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