Treatment of Newly Diagnosed Patients With Acute Promyelocytic Leukemia in Children: Remission Induction With All-transretinoic Acid (ATRA) and Arsenic Trioxide (As2O3). Consolidation With Daunorubicin(DNR)+Ara-c or DNR Alone.
Phase: PHASE4
Conditions: Leukemia
Sponsor: Xiaofan Zhu

Initial version dated: 08-20-2010 
Study protocol for the Cytarabine (Ara-C) in Children With Acute 
Promyelocytic Leukemia (APL)  (NCT01191541) 
 
 
Principal Investigator 
 
Xiaofan Zhu MD 
 
 
1Department of Pediatrics, State Key Laboratory of Experimental Hematology and Division of 
Pediatric Blood Diseases Center, Institute of Hematology and Blood Diseases Hospital, 
Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.  
 
 
 
 
Eligibility criteria  
Eligible patients were those who were less than 14 years old, were newly diagnosed 
with APL, and had not previously received chemotherapy. A molecular diagnosis was 
not required for enrollment, but a subsequent molecular confirmation, including the 
demonstration of PML-RARA transcripts, was required for inclusion in the analysis. 
Written informed consent was obtained from all patients before study entry. 
Study design and treatment groups  
The study was a prospective, randomized, single-centre trial. It was designed to 
determine whether the combination of ATRA and ATO is safe and effective in 

paediatric APL and whether Ara-C can be omitted when ATO is added for 2 courses. 
Patients were assigned to receive ATRA plus ATO for induction followed by 1 
consolidation course of idarubicin (IDA) and 1 consolidation course of a 28-day cycle 
of ATO. The patients were then randomly assigned using a computer-generated 
random allocation schedule to receive 2 courses of either daunorubicin (DNR) or 
DNR+Ara-C. Patients who were treated with DNR alone were included as the 
no-Ara-C group. Patients who were treated with DNR+Ara-C were included as the 
Ara-C group. The patients were subsequently treated with maintenance therapy 
consisting of oral ATRA, 6-mercaptopurine, and methotrexate for 1.5 years. When CR 
was achieved, all patients received a prophylactic intrathecal injection (cytarabine, 
methotrexate, and dexamethasone) for the first time. The patients with an initial white 
blood cell count >10×10 9/L then received intrathecal injection once every course. 
Patients with an indication of CNS leukaemia received intrathecal injection once 
every other day until normal results were achieved.   
All children were monitored using reverse transcription polymerase chain 
reaction (RT-PCR) of bone marrow samples. After consolidation, the patients were 
assessed every 3 months for 1 year and then every 6 months for 1 year.   
Criteria for response and end points  
Haematological complete remission (HCR) and haematologic relapse were defined as 
described in previous publications. Molecular remission was defined as undetectable 
PML/RARa fusion transcripts. Molecular relapse was defined as the detection of the 
fusion oncogene PML/RARa in multiple samples within 2 weeks in the same patient. 

Early death (ED) was considered a death that occurred within two weeks of the 
beginning of treatment.  
Supportive measures and management of complications 
Coagulopathy was treated using fresh frozen plasma or fibrinogen. Platelet 
transfusions were administered to maintain a platelet count above 50×10 9/L until any 
significant sign of coagulopathy was resolved. The patients were administered 
hydroxyurea (1-1.5 g per day), or homoharringtonine (HHT, 1-2 mg per day for 5-10 
days) when their peripheral white blood cell (WBC) counts were greater than 
25×10 9/L. At the earliest manifestation of suspected differentiation syndrome, ATRA, 
arsenic trioxide, or both were temporarily discontinued, and intravenous 
dexamethasone was administered at a dose of 5-10 mg/m2 until these signs and 
symptoms disappeared. Antibiotics and antifungal drugs were administered for fever 
when required.