Breakthroughs in the treatment of
acute promyelocytic leukemia:
curable disease with retinoic and
arsenic
Jiong HU
Shangha...
1. Treatment of APL: view of guidelines
2. Recent studies for optimization
- Role of arsenic as upfront treatment
- ATRA+a...
Treatment of APL: view of guidelines
ELN guideline / NCCN guideline / Consensus of CSH:
- Induction: simultaneous administ...
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 plate...
1. Treatment of APL: view of guidelines
2. Recent studies for optimization
- Role of arsenic as upfront treatment
- ATRA+a...
Optimization: role of upfront arsenic
Rationale:
- Clinical evidence:
efficacy in relapse patients: high remission rate wi...
Arsenic as Induction and maintenance therapy:
- Induction:
ATRA 25mg/m2
/d, given orally , until CR
As2
O3
0.16mg/kg/d , i...
Follow-up data – 85 patients with
ATRA+ATO: Survival at 70 months
Overall survival Event-free survival
n=85, 91.7±3.0% n=8...
Follow-up data – 80 patients with ATRA+ATO
entered CR: Survival at 70 months
Overall survival Relapse-free survival
n=80, ...
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...
North American Leukemia Intergroup
Study C9710 (NCT00003934)
Powell BL, Blood First Edition Paper, DOI 10.1182/blood-2010-...
North American Leukemia Intergroup
Study C9710 (NCT00003934)
Powell BL, Blood First Edition Paper, DOI 10.1182/blood-2010-...
• Arsenic as induction and post-remission therapy
- ATRA + ATO ± gemtuzumab ozogamicin (GO) (high-risk
disease: WBC ≥ 10 x...
1. Treatment of APL: view of guidelines
2. Recent studies for optimization
- Role of arsenic as upfront treatment
- ATRA+a...
ATRA+arsenic without chemotherapy
• “appealing concept” of curative regimen by target therapy
only in leukemia
• avoid the...
ATRA+arsenic without chemotherapy
Rationales:
- ATRA and arsenic synergy in targeting APL
targeting PML-RARA
upregulation ...
Importance of ATRA/ATO vs. ATRA/chemo?
Synergy of ATO and ATRA eradicate leukemia
initiating cells (LIC)
• ATRA and ATO di...
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):1570-15...
ATRA/ATO reduce significantly use of
chemotherapy: Australian APML4 study
2-year relapse-free survival 97.5%; failure-free...
ATRA/ATO reduce significantly use of
chemotherapy: Australian APML4 study
Superior to APML3 trial: ATRA+Ida in induction; ...
ATRA + ATO vs AIDA in newly-diagnosed
non high-risk APL: Gimema-SAL-AMLSG
ASH 2012, Plenary Scientific Session
• Phase III...
ATRA + ATO vs AIDA in newly-diagnosed
non high-risk APL: Gimema-SAL-AMLSG
ASH 2012, Plenary Scientific Session
ATRA+ATO AI...
ASH 2012, Plenary Scientific Session
ATRA + ATO vs AIDA in newly-diagnosed
non high-risk APL: Gimema-SAL-AMLSG
For newly d...
ATRA/ATO with or without chemotherapy in
newly-diagnosed APL in China
• Chinese 863 Key program study
• Multiple-center ra...
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+a...
Oral Arsenic trioxide: Hong Kong
Au WY et al. Blood. 2011;118(25):6535-6543
• Retrospective analysis of 76 APL in 1st
CR
•...
Oral Arsenic trioxide: Hong Kong
Au WY et al. Blood. 2011;118(25):6535-6543
• Toxicities observed in maintenance:
- headac...
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
HA
ATRA +As2O3
ATRA+As4S4
DA
MA...
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...
Oral As4S4 iv ATO p
n=112 n=121
CR 98% 98% >0.05
Time to CR 30 days 29 days >0.05
PML/RARα level
CR 15.0% 2.1% <0.05
End c...
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 for...
1. Treatment of APL: view of guidelines
2. Recent studies for optimization
- Role of arsenic as upfront treatment
- ATRA+a...
