphenotypic leukemia, dominant myelogenous; lineage switch)
• Children and adolescents younger 18 years of age at start of initial chemotherapy
• Acceptance that vaccination with live vaccines is not possible while participating in the trial

Group B

• Patients with first relapsed (including relapse after SCT) or primary refractory AML
• Children and adolescents younger 18 years of age at start of initial chemotherapy and younger 21 years of age at start of this relapsed AML treatment

Group C

• Patients with AML and indication for first allogenic HSCT of an HLA-identical donor (at least high-resolution typing minimal 9/10)
• Age at time of inclusion from 1 month (28 days) to less than 18 years at diagnosis; up to 21 years at time of HSCT
• Criteria for allogeneic HSCT: in AML complete remission (CR), available Matched sibling donor (MSD), Matched family donor (MFD) or Matched unrelated donor (MUD); matched is defined as at least 9/10 after 4 digit typing for HLA-A, B, C, DRB1, DQB1 loci

All groups

• Existing syndromes which exclude treatment including Fanconi anemia or chromosomal instability syndromes
• Patients with trisomy 21 and ML-DS and/or transient myeloproliferative syndrome
• Patients with an acute promyelocytic leukemia (APL), AML with t(15;17)
• Treatment-related or secondary AML
• Symptomatic cardiac dysfunction (CTCAE 5.0 Grade 3 or 4)
• Any other organ dysfunction (CTCAE 5.0 Grade 3 or 4)
• Evidence of invasive fungal infection or other severe systemic infection requiring treatment doses of systemic/parenteral therapy including known active viral infection with human immunodeficiency virus (HIV) or hepatitis type B and C
• Participation in another clinical trial with an intervention interfering with the aims of this trial
• Pregnant or breast-feeding patients
• Female and male subjects with child-bearing potential who avoid using highly effective anticonceptive measure(ment)s
• Hypersensitivity to the active substance or other excipients contained in the investigational medical product listed in the summary of product characteristics (SmPC) or Investigators Brochure (IB)

Group A

• Previous therapy with cytostatic medicines of more than 14 days and other than specified in protocol as allowed prephase
• Diagnosed Wilson´s Disease.

Group B

• Fractional Shortening at echocardiography below 29 %
• A Karnofsky performance status smaller 40 % (children from 16 years) or a Lansky performance status of smaller 40 % (children younger 16 years) before start of the first course
• impaired liver function: Bilirubin similar or higher 3 times upper normal limit; transaminases similar or higher 3 times upper normal limit
• History of VOD
• Renal impairment with creatinine under 30 ml/min
• Decompensated haemolytic anaemia

Group C

• A Karnofsky performance status under 60 % (children from 16 years) or a Lansky performance status of under 60 % (children younger 16 years) before start of the Group treatment treatment with cytotoxic drugs within 10 days prior to planned study drug administration
• Impaired liver function: Bilirubin similar or higher 3 times upper normal limit; transaminases similar or higher 5 times upper normal limit
• Renal impairment with creatinine under 30 ml/min
• Cardiac insufficiency requiring treatment; LVEF similar or under 35 % (for patients with history of cardiac disease or anthracycline exposure)
• Impaired pulmonary function: PO2 similar or under 70 mm Hg or DLCO similar or under 60 %
• Requirement of supplementary continuous oxygen
• Symptomatic involvement of CNS: leukemic infiltration not cleared by prior intrathecal chemotherapy and/or cranial radiotherapy
• Other disease, comorbidity or condition that would severely limit life expectancy