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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.

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Presentation on theme: "Breakthroughs in the treatment of acute promyelocytic leukemia: curable disease with retinoic and arsenic Jiong HU Shanghai Institute of Hematology, Department."— Presentation transcript:

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 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/m 2 /d, given orally , until CR As 2 O mg/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/m 2 /d,given orally for days As 2 O 3 : 0.16mg/m 2 /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 survivalEvent-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 survivalRelapse-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 (NCT ) Arsenic as consolidation Powell BL, Blood First Edition Paper, DOI /blood

13 North American Leukemia Intergroup Study C9710 (NCT ) Powell BL, Blood First Edition Paper, DOI /blood

14 North American Leukemia Intergroup Study C9710 (NCT ) Powell BL, Blood First Edition Paper, DOI /blood

15 Arsenic as induction and post-remission therapy - ATRA + ATO  gemtuzumab ozogamicin (GO) (high-risk disease: WBC  10 x 10 9 /L) - 75 / 82 achieved CR (92%), 7 death - Median follow-up: 99 weeks ( ) - 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/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 RNasr 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): ATRA/ATO reduce significantly use of chemotherapy: Australian APML4 study

22 2-year relapse-free survival 97.5%; failure-free survival 88.1%, and overall survival 93.2%. Iland HJ, Blood. 2012;120(8):

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):

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/m 2 induction --- ATO 5 days/week (4 weeks on/off) 4 courses + ATRA (2 weeks on/off) 7 courses - AIDA: ATRA+Ida induction 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+ATOAIDAP CR75/75 (100%)75/79 (95%) year EFS97% ( )86.7% ( )0.03 Event1 death in CR; 2 rel7 deaths (4 ED/3 in CR) ; 4 rel OS98.7%91.1%0.03 DFS97%91.6% (P=0.19)0.19 CIR1.6%4.3%0.41 Patients: -162 enrolled 154 evaluable - median age 45.3( ); median WBC 1.50 x 10 9 /L - risk: 61.8% intermediate and 38.2% low-risk - median FU: 31 months (range )

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): Retrospective analysis of 76 APL in 1 st 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): 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, 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): Oral Arsenic trioxide: Hong Kong

33 Oral Realgar-Indigo Naturalis Formula (As4S4) vs. ATO: Multi-Center Randomized Trial APL07 HA ATRA +As 2 O 3 ATRA+As 4 S 4 DA MA As 2 O 3 / ATRA As 4 S 4 / ATRA Newly- diagnosed APL Induction Consolidation Maintenance (2 years) Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session

34 Oral As4S4iv ATO p n=112n=121 CR 98%98% >0.05 Time to CR30 days29 days >0.05 PML/RAR  level CR15.0%2.1% <0.05 End consolidation00 >0.05 Mol CR 100%100% >0.05 Median Time to Mol CR60 days60 days>0.05 Relapse0.9%0.8%>0.05 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 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.

36 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

37 Arsenic as front-line treatment for newly- diagnosed APL SIH * MD Anderson ** North American Intergroup** APML4 *GIMEMA ** Induction++-++ Conso-++++ Maint+---+ Total cycles65235 *Dose: 0.16mg/kg/day D1-28; **Dose: 0.15mg/kg/day Monday through Friday of 4 weeks

38 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

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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