Oral tetra-arsenic tetra-sulphide formula achieved similar efficacy and safety compared to intravenous arsenic trioxide as first-line treatment of APL (multi-center randomized controlled trial APL07) Hong-Hu Zhu, De-Pei Wu, Jie Jin, Jian-Yong Li, Jun Ma, Jian-Xiang Wang, Hao Jiang, Gordon G. Liu, Sai-Juan Chen, Xiao-Jun Huang Peking University Institute of Hematology （ PUIH ） Peking University People’s Hospital, Beijing, P.R.C.

Arsenic plays a key role in cure of APL Introduction Chen SJ, et al. Blood 2011;117:6425 Shen ZX, et al. PNAS 2004;101:5328 Hu J, et al. PNAS 2009;106:3342 Sanz MA, et al. Blood 2010;115:5137 (ATO: arsenic trioxide)

Intravenous vs. Oral arsenic Effective inconvenient : iv Inpatients Introduction Lu DP, et al. Blood 2002; 99:3136 Xiang Y, et al. Chin J Clin Hematol 2007;16:204 Wang L, et al. PNAS 2008;105:4826 Intravenous arsenicOral arsenic Effective convenient : oral Outpatients

Question No randomised controlled trial to answer whether oral arsenic has similar efficacy and safety with intravenous arsenic in treating APL. Introduction

Purpose of our study To demonstrate oral arsenic can be used in place of arsenic trioxide as first-line treatment in newly diagnosed APL Multicenter, randomised controlled trial Introduction

Design Chinese APL Cooperative Group(7 Centers) Multicenter, randomised controlled trial: APL07 (registered number ChiCTR -TRC ) Enrollment : to Last follow-up: (median 32 months) Methods

Arsenic used in our study Control group: intravenous arsenic trioxide(As2O3, ATO) Trial group: oral tetra-arsenic tetra-sulphide formula (As4S4; Realgar-Indigo naturalis formula, RIF ) Lu DP, et al. Blood 2002; 99:3136 Xiang Y, et al. Chin J Clin Hematol 2007;16:204 Wang L, et al. PNAS 2008;105:4826 Methods

Inclusion Criteria de novo APL Age :15-60 years WBC <50×10 9 /L before treatment Adequate hepatic and renal function Performance Status score 0-2 Able to provide written informed consent Methods

Trial Design HA: homoharringtonine ; cytarabine MA: mitoxantrone ; cytarabine DA: daunorubicin ; cytarabine RIF: Realgar-Indigo naturalis formula ATO: Arsenic trioixide ATRA: all-trans retinoic acid Methods

Induction Therapy RIF: 60 mg/kg, d1-CR ATO : 0.16 mg per kg, d1-CR ATRA: 25 mg/m2, d1-CR Mitoxantrone 1.4 mg/m2, for 5-10 days Methods

Consolidation Therapy HA homoharringtonine 2 mg/m2 for 7 days cytarabine 100 mg/m2 for 5 days MA mitoxantrone 6 mg/m2 for 3 days cytarabine 100 mg/m2 for 5 days DA daunorubicin 40 mg/m2 for 3 days cytarabine 100 mg/m2 for 5 days Methods

Maintenance Therapy RIF: 60 mg/kg, for14 days ATO : 0.16 mg per kg, for14 days ATRA: 25 mg/m2, for14 days Methods

Endpoints Primary endpoint: `Disease-Free Survival (DFS) Second endpoints: Complete remission (CR) Overall survival (OS) Safety Methods

Trial Profile of APL07 Methods

Patients Characteristics RIF group ATO group Characteristic (n=114) (n=117) p Age (yr) 33(15-60)39(15-60) ns Median (range) Sex （ M/F) 61/5365/52 ns WBC (10 9 /L) 2.1( )2.2( ) ns Median (range) PLT(10 9 /L) 29(5-333)31(5-164) ns Median (range) Sanz Score ns Low-risk3339 Intermediate-risk6053 High-risk2125 Blasts (BM)(%) 82(35-96) 81(19-96) ns Results

Outcome of RIF and ATO RIF group ATO group (n=114) (n=117) Outcome No.% % P CR Induction failure Dead13 no CR00 DFS Living in CR112 Death during CR01 Relapse11 OS Living113 Dead 1 4 Results

Disease-Free Survival 99.0% ( 3ys) 98.2% (3ys) Results

Overall Survival 99.1% ( 3ys) 96.6% ( 3ys) Results

Molecular Kinetics RIFATO Results

Similar liver toxicity Results RIFATORIFATO Induction Maintenance

Similar differentiation syndrome RIFATO 19% 25%

Conclusions Oral arsenic achieves similar efficacy and safety when compared to intravenous arsenic trioxide Our results suggest that arsenic/ATRA/ chemo combination might be an alternative to current frontline treatment of APL