Oral Tetra-Arsenic Tetra-Sulfide Formula Versus Intravenous Arsenic Trioxide As First-Line Treatment of Acute Promyelocytic Leukemia: A Multicenter Randomized Controlled Trial Hong-Hu Zhu, De-Pei Wu, Jie Jin, Jian-Yong Li, Jun Ma, Jian-Xiang Wang, Hao Jiang, Sai-Juan Chen, and Xiao-Jun Huang Hong-Hu Zhu, Hao Jiang, and Xiao-Jun Huang, Peking University People’s Hospital, Beijing; De-Pei Wu, First Affili- ated Hospital of Soochow University, Suzhou, Jiangsu; Jie Jin, First Affiliated Hospital of Zhejiang University, Hang- zhou, Zhejiang; Jian-Yong Li, First Affili- ated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing; Jun Ma, Harbin Institute of Hematology and Oncology, Harbin; Jian-Xiang Wang, Institute of Hematol- ogy and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tian- jin; and Sai-Juan Chen, Rui Jin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shang- hai, People’s Republic of China. Published online ahead of print at www.jco.org on October 14, 2013. Supported by Grants No. 2006AA02A405 and 2012AA02A505 from the National High-Tech R&D (863) Program, Grant No. 2008ZX09312-026 from the Mega Project of the Ministry of Science and Technology, and Grant No. Z111107067311070 from the Beijing Municipal Science & Technology Commission. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Corresponding author: Xiao-Jun Huang, MD, PhD, Peking University People’s Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South St, Beijing, China; e-mail: xjhrm@ medmail.com.cn. © 2013 by American Society of Clinical Oncology 0732-183X/13/3133w-4215w/$20.00 DOI: 10.1200/JCO.2013.48.8312 A B S T R A C T Purpose This randomized, multicenter, phase III noninferiority trial was designed to test the efficacy and safety of an oral tetra-arsenic tetra-sulfide (As 4 S 4 ) – containing formula named the Realgar-Indigo naturalis formula (RIF) compared with intravenous arsenic trioxide (ATO) as both induction and maintenance therapies for newly diagnosed acute promyelocytic leukemia (APL). Patients and Methods In all, 242 patients with APL were randomly assigned (1:1) to oral RIF (60 mg/kg) or ATO (0.16 mg/kg) combined with all-trans retinoic acid (ATRA; 25 mg/m 2 ) during induction therapy. After achieving complete remission (CR), all patients received three courses of consolidation chemo- therapy and maintenance treatment with sequential ATRA followed by either RIF or ATO for 2 years. The primary end point was the rate of disease-free survival (DFS) at 2 years, which was assessed for noninferiority with a 10% noninferiority margin. Results The median follow-up time was 39 months. DFS at 2 years was 98.1% (106 of 108) in the RIF group and 95.5% (107 of 112) in the ATO group. The DFS difference was 2.6% (95% CI, -3.0% to 8.0%). The lower limit of the 95% CI of DFS difference was greater than the -10% noninferiority margin, confirming noninferiority ( P  .001). No significant differences were noted between the RIF and ATO groups with regard to the CR rate (99.1% v 97.2%; P = .62) or the overall survival at 3 years (99.1% v 96.6%; P = .18). The rates of adverse events were similar in the two groups. Conclusion Oral RIF plus ATRA is not inferior to intravenous ATO plus ATRA as first-line treatment of APL and may be considered as a routine treatment option for appropriate patients. J Clin Oncol 31:4215-4221. © 2013 by American Society of Clinical Oncology INTRODUCTION Acute promyelocytic leukemia (APL) has changed from a highly fatal disease to a highly curable disease. The chromosomal aberration t(15;17) plays a cen- tral role in the development of APL and results in the formation of the promyelocytic leukemia/retinoic acid receptor alpha (PML/RAR) fusion protein. 1 Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) target the PML and RAR proteins, respec- tively, 2,3 and both drugs represent successful molecular target– based induction that targets dif- ferentiation and apoptosis, respectively. Previous studies from our group and others have demon- strated that high complete remission (CR) and 5-year disease-free survival (DFS) rates above 90% can be achieved by a combination of ATRA and ATO during induction followed by their sequential application during maintenance therapy. 4-7 Although this treatment leads to improved out- comes, ATO must be intravenously administered in a hospital setting. Therefore, the development of an orally active arsenic-containing formulation with comparable efficacy and adverse effects is highly de- sirable. In a pilot trial in patients with APL, we dem- onstrated that an oral tetra-arsenic tetra-sulfide (As 4 S 4 ) treatment alone can serve as a highly effec- tive and safe remission induction and maintenance therapy, which was prepared in our hospital. 8 We also demonstrated that another oral As 4 S 4 - containing formula named the Realgar-Indigo natu- ralis formula (RIF), which contains realgar (As 4 S 4 ), Indigo naturalis, Radix salviae miltiorrhizae, and Radix pseudostellariae, exhibited anti-APL activity JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 31  NUMBER 33  NOVEMBER 20 2013 © 2013 by American Society of Clinical Oncology 4215 from 12.189.148.4 Information downloaded from jco.ascopubs.org and provided by at Copyright Clearance Center, Inc on November 20, 2013 Copyright © 2013 American Society of Clinical Oncology. All rights reserved.