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; 99:3136Xiang Y, et al. Chin J Clin Hematol 2007;16:204Wang L, et al. PNAS 2008;105:4826

Intravenous arsenic Oral 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-12002151)

• Enrollment :2007.11 to 2011.09

• Last follow-up: 2012.09 (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; 99:3136Xiang Y, et al. Chin J Clin Hematol 2007;16:204Wang L, et al. PNAS 2008;105:4826

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

Methods

Trial Design

HA: homoharringtonine ; cytarabineMA: mitoxantrone ; cytarabineDA: daunorubicin ; cytarabine

RIF: Realgar-Indigo naturalis formula ATO: Arsenic trioixideATRA: 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) 61/53 65/52 ns

WBC　(109/L)　

2.1(0.3-50.0) 2.2(0.3-50.0)

　　　　　　　　　　　　　

　　　　　　　　　ns

Median (range)

PLT(109/L)　

29(5-333) 31(5-164)

ns

Median (range)

Sanz　Score ns

Low-risk 33 39

Intermediate-risk 60 53

High-risk 21 25

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. % No. % P

CR 113 99.1 114 97.4 0.62

Induction failure 1 0.1 3 2.6 0.62

Dead 1 3

no CR 0 0

DFS 99.0 98.2 0.58

Living in CR 112 112

Death during CR 0 1

Relapse 1 1

OS 99.1 96.6 0.19

Living 113 113

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

RIF ATO

Results

Similar liver toxicity

Results

55%

10%

63%

12%

0%

10%

20%

30%

40%

50%

60%

70%

1 2

1-2 grade3-4 grade

RIF ATO

13%

0%

19%

0%

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

20%

1 2

1- 2 grade3- 4 grade

RIF ATOInduction Maintenance

Similar differentiation syndrome

0

5

10

15

20

25

1 2

RIF ATO

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