Breakthroughs in the treatment of
acute promyelocytic leukemia:
curable disease with retinoic and
arsenic
Jiong HU
Shanghai Institute of Hematology, Department of Hematology,
Rui-Jin Hospital, Shanghai Jiao Tong University School of
Medicine
1. Treatment of APL: view of guidelines
2. Recent studies for optimization
- Role of arsenic as upfront treatment
- ATRA+arsenic with or without chemotherapy
- Oral formula of arsenic
3. Perspectives
Treatment of APL: view of guidelines
ELN guideline / NCCN guideline / Consensus of CSH:
- Induction: simultaneous administration of ATRA and
anthracycline-based chemotherapy as standard
- Relapse: Arsenic as the best treatment option
Blood 2009;113:1875
Chin J Hematol 2010;31:69
Treatment of APL: view of guidelines
Tallman M, Blood 2009;114(25):5126
Risk Stratification
RFS outcome
• Low risk: WBC <10,000
and platelets >40,000
• Intermediate risk : WBC
< 10,000 and platelets <
40,000
• High risk: WBC > 10,000
Sanz MA, Blood. 2000;96:1247
1. Treatment of APL: view of guidelines
2. Recent studies for optimization
- Role of arsenic as upfront treatment
- ATRA+arsenic with or without chemotherapy
- Oral formula of arsenic
3. Summary
Optimization: role of upfront arsenic
Rationale:
- Clinical evidence:
efficacy in relapse patients: high remission rate with sizable
proportion of long-term survival
efficacy in newly-diagnosed patients as single agent: longterm survival
Outcome from Shanghai Institute of Hematology
Arsenic as Induction and maintenance therapy:
- Induction:
ATRA 25mg/m2/d, given orally，until CR
As2O3 0.16mg/kg/d，iv drip until CR
chemotherapy added to control hyperleukocytosis
- Consolidation therapy: DA, ID-Ara-C, HA
- Maintenance: 3 months of sequential use of RA/Arsenic/chemo
ATRA:25mg/m2/d,given orally for 15-30 days
As2O3: 0.16mg/m2/d for 28 days
6-mercaptopurine (6-MP): 100mg/d for 30 days
or Methotrexate 15mg, once a week, for 4 weeks
Follow-up data – 85 patients with
ATRA+ATO: Survival at 70 months
n=85, 91.7±3.0%
Overall survival
n=85, 89.2±3.4%
Event-free survival
Hu J, PNAS 2009;106:3342
Follow-up data – 80 patients with ATRA+ATO
entered CR: Survival at 70 months
n=80, 97.41.8%
Overall survival
n=80, 94.82.5%
Relapse-free survival
Hu J, PNAS 2009;106:3342
Arsenic concentration 2 years after the treatment
Hu J, PNAS 2009;106:3342
North American Leukemia Intergroup
Study C9710 (NCT00003934)
Arsenic as consolidation
Powell BL, Blood First Edition Paper, DOI 10.1182/blood-2010-02-269621
North American Leukemia Intergroup
Study C9710 (NCT00003934)
Powell BL, Blood First Edition Paper, DOI 10.1182/blood-2010-02-269621
North American Leukemia Intergroup
Study C9710 (NCT00003934)
Powell BL, Blood First Edition Paper, DOI 10.1182/blood-2010-02-269621
MDACC Study
• Arsenic as induction and post-remission therapy
- ATRA + ATO  gemtuzumab ozogamicin (GO) (high-risk
disease: WBC  10 x 109/L)
- 75 / 82 achieved CR (92%), 7 death
- Median follow-up: 99 weeks (2 - 282)
- 3 relapse (39, 52, 53 weeks)
- 3 death (14, 21, 71 weeks; all due to secondary malignancies)
- estimated 3-year OS: 85%
Ravandi F, J Clin Oncol,2009;27:504
1. Treatment of APL: view of guidelines
2. Recent studies for optimization
- Role of arsenic as upfront treatment
- ATRA+arsenic combination with or
without chemotherapy
- Oral formula of arsenic
3. Summary
ATRA+arsenic without chemotherapy
• “appealing concept” of curative regimen by target therapy
only in leukemia
• avoid the potential toxicity of chemotherapy
ATRA+arsenic without chemotherapy
Rationales:
- ATRA and arsenic synergy in targeting APL
targeting PML-RARA
upregulation of expression of AQP9 and arsenic uptake
animal data
potentially targeting FLT-3
- Arsenic targeting LSC/LIC
Importance of ATRA/ATO vs. ATRA/chemo?
