Risk-Group Stratified and Minimal Residual Disease (MRD)-Guided Treatment with Extended ATRA and Reduced-Anthracycline Chemotherapy in Childhood Acute Promyelocytic Leukemia (APL): Results from ICC APL Study 01 (NCT01226303; EudraCT 2008-002311-40)
Authors: Testi Anna Maria , Pession Andrea , Grimwade David , Diverio Daniela , Ragu Christine , Elitzur Sarah , Fynn Alcira , Hasle Henrik , Van der Werff ten Bosch Jutte , Smith Owen , Gibson Brenda , Locatelli Franco , Kaspers Gertjan J.L. 
Published: October 2019

Abstract
The combined treatment of all-trans retinoic acid (ATRA) and anthracyclines at high cumulative doses (>500-600 mg/m2) is associated with good outcomes in adults and children with acute promyelocytic leukemia (APL). However, high cumulative anthracyclines doses carry a significant risk of late cardiotoxicity, especially in children. In addition, children are more susceptible to ATRA-related side effects (particularly pseudo-tumor cerebri). This suggests that children should receive a lower dose of ATRA. We therefore established an international consortium on childhood APL, ICC APL, and developed the first multinational, multicenter childhood APL study, ICC APL Study 01, with the aim of investigating the safety and efficacy of a regimen with reduced anthracycline cumulative doses and modified ATRA. In some countries the protocol treatment was delivered out as a treatment guideline. Eligible patients had either typical cytogenetics (t(15;17)) or ATRA-sensitive molecular aberration (predominantly PML-RARα). Treatment was stratified by risk group (standard-SR or high-HR, based on white blood cell (WBC) count at diagnosis < or > 10x109/L) and minimal residual disease (MRD) level during post-remissional treatment. SR patients received induction (ATRA plus idarubicin on days 3-5-7) followed by two consolidation courses (I: ATRA, intermediate-dose cytarabine, mitoxantrone; II: ATRA plus idarubicin). HR patients received ATRA plus idarubicin (days 1-3-5) in induction, followed by 3 consolidation courses (I and II identical to SR patients, III: ATRA, intermediate-dose cytarabine, idarubicin). This therapy was followed by 2 years of maintenance in all patients with ATRA given every 3 months, methotrexate weekly and mercaptopurine daily. The daunorubicin-equivalent dose of anthracyclines was 355 mg/m2 and 405 mg/m2 for SR and HR patients, respectively. The cytarabine dose was 6,000 mg/m2 and 12,000 mg/m2 for SR and HR patients, respectively. ATRA was given at a dose of 25mg/m2. Treatment was guided by MRD bone marrow monitoring at the end of consolidation and 3 monthly during and for one year after maintenance completion. SR patients with persistent molecular disease after consolidation received a third course of treatment identical to that given to HR patients. Children with persistent molecular disease after 3 courses, and those with molecular or frank relapse during or after treatment, were eligible for salvage arsenic-trioxide (ATO) treatment. A total of 227 patients were enrolled into the study between January 2008 and May 2015; median age was 10,7 years (range, 0 - 19,9) and 53% of patients were female. FAB type was M3 in 81% and M3 variant in 16% (data N/A for 3% of patients). One hundred and twenty-nine (57%) and 98 (43%) were assigned to the SR and HR groups, respectively. Median WBC and platelet count at diagnosis were 6.1x109/L (range, 0.59-454) and 26x109/L (range, 2-262), respectively. PML/RARα fusion transcript was bcr 1 in 100, 2 in 6, 3 in 88 and not known in 33 patients. Clinical response and MRD data are available for 179/227 patients (79%). Early death rate was 3.1%. MRD positivity decreased over time; 80% of patients MRD were positive after induction, 31% after consolidation course I, 11% after consolidation course II and 4% after consolidation course III. A frank or molecular relapse occurred in 6 (all HR) and 8 (4 HR; 4 SR) patients, respectively; salvage ATO treatment was effective in 12 of these patients. One patient died of therapy-related leukemia. The 3-year probability of overall survival was 95% in the whole cohort of patients (96.5% and 93% in SR and HR patients, respectively; p 0.17). The 3-year probability of event-free survival was 83% for all patients (87% and 79% in SR and HR patients, respectively; p 0.09). In summary, the ICC APL study 01 produced an outcome comparable to that of children treated with AIDA 2000 protocol, which employed higher anthracyclines doses (650 mg/m2 daunorubicin-equivalent) (Testi et al. ASH 2010). These results confirm those reported by Creutzig et al. (BrJHaematol 2010), delivering reduced anthracyclines (cumulative dose 350 mg/m2) with extended ATRA and cytarabine. Data from a randomised study published by Lo Coco et al. (NEJM 2013) urged our consortium to develop ICC APL Study 02, in which SR patients will be treated with ATRA plus ATO and HR patients with ATRA, ATO and gemtuzumab ozogamicin; a front-line treatment without conventional chemotherapy.

Disclosures
Kaspers: Janssen-Cilag: Research Funding.