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

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  • 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. 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. 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. Treatment of APL: view of guidelines Tallman M, Blood 2009;114(25):5126
  • 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. 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. 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. 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. 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. 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. Arsenic concentration 2 years after the treatment Hu J, PNAS 2009;106:3342
  • 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. North American Leukemia Intergroup Study C9710 (NCT00003934) Powell BL, Blood First Edition Paper, DOI 10.1182/blood-2010-02-269621
  • 14. North American Leukemia Intergroup Study C9710 (NCT00003934) Powell BL, Blood First Edition Paper, DOI 10.1182/blood-2010-02-269621
  • 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. 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. ATRA+arsenic without chemotherapy • “appealing concept” of curative regimen by target therapy only in leukemia • avoid the potential toxicity of chemotherapy
  • 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. 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. Synergy of ATO and ATRA eradicate leukemia initiating cells (LIC) Scott Kogan, Cancer Cell 2009;15:7
  • 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. 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. 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. 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. 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. 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. 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. ATRA/ATO with or without chemotherapy in newly-diagnosed APL in China
  • 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. 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. 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. Au WY et al. Blood. 2011;118(25):6535-6543 Oral Arsenic trioxide: Hong Kong
  • 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. 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. 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. 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. 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. 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. • 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. 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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