Synergy of ATO and ATRA eradicate leukemia
initiating cells (LIC)
• ATRA and ATO directly target PML/RAR by RARA
moiety of the fusion and PML part
• ATRA-ATO
synergizes
for
PML/RAR
induced
differentiation and apoptosis which has a major role in
debulking of the leukemia cells
• degradation PML-RAR rapidly clears leukemia initiating
cells (LIC), resulting in APL eradication in murine APL
models
• Bortezomib blocked PML-RAR degradation and reversed
the curative effect of the ATRA + ATO
Nasr R, Nat Med. 2008;14:1333
and Clin Cancer Res 2009 Oct 6.
Synergy of ATO and ATRA eradicate
leukemia initiating cells (LIC)
Scott Kogan, Cancer Cell 2009;15:7
ATRA/ATO reduce significantly use of
chemotherapy: Australian APML4 study
3 cycles of ATRA + ATO in induction/consolidation; 1 cycle
of idarubicin in induction
Iland HJ, Blood. 2012;120(8):1570-1580
ATRA/ATO reduce significantly use of
chemotherapy: Australian APML4 study
2-year relapse-free survival 97.5%; failure-free survival
88.1%, and overall survival 93.2%.
Iland HJ, Blood. 2012;120(8):1570-1580
ATRA/ATO reduce significantly use of
chemotherapy: Australian APML4 study
Superior to APML3 trial: ATRA+Ida in induction; Ida/Arac+VP-16 consolidaiton; ATRA+MTX-6-MP maintenance
Iland HJ, Blood. 2012;120(8):1570-1580
ATRA + ATO vs AIDA in newly-diagnosed
non high-risk APL: Gimema-SAL-AMLSG
• Phase III, randomized study
•Treatment:
- ATO 0.15/kg + ATRA 45mg/m2 induction --- ATO 5 days/week
(4 weeks on/off) 4 courses + ATRA (2 weeks on/off) 7 courses
- AIDA: ATRA+Ida induction --- 3 cycles of anthracycline +
ATRA consolidation --- low dose CHT + ATRA maintenance
• Primary endpoint: 2-year EFS
• Secondary endpoints: OS, DFS, CIR rates, molecular response
and toxicity profile
ASH 2012, Plenary Scientific Session
ATRA + ATO vs AIDA in newly-diagnosed
non high-risk APL: Gimema-SAL-AMLSG
• Patients:
-162 enrolled 154 evaluable
- median age 45.3(18.7-70.2); median WBC 1.50 x 109/L
- risk: 61.8% intermediate and 38.2% low-risk
- median FU: 31 months (range 0.07-50.4)
ATRA+ATO
AIDA
P
75/75 (100%)
75/79 (95%)
0.12
97% (93.1-100)
86.7% (80.3-93.6)
0.03
1 death in CR; 2 rel
7 deaths (4 ED/3 in CR) ; 4 rel
OS
98.7%
91.1%
0.03
DFS
97%
91.6% (P=0.19)
0.19
CIR
1.6%
4.3%
0.41
CR
2 year EFS
Event
ASH 2012, Plenary Scientific Session
ATRA + ATO vs AIDA in newly-diagnosed
non high-risk APL: Gimema-SAL-AMLSG
For newly diagnosed non-high-risk APL, the front-line
chemo-free ATO+ATRA therapy is at least not inferior to
AIDA in terms of 2 year EFS.
