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Jan 15, 2015
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
Blood 2008 Mar 1;111(5):2505-15.
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
Overview of APL
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%
Blood 2008 Mar 1;111(5):2505-15.
• Recognition of APL as a highly fatal disease
ATRA treatment in APL
Blood 2008 Mar 1;111(5):2505-15.
(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
ATRA treatment in APL
Blood 2008 Mar 1;111(5):2505-15.
ATRA treatment in APL- 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;113:1875Chin 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
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;14:1333and Clin Cancer Res 2009 Oct 6.
Synergy of ATRA and arsenic in eradicating leukemia stem cells
Synergy of ATRA and Arsenic: mice model
Scott Kogan, Cancer Cell 2009;15:7
SIH study: Front-line therapy with ATRA + Arsenic
Overall survival at 70 months Event-free survival at 70 months
n=85, 91.7±3.0% n=85, 89.2±3.4%
Hu J, PNAS 2009;106:3342
SIH study: Follow-up for all patients
Overall survival at 70 months Relapse-free survival at 70 months
n=80, 97.41.8% n=80, 94.82.5%
Hu J, PNAS 2009;106:3342
SIH study: Follow-up for patients in CR
Hu J, PNAS 2009;106:3342
SIH study: safety of front-line arsenic therapy
Update of SIH study 2014
Zhu HM and Hu J, et al. Submitted
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
Update of SIH study 2014
Update of SIH study 2014
Ravandi F, J Clin Oncol 2009;27:504
MDACC Study: ATRA + Arsenic GO
Ravandi F, J Clin Oncol 2009;27:504
MDACC Study: ATRA + Arsenic GO
North American Leukemia Intergroup Study C9710 (NCT00003934)
Powell BL, Blood First Edition Paper, DOI 10.1182/blood-2010-02-269621
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
No arsenic: high vs. low
Arsenic: high vs. low
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
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
ASH 2012, Plenary Scientific Session
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
• 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)
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.
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
Au WY et al. Blood. 2011;118(25):6535-6543
• 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%
Blood. 2002 May 1;99(9):3136-43.
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%
- 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
Develop of oral Arsenic trioxide in China: Crystallized realgar (high-purity As4S4)
Blood. 2002 May 1;99(9):3136-43.
Develop of oral Arsenic trioxide in China: Crystallized realgar (high-purity As4S4)
Realgar-Indigo Naturalis Formula (RIF; As4S4) vs. ATO: Multi-Center Randomized Trial APL07
Newly-diagnosed APL
Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session
oral RIF (60 mg/kg) vs. ATO (0.16 mg/kg)
Realgar-Indigo Naturalis Formula (RIF) vs. ATO: Multi-Center Randomized Trial APL07
Newly-diagnosed APL
Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session
Realgar-Indigo Naturalis Formula (RIF) vs. ATO: Multi-Center Randomized Trial APL07
RIF iv ATO p n=112 n=121
CR 98% 98% >0.05Time 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% >0.05Median Time to Mol CR 60 days 60 days >0.05 Relapse 0.9% 0.8% >0.05
Bei Jin University, Institute of Hematology
Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session
Bei Jin University, Institute of Hematology
Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session
Bei Jin University, Institute of Hematology
Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session
Oral Realgar-Indigo naturalis formula yielded comparable high remission and long-term survival with ATO in newly
diagnosed APL.
Bei Jin University, Institute of Hematology
Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session
• 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
Ongoing study
• Early death:
- 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:
Two issues ……
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
Oral ATRA and oral arsenic as curable regimen
(for low/Int risk APL)
… future direction …
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