Long-Term Outcome of Children with Acute Promyelocytic Leukaemia: A Randomised Study of Oral Versus Intravenous Arsenic by SCCLG-APL Group

Background: Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine mainly containing Realgar (As 4 S 4 ), has been shown to be effective as front-line treatment for adult acute promyelocytic leukemia (APL). However, the treatment efficacy and safety of RIF have not been verified in paediatric patients. Methods: SCCLG-APL group conducted a multicenter randomised non-inferiority trial to determine whether intravenous arsenic trioxide (ATO) can be substituted by oral RIF in treating children with APL. Of 176 eligible patients enrolled, 91 and 85 were randomised to ATO and RIF groups respectively. Patients were treated with risk-adapted protocol. Induction and consolidation treatment contained all-trans-retinoic acid and low intensity chemotherapy, and either ATO or RIF. The primary end-point was 5-year event-free survival. The secondary end-points were adverse events and the number of hospital days during induction and consolidation therapy. Findings: After a median 5.9-year follow-up, the 5-year overall and event-free survivals in both groups were 100% and 97.6% respectively (p=0.617). Patients in RIF group had significantly shorter hospital stays during induction and consolidation, and a lower incidence of infection or fever of unknown origin during consolidation, and tended to have less cardiac toxicity (p=0.054). All relapses occurred within 3.3 years after the end of consolidation. The excretion of urine arsenic retuned to base level at the end of maintenance therapy in both groups. Interpretation: The substitution of oral RIF for ATO not only does not compromise treatment efficacy, but also reduces hospital days and adverse events in treating paediatric APL, and may be a future treatment strategy for APL. Trial Registration: The trial was registered at www.clinicaltrials.gov as NCT02200978. Funding: Youth Talent Promotion project of Guangzhou Association for Science and Technology, The Medical Science and Technology Research Project of Guangdong Province, Basic and Applied Basic Research Project of Guangdong Province, the Science and Technology Planning Project of Guangzhou, and the Science and Technology Planning Project of Guangdong Province. Declaration of Interest: The authors declare no competing financial interests. Ethical Approval: The study received institutional review board approval. Patients' families and/or patients provided informed consent in accordance with the Declaration of Helsinki.