Acute Promyelocytic Leukemia

Treatment of acute promyelocytic
leukemia with ATRA and arsenic:
experience from China
Jiong HU
Shanghai Institute of Hematology, Department of
Hematology, Rui-Jin Hospital, Shanghai Jiao Tong
University School of Medicine

• Front-line therapy with ATRA
• Salvage therapy with arsenic
• Combination therapy with ATRA and arsenic
• Oral arsenic
• Future direction: APL therapy without
chemotherapy

Overview of APL
Clinical and molecular
features:
(A) severe bleeding tendency:
fibrinogenopenia and DIC
(B) promyelocytes in BM and
peripheral blood
(C) chromosomal translocation
t(15;17)(q22; q21)
(D) fusion transcripts PML-RAR
Blood 2008 Mar 1;111(5):2505-15.


Overview of APL treatment
• pre-ATRA period: chemotherapy
• ATRA:
- introduction of ATRA
- optimization of ATRA-chemo combination regimens
• Arsenic:
- introduction of ATO in relapsed APL
- ATRA/ATO combination as front-line therapy
- Oral arsenic

Chemotherapy
• Chemotherapy: anthracycline (DNR or Ida) + Ara-C:
- CR rates 70%~80% in newly diagnosed patients
- aggravation of bleeding syndrome: high early death rate
- relapse in large proportion of patients with median duration
of CR: 11~25 months
- long-term survival: 35% ~ 45%
• Recognition of APL as a highly fatal disease
Blood 2008 Mar 1;111(5):2505-15.

ATRA treatment in APL
(A) Isomers of retinoic acid
(B) ATRA induces terminal
differentiation of APL
(C) ATRA treatment leads to
elimination of PML-RAR–
positive cells by quantitative
real-time RT-PCR for
assessment of PML-RAR
transcript.
Blood 2008 Mar 1;111(5):2505-15.

 Pilot study in Shanghai Institute of Hematology (SIH)
- 1985~1988
- 24 APL patients: 16 newly diagnosed / 8 refractory disease
- ATRA: 45mg/m2 oral until response or max 60 days
- outcome:
23 achieved CR
differentiation syndrome
1 patient achieved CR by adding low-dose Ara-C
Blood 2008 Mar 1;111(5):2505-15.

Blood 2008 Mar 1;111(5):2505-15.
- Chemotherapy + ATRA:
anthracycline (Ida, DNR, Mitoxantrone, or HHT) and Ara-C
- Induction:
high remission rate
reduce differentiation syndrome
- Consolidation/maintenance:
3 monthly courses of anthracycline-based chemo/low-dose
maintenance (6-MP+MTX with ATRA)
5-year EFS/DFS: up to 70%

ATRA added to chemotherapy
improve outcome
Tallman M, Blood 2009;114(25):5126

Arsenic as salvage therapy
- arsenic developed as TCM in Northeastern China
- Harbin group(1992): iv 1% ATO
32 APL, 21 obtained CR
10-year survival 30%
- SIH(1996~1997):
47 relapsed and 11 newly diagnosed APL
CR rate of 85.1% and 72.7%
molecular remission documented ~60%
long-term survival in relapsed APL: 50~60%
Blood 2008 Mar 1;111(5):2505-15.

Treatment of APL: guidelines
ELN guideline / NCCN guideline / Consensus of CSH:
- Newly-diagnosed APL: simultaneous administration of ATRA
and anthracycline-based chemotherapy as standard
- Relapse disease: arsenic is the best option with or without
chemotherapy
Blood 2009;113:1875
Chin J Hematol 2010;31:69

Rationale of arsenic as front-line treatment
- efficacy in relapse patients: high remission rate with sizable
proportion of long-term survival
- efficacy in newly-diagnosed patients as single agent: long-term
survival observed

Synergy of ATRA and aarsenic in
degrading PML-RAR

ATRA increase aquaglyceroporin
9(AQP9) expression associated with
arsenic sensitivity
Relationship of AQP9 with arsenic uptake and sensitivity in leukemia cells. Blood 2007; 109: 740-746.

ATRA increase AQP9 expression
associated with arsenic sensitivity in
patients

Synergy of ATRA and arsenic in
eradicating leukemia stem cells
ATRA and arsenic synergy in targeting APL
- ATRA/Arsenic targeting PML-RAR
- ATRA  of expression of AQP9,  arsenic uptake
- Degradation PML-RAR rapidly clears LIC and eradication
in murine APL models; blocked PR degradation by
bortezomib reversed the curative effect of arsenic
Nasr R, Nat Med. 2008;14:1333
and Clin Cancer Res 2009 Oct 6.

