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Hong-Hu Zhu, De-Pei Wu, Jie Jin, Jian-Yong Li, Jun Ma,

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,

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Hong-Hu Zhu, De-Pei Wu, Jie Jin, Jian-Yong Li, Jun Ma,

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  1. Oral tetra-arsenic tetra-sulphide formulaachieved 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.

  2. Arsenic plays a key role in cure of APL Introduction (ATO: arsenic trioxide) 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

  3. Intravenous vs. Oral arsenic Introduction Intravenous arsenic Oral arsenic • Effective • convenient : oral • Outpatients 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 Effective inconvenient : iv Inpatients

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

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

  6. Methods Design • Chinese APL Cooperative Group(7Centers) • Multicenter, randomised controlled trial: APL07 (registered number ChiCTR -TRC-12002151) • Enrollment :2007.11 to 2011.09 • Last follow-up: 2012.09 (median 32 months)

  7. 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

  8. Methods Inclusion Criteria • de novo APL • Age :15-60 years • WBC <50×109/L before treatment • Adequate hepatic and renal function • Performance Status score 0-2 • Able to provide written informed consent

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

  10. 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

  11. 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

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

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

  14. Methods Trial Profile of APL07

  15. Results Patients Characteristics

  16. Results Outcome of RIF and ATO

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

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

  19. RIF ATO Results Molecular Kinetics

  20. RIF ATO RIF ATO Induction Maintenance Results Similar liver toxicity

  21. 25% 19% RIF ATO Similar differentiation syndrome

  22. Conclusions • Oral arsenicachieves 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

  23. Thank You

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