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.
Introduction
Arsenic plays a key role in cure of APL
(ATO: arsenic trioxide)
Chen SJ, et al. Blood 2011;117:6425
Hu J, et al. PNAS 2009;106:3342
Shen ZX, et al. PNAS 2004;101:5328
Sanz MA, et al. Blood 2010;115:5137
Introduction
Intravenous vs. Oral arsenic
Intravenous arsenic
Oral arsenic
• Effective
• Effective
•
• convenient : oral
inconvenient : iv
• Inpatients
• 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
Introduction
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
Methods
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; 99:3136
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 <50×109/L before treatment
Adequate hepatic and renal function
Performance Status score 0-2
Able to provide written informed consent
Methods
Trial Design
RIF: Realgar-Indigo naturalis formula
ATO: Arsenic trioixide
ATRA: all-trans retinoic acid
HA: homoharringtonine ; cytarabine
MA: mitoxantrone ; cytarabine
DA: daunorubicin ; cytarabine
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
Results
Patients Characteristics
Characteristic
RIF group
ATO group
(n=114)
(n=117)
ns
Age (yr)
Median (range)
Sex（M/F)
33(15-60)
39(15-60)
61/53
65/52
WBC (109/L)
Median (range)
ns
ns
2.1(0.3-50.0)
2.2(0.3-50.0)
ns
PLT(109/L)
Median (range)
p
29(5-333)
31(5-164)
ns
Sanz Score
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
1
0.1
3
2.6
0.62
98.2
0.58
96.6
0.19
Induction failure
Dead
1
3
no CR
0
0
DFS
99.0
Living in CR
112
112
Death during CR
0
1
Relapse
1
1
OS
99.1
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
70%
19%
63%
20%
18%
55%
60%
16%
50%
40%
1-2 grade
3-4 grade
30%
12%
10%
20%
8%
6%
10%
2%
0%
0%
2
ATO
Induction
1-2 grade
3-4 grade
10%
4%
1
RIF
13%
14%
12%
0%
1
RIF
0%
2
ATO
Maintenance
Similar differentiation syndrome
25
20
15
19%
25%
10
5
0
1
RIF
2
ATO
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