Arsenic as front-line treatment for newly-
diagnosed APL
SIH
*
MD
Anderson
**
North
American
Intergroup**
APML4 * GIMEMA
I...
• arsenic + ATRA: mainstay of upfront treatment for newly-
diagnosed APL
• Oral arsenic: better tolerance and convenience
...
Acknowledgements
• Prof Zhen-yi Wang; Zhu Chen and Sai-juan Chen;
Zhi-xiang Shen; Jun-min Li and colleagues at
Shanghai In...
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Breakthroughs in the treatment of acute promyelocytic leukemia: curable disease with retinoic and arsenic

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Breakthroughs in the treatment of acute promyelocytic leukemia: curable disease with retinoic and arsenic

  1. 1. 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
  2. 2. 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
  3. 3. 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
  4. 4. Treatment of APL: view of guidelines Tallman M, Blood 2009;114(25):5126
  5. 5. 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
  6. 6. 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
  7. 7. 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
  8. 8. Arsenic as Induction and maintenance therapy: - Induction: ATRA 25mg/m2 /d, given orally , until CR As2 O3 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 As2 O3 : 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
  9. 9. 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
  10. 10. Follow-up data – 80 patients with ATRA+ATO entered CR: Survival at 70 months Overall survival Relapse-free survival n=80, 97.4±1.8% n=80, 94.8±2.5% Hu J, PNAS 2009;106:3342
  11. 11. Arsenic concentration 2 years after the treatment Hu J, PNAS 2009;106:3342
  12. 12. North American Leukemia Intergroup Study C9710 (NCT00003934) Arsenic as consolidation Powell BL, Blood First Edition Paper, DOI 10.1182/blood-2010-02-269621
  13. 13. North American Leukemia Intergroup Study C9710 (NCT00003934) Powell BL, Blood First Edition Paper, DOI 10.1182/blood-2010-02-269621
  14. 14. North American Leukemia Intergroup Study C9710 (NCT00003934) Powell BL, Blood First Edition Paper, DOI 10.1182/blood-2010-02-269621
  15. 15. • 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
  16. 16. 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
  17. 17. ATRA+arsenic without chemotherapy • “appealing concept” of curative regimen by target therapy only in leukemia • avoid the potential toxicity of chemotherapy
  18. 18. 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
  19. 19. Importance of ATRA/ATO vs. ATRA/chemo? Synergy of ATO and ATRA eradicate leukemia initiating cells (LIC) • ATRA and ATO directly target PML/RARα by RARA moiety of the fusion and PML part • ATRA-ATO synergizes for PML/RARα induced differentiation and apoptosis which has a major role in debulking of the leukemia cells • degradation PML-RARα rapidly clears leukemia initiating cells (LIC), resulting in APL eradication in murine APL models • Bortezomib blocked PML-RARα degradation and reversed the curative effect of the ATRA + ATO Nasr R, Nat Med. 2008;14:1333 and Clin Cancer Res 2009 Oct 6.
  20. 20. Synergy of ATO and ATRA eradicate leukemia initiating cells (LIC) Scott Kogan, Cancer Cell 2009;15:7
  21. 21. 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
  22. 22. 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
  23. 23. 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
  24. 24. 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
  25. 25. 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)
  26. 26. 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.
  27. 27. 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
  28. 28. ATRA/ATO with or without chemotherapy in newly-diagnosed APL in China
  29. 29. 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
  30. 30. 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
  31. 31. 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%
  32. 32. Au WY et al. Blood. 2011;118(25):6535-6543 Oral Arsenic trioxide: Hong Kong
  33. 33. Oral Realgar-Indigo Naturalis Formula (As4S4) vs. ATO: Multi-Center Randomized Trial APL07 HA ATRA +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
  34. 34. 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
  35. 35. Oral As4S4 iv ATO p n=112 n=121 CR 98% 98% >0.05 Time to CR 30 days 29 days >0.05 PML/RARα 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 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
  36. 36. 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.
  37. 37. 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
  38. 38. 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
  39. 39. • 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
  40. 40. 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
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