ASH 2012, Plenary Scientific Session
ATRA/ATO with or without chemotherapy in
newly-diagnosed APL in China
•
•
•
•
Chinese 863 Key program study
Multiple-center randomized study
Newly-diagnosed APL
Risk stratification: low-risk vs. int/high-risk
- Low-risk: ATO replacing chemotherapy
- Int or high- risk: ATO reduce chemotherapy (Ara-C)
• 20 clinical centers enrolled from Aug 2012 to Aug 2015
ATRA/ATO with or without chemotherapy in
newly-diagnosed APL in China
1. Treatment of APL: view of guidelines
2.
Recent studies for optimization
- Role of arsenic as upfront treatment
- ATRA+arsenic without chemotherapy
- Oral formula of arsenic
3. Summary
Oral Arsenic trioxide: Hong Kong
• Retrospective analysis of 76 APL in 1st CR
• Treatment:
- Induction/consolidation: daunorubicin and Ara-C
- Maintenance: oral arsenic trioxide based regimen
oral ATO (10 mg/day);
oral ATO + ATRA(45mg/m2);
oral ATO+ATRA+ascorbic acid (1000 mg/day)
given 2 weeks every 2 months for 2 years
Au WY et al. Blood. 2011;118(25):6535-6543
Oral Arsenic trioxide: Hong Kong
• Toxicities observed in maintenance:
- headache, dyspepsia, reversible liver function abnormality
and herpes zoster reactivation
- QT prolongation not significant
• Median follow-up of 24 months (range, 1-115 months):
- relapse only in 8 patients
- 3-year LFS and OS: 87.7% and 90.6%
Au WY et al. Blood. 2011;118(25):6535-6543
Oral Arsenic trioxide: Hong Kong
Au WY et al. Blood. 2011;118(25):6535-6543
Oral Realgar-Indigo Naturalis Formula (As4S4)
vs. ATO: Multi-Center Randomized Trial APL07
ATRA +As2O3
Newlydiagnosed APL
HA
As2O3 / ATRA
MA
ATRA+As4S4
DA
Induction
Consolidation
As4S4 / ATRA
Maintenance (2 years)
Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session
北京大学人民医院 北京大学血液病研究所
CR
Time to CR
PML/RAR level
CR
End consolidation
Mol CR
Median Time to Mol CR
Relapse
Oral As4S4
n=112
iv ATO
n=121
p
98%
30 days
98%
29 days
>0.05
>0.05
15.0% 2.1%
0
100%
60 days
0.9%
<0.05
0
100%
60 days
0.8%
>0.05
>0.05
>0.05
>0.05
Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session
北京大学人民医院 北京大学血液病研究所
Oral Realgar-Indigo naturalis formula yielded comparable
high remission and long-term survival with ATO in newly
diagnosed APL.
Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session
1. Treatment of APL: view of guidelines
2.
Recent studies for optimization
- Role of arsenic as upfront treatment
- ATRA+arsenic without chemotherapy
- Oral formula of arsenic
3. Summary
Arsenic as front-line treatment for newlydiagnosed APL
SIH
*
MD
Anderson
**
North
American
Intergroup**
APML4 * GIMEMA
**
Induction
Conso
Maint
+
+
+
+
-
+
-
+
+
-
+
+
+
Total cycles
6
5
2
3
5
*Dose: 0.16mg/kg/day D1-28;
**Dose: 0.15mg/kg/day Monday through Friday of 4 weeks
Future therapy for newly-diagnosed
APL
• arsenic + ATRA: mainstay of upfront treatment for newlydiagnosed APL
• Oral arsenic: better tolerance and convenience
• Chemotherapy: based on risk stratification
Acknowledgements
• Prof Zhen-yi Wang; Zhu Chen and Sai-juan Chen;
Zhi-xiang Shen; Jun-min Li and colleagues at
Shanghai Institute of Hematology, Department of
Hematology, RuiJin Hospital