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Acute Promyelocytic Leukemia

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Three major advancements in the field of acute promyelocytic leukemia treatment in the 21st century
Jiong Hu, MD

Published in: Health & Medicine
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Acute Promyelocytic Leukemia

  1. 1. 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
  2. 2. • Front-line therapy with ATRA • Salvage therapy with arsenic • Combination therapy with ATRA and arsenic • Oral arsenic • Future direction: APL therapy without chemotherapy
  3. 3. Overview of APL 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 Blood 2008 Mar 1;111(5):2505-15. 
  4. 4. 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
  5. 5. 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% • Recognition of APL as a highly fatal disease Blood 2008 Mar 1;111(5):2505-15.
  6. 6. ATRA treatment in APL (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.
  7. 7. ATRA treatment in APL  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 Blood 2008 Mar 1;111(5):2505-15.
  8. 8. ATRA treatment in APL Blood 2008 Mar 1;111(5):2505-15. - 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%
  9. 9. ATRA added to chemotherapy improve outcome Tallman M, Blood 2009;114(25):5126
  10. 10. 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.
  11. 11. 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;113:1875 Chin J Hematol 2010;31:69
  12. 12. 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
  13. 13. Synergy of ATRA and aarsenic in degrading PML-RAR
  14. 14. 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.
  15. 15. ATRA increase AQP9 expression associated with arsenic sensitivity in patients
  16. 16. Synergy of ATRA and arsenic in eradicating leukemia stem cells 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;14:1333 and Clin Cancer Res 2009 Oct 6.
  17. 17. Synergy of ATRA and Arsenic: mice model Scott Kogan, Cancer Cell 2009;15:7
  18. 18. SIH study: Front-line therapy with ATRA + Arsenic
  19. 19. SIH study: Follow-up for all patients n=85, 91.7±3.0% n=85, 89.2±3.4% Overall survival at 70 months Event-free survival at 70 months Hu J, PNAS 2009;106:3342
  20. 20. SIH study: Follow-up for patients in CR n=80, 97.41.8% n=80, 94.82.5% Overall survival at 70 months Relapse-free survival at 70 months Hu J, PNAS 2009;106:3342
  21. 21. SIH study: safety of front-line arsenic therapy Hu J, PNAS 2009;106:3342
  22. 22. Update of SIH study 2014 Zhu HM and Hu J, et al. Submitted
  23. 23. Update of SIH study 2014 Zhu HM and Hu J, et al. Submitted
  24. 24. Update of SIH study 2014: all patients Zhu HM and Hu J, et al. Submitted
  25. 25. Update of SIH study 2014
  26. 26. Update of SIH study 2014
  27. 27. MDACC Study: ATRA + Arsenic  GO Ravandi F, J Clin Oncol 2009;27:504
  28. 28. MDACC Study: ATRA + Arsenic  GO Ravandi F, J Clin Oncol 2009;27:504
  29. 29. North American Leukemia Intergroup Study C9710 (NCT00003934) Powell BL, Blood First Edition Paper, DOI 10.1182/blood-2010-02-269621
  30. 30. North American Leukemia Intergroup Study C9710: benefit of arsenic in different risk groups Arsenic: high vs. low No arsenic: high vs. low Powell BL, Blood First Edition Paper, DOI 10.1182/blood-2010-02-269621
  31. 31. 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
  32. 32. 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
  33. 33. 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) 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 ASH 2012, Plenary Scientific Session
  34. 34. 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
  35. 35. 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% /
  36. 36. Treatment of APL: guidelines NCCN 2013 guideline: - Newly-diagnosed APL: simultaneous administration of ATRA and arsenic as standard
  37. 37. Develop of oral Arsenic trioxide in China: oral arsenic trioxide • 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
  38. 38. 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% Au WY et al. Blood. 2011;118(25):6535-6543
  39. 39. Develop of oral Arsenic trioxide in China: Crystallized realgar (high-purity As4S4) - 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 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% Blood. 2002 May 1;99(9):3136-43.
  40. 40. Develop of oral Arsenic trioxide in China: Crystallized realgar (high-purity As4S4) Blood. 2002 May 1;99(9):3136-43.
  41. 41. Realgar-Indigo Naturalis Formula (RIF; As4S4) vs. ATO: Multi-Center Randomized Trial APL07 Newly-diagnosed APL oral RIF (60 mg/kg) vs. ATO (0.16 mg/kg) Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session
  42. 42. 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
  43. 43. Realgar-Indigo Naturalis Formula (RIF) vs. ATO: Multi-Center Randomized Trial APL07
  44. 44. Bei Jin University, Institute of Hematology RIF iv ATO p n=112 n=121 CR 98% 98% >0.05 Time 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% >0.05 Median Time to Mol CR 60 days 60 days >0.05 Relapse 0.9% 0.8% >0.05 Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session
  45. 45. Bei Jin University, Institute of Hematology Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session
  46. 46. Bei Jin University, Institute of Hematology 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
  47. 47. Bei Jin University, Institute of Hematology Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session
  48. 48. Ongoing study • 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
  49. 49. • Early death: Two issues …… - start ATRA in clinical suspected patients without morphology confirmation - start arsenic arsenic with morphological support - management of differentiation syndrome - best supportive care
  50. 50. Two issues …… • Relapse/resistance to ATRA and Arsenic: Xiao-jun Huang, Hong-hu Zhu, NEJM 2014
  51. 51. • 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
  52. 52. … future direction … Oral ATRA and oral arsenic as curable regimen (for low/Int risk APL)
  53. 53. 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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