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Treatment of APL: view of guidelines 2. Recent studies for optimization

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. Treatment of APL: view of guidelines

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Treatment of APL: view of guidelines 2. Recent studies for optimization

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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. 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. 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 Risk Stratification Sanz MA, Blood. 2000;96:1247

  6. 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. Outcome from Shanghai Institute of Hematology • 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

  9. n=85, 91.7±3.0% n=85, 89.2±3.4% Follow-up data – 85 patients with ATRA+ATO: Survival at 70 months Overall survival Event-free survival Hu J, PNAS 2009;106:3342

  10. n=80, 94.82.5% n=80, 97.41.8% Follow-up data – 80 patients with ATRA+ATO entered CR: Survival at 70 months Overall survival Relapse-free survival 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. MDACC Study • 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

  16. 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/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;14:1333 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. 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

  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 • 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      ASH 2012, Plenary Scientific Session

  25. 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) ASH 2012, Plenary Scientific Session

  26. 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

  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. 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 • 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

  31. Oral Arsenic trioxide: Hong Kong • 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

  32. Oral Arsenic trioxide: Hong Kong Au WY et al. Blood. 2011;118(25):6535-6543

  33. Oral Realgar-Indigo Naturalis Formula (As4S4) vs. ATO: Multi-Center Randomized Trial APL07 HA As2O3 / ATRA ATRA +As2O3 Newly-diagnosed APL MA ATRA+As4S4 As4S4 / ATRA DA Induction Consolidation Maintenance (2 years) Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session

  34. 北京大学人民医院 北京大学血液病研究所 Oral As4S4iv ATOp n=112 n=121 CR 98% 98% >0.05 Time to CR 30 days29 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 days60 days>0.05 Relapse 0.9% 0.8% >0.05 Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session

  35. 北京大学人民医院 北京大学血液病研究所 Oral Realgar-Indigo naturalis formula yielded comparable high remission and long-term survival with ATO in newly diagnosed APL. Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session

  36. 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

  37. Arsenic as front-line treatment for newly-diagnosed APL *Dose: 0.16mg/kg/day D1-28; **Dose: 0.15mg/kg/day Monday through Friday of 4 weeks

  38. Future therapy for newly-diagnosed APL • arsenic + ATRA: mainstay of upfront treatment for newly-diagnosed APL • Oral arsenic: better tolerance and convenience • Chemotherapy: based on risk stratification

  39. 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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