breakthroughs in the treatment of acute promyelocytic leukemia: curable disease with retinoic and...
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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;113:1875Chin 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: long-
term survival
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
Outcome from Shanghai Institute of Hematology
Follow-up data – 85 patients with ATRA+ATO: Survival at 70 months
Overall survival Event-free survival
n=85, 91.7±3.0% n=85, 89.2±3.4%
Hu J, PNAS 2009;106:3342
Follow-up data – 80 patients with ATRA+ATO entered CR: Survival at 70 months
Overall survival Relapse-free survival
n=80, 97.41.8% n=80, 94.82.5%
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
• 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
MDACC Study
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;14:1333and Clin Cancer Res 2009 Oct 6.
Synergy of ATO and ATRA eradicate leukemia initiating cells (LIC)
Scott Kogan, Cancer Cell 2009;15:7
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 reduce significantly use of chemotherapy: Australian APML4 study
Superior to APML3 trial: ATRA+Ida in induction; Ida/Ara-c+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
ASH 2012, Plenary Scientific Session
• 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
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.
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
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
Oral Arsenic trioxide: Hong Kong
Au WY et al. Blood. 2011;118(25):6535-6543
• 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
Oral Realgar-Indigo Naturalis Formula (As4S4) vs. ATO: Multi-Center Randomized Trial APL07
HAATRA +As2O3
ATRA+As4S4
DA
MA
As2O3 / ATRA
As4S4 / ATRA
Newly-diagnosed APL
Induction Consolidation Maintenance (2 years)
Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session
Oral As4S4 IV ATO p
Low-risk 33 40
Int-risk 58 55
High-risk 21 26
Subtotal 112 121 NS
北京大学人民医院 北京大学血液病研究所北京大学人民医院 北京大学血液病研究所
Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session
Oral As4S4 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
北京大学人民医院 北京大学血液病研究所北京大学人民医院 北京大学血液病研究所
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北京大学人民医院 北京大学血液病研究所
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.
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 newly-diagnosed 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
• arsenic + ATRA: mainstay of upfront treatment for newly-
diagnosed APL
• Oral arsenic: better tolerance and convenience
• Chemotherapy: based on risk stratification
Future therapy for newly-diagnosed 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