Synergy of ATRA and Arsenic: mice
model
Scott Kogan, Cancer Cell 2009;15:7

SIH study:
Front-line therapy with ATRA + Arsenic

SIH study: Follow-up for all patients
n=85, 91.7±3.0% n=85, 89.2±3.4%
Overall survival at 70 months Event-free survival at 70 months
Hu J, PNAS 2009;106:3342

SIH study: Follow-up for patients in CR
n=80, 97.41.8% n=80, 94.82.5%
Overall survival at 70 months Relapse-free survival at 70 months
Hu J, PNAS 2009;106:3342

SIH study: safety of front-line arsenic therapy
Hu J, PNAS 2009;106:3342

Update of SIH study 2014
Zhu HM and Hu J, et al. Submitted

Update of SIH study 2014: all patients
Zhu HM and Hu J, et al. Submitted

MDACC Study: ATRA + Arsenic  GO
Ravandi F, J Clin Oncol 2009;27:504

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: benefit of arsenic in different risk groups
Arsenic: high vs. low
No arsenic: high vs. low
Powell BL, Blood First Edition Paper, DOI 10.1182/blood-2010-02-269621

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 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
CR 75/75 (100%) 75/79 (95%) 0.12
2 year EFS 97% (93.1-100) 86.7% (80.3-93.6) 0.03
Event 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
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

Summary of ATRA + arsenic combination
as front-line therapy
Median FU or
Estimate sur
Low/inter-mediate
High-risk
SIH 88 months OS 93~95%; RFS
90%
OS 89%; RFS 80%
MDACC 99 weeks OS ~85% OS ~60 %
North Am 3-year OS 83% OS 60%
APML4 2-year FFS 88~97% FFS 76%
GIMEMA 2 year DFS 97% /

Treatment of APL: guidelines
NCCN 2013 guideline:
- Newly-diagnosed APL: simultaneous administration of ATRA
and arsenic as standard

Develop of oral Arsenic trioxide in China: oral
arsenic trioxide
• 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

Develop of oral Arsenic trioxide in China: oral
arsenic trioxide
• 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

Develop of oral Arsenic trioxide in China:
Crystallized realgar (high-purity As4S4)
- Retrospective study:
- 50 mg/kg daily (750mg 4 times) until CR; post-remission pts: 2
weeks on and 2 weeks off in 1st year and every 2 months for 4
years
newly diagnosed Rel1 CR
No of pts 19 7 103
Follow-up 13.5 mths (2~40) / 23 mths(2~71)
Mol remission 14/16 5/7 35/44
1-year DFS 86.1% / 96.7%
3/6-year DFS 76.6% / 87.4%
Blood. 2002 May 1;99(9):3136-43.

Develop of oral Arsenic trioxide in China:
Crystallized realgar (high-purity As4S4)
Blood. 2002 May 1;99(9):3136-43.

Realgar-Indigo Naturalis Formula (RIF; As4S4)
vs. ATO: Multi-Center Randomized Trial APL07
Newly-diagnosed
APL
oral RIF (60 mg/kg) vs. ATO (0.16 mg/kg)
Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session

Realgar-Indigo Naturalis Formula (RIF) vs. ATO:
Multi-Center Randomized Trial APL07
Newly-diagnosed
APL

Realgar-Indigo Naturalis Formula (RIF) vs. ATO:
Multi-Center Randomized Trial APL07

Bei Jin University, Institute of Hematology
RIF iv ATO p
n=112 n=121
CR 98% 98% >0.05
Time to CR 30 days 29 days >0.05
PML/RAR level
CR 15.0% 2.1% <0.05
End consolidation 0 0 >0.05
Mol CR 100% 100% >0.05
Median Time to Mol CR 60 days 60 days >0.05
Relapse 0.9% 0.8% >0.05

Oral Realgar-Indigo naturalis formula yielded comparable
high remission and long-term survival with ATO in newly
diagnosed APL.

Ongoing study
• Chinese 863 Key program: multiple-center randomized study
• Newly-diagnosed APL
• Risk stratification: low/int-risk vs. high-risk
- Low/Int-risk: ATO replacing chemotherapy ?
- high- risk: ATO replace Ara-C
• 20 clinical centers: enrolled from Aug 2012 to Aug 2015

• Early death:
Two issues ……
- start ATRA in clinical suspected patients without morphology
confirmation
- start arsenic arsenic with morphological support
- management of differentiation syndrome
- best supportive care

Two issues ……
• Relapse/resistance to ATRA and Arsenic:
Xiao-jun Huang, Hong-hu Zhu, NEJM 2014

• Development of ATRA and arsenic treatment dramatically
improve the outcome of APL: curable disease
• arsenic + ATRA: mainstay of front-line treatment for newly-diagnosed
APL
• Arsenic + ATRA without chemo: promising outcome in low or
low/intermediate risk pts
• Importance of chemotherapy remain in high-risk group
• Oral arsenic: better tolerance/convenience and comparable
efficacy
Summary

… future direction …
Oral ATRA and oral arsenic as curable regimen
(for low/Int risk APL)

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

Acute Promyelocytic Leukemia

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