The trial is open to all patients with a diagnosis of acute promyelocytic leukemia (APL) who are PCR-positive for the PML-RARα transcript and less than 18 years of age.

Acute promyelocytic leukemia (APL) in children has become a highly curable disease with the combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy with an overall remission rates equal to or higher than 98% and cure rates now exceeding 80% 1-9.

Based on data coming from adults indicating that at least standard-risk APL patients may be cured without chemotherapy (i.e., with a treatment combining arsenic trioxide (ATO) and ATRA only) 10-12, this ICC APL 02 study was designed with the aim of validating the efficacy of a treatment combining:

• ATO and ATRA in newly diagnosed APL standard-risk (SR) children and adolescents and
• ATO, ATRA and gemtuzumab ozogamicin (GO) in newly diagnosed APL high-risk (HR) children and adolescents.

Following one induction course of treatment combining ATO and ATRA +/- GO depending on risk stratification, patients will receive 4 ATO/ATRA based consolidation blocks. This is the first pediatric trial delivering a non-chemotherapy-based treatment for children with APL, being the whole treatment based on the use of ATRA, ATO (and GO in HR patients). The aim of the study is to demonstrate at least an equivalent efficacy and safety of this treatment not containing cytostatic agents compared to the standard protocols combining ATRA and chemotherapy (i.e. ICC APL Study 01).

The trial is open to all patients with a diagnosis of acute promyelocytic leukemia (APL) who are PCR-positive for the PML-RARα transcript and less than 18 years of age.

This will be an international study, comprising the most important pediatric European groups, expecting to recruit 46 and 43 patients in SR and HR arms, respectively, in 3 years. The duration of study recruitment will be 36 months with a minimum follow-up per patient of 2 years.

The evaluation of morphological CR will be carried out after induction therapy, prior to the first block of consolidation therapy. MRD results after induction will not have an impact on subsequent therapy. By contrast, MRD results after the third consolidation course will influence the subsequent treatment, MRD-positive patients being eligible to rescue treatment, including hematopoietic stem cell transplantation (HSCT). BM aspirates will be repeated after the end of therapy, and 3 months, 6 months, 9 months and 12 months after treatment discontinuation.

This is a collaborative international study in APL in children and adolescents aimed at providing information about procedures for the entry, treatment and follow-up of pediatric patients with APL. It is not intended that this document be used as an aide-memoir or guide for the treatment of other patients. Every care has been taken in its drafting, but corrections and amendments may be necessary. Before entering patients into the study, clinicians must ensure that the study has received clearance from their Local Research Ethics Committee and any other necessary body.

Inclusion Criteria:

• Newly diagnosed APL confirmed by the presence of PML/RARα fusion gene
• Age <18 years
• Written informed consent by parents or legal guardians

Exclusion Criteria:

• Patients with a clinical diagnosis of APL but subsequently found to lack PML/RARα rearrangement should be withdrawn from the study and treated on an alternative protocol
• Significant liver dysfunction (bilirubin serum levels >3 mg/dL, ALT/AST serum levels greater than 5 times the normal values)
• Creatinine serum levels >2 times the normal value for age
• Significant arrhythmias, EKG abnormalities (*see below), other cardiac contraindications (L-FEV <50% or LV-FS <28%)
• Neuropathy
• Concurrent active malignancy
• Uncontrolled life-threatening infections
• Pregnant or lactating female
• Patients who had received alternative therapy (APL not initially suspected; ATRA and/or ATO not available