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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 of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine. Treatment of APL: view of guidelines

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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 of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine


  • Treatment of APL: view of guidelines leukemia: curable disease with retinoic and arsenic

    2. Recent studies for optimization

    - Role of arsenic as upfront treatment

    - ATRA+arsenic with or without chemotherapy

    - Oral formula of arsenic

    3. Perspectives


Treatment of APL: view of guidelines leukemia: curable disease with retinoic and arsenic

  • 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


Treatment of APL: view of guidelines leukemia: curable disease with retinoic and arsenic

Tallman M, Blood 2009;114(25):5126


Risk stratification

RFS outcome leukemia: curable disease with retinoic and arsenic

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


  • Treatment of APL: view of guidelines leukemia: curable disease with retinoic and arsenic

    2. Recent studies for optimization

    - Role of arsenic as upfront treatment

    - ATRA+arsenic with or without chemotherapy

    - Oral formula of arsenic

    3. Summary


Optimization: role of upfront arsenic leukemia: curable disease with retinoic and 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


Outcome from Shanghai Institute of Hematology leukemia: curable disease with retinoic and arsenic

  • 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


n=85, 91.7±3.0% leukemia: curable disease with retinoic and arsenic

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


n=80, 94.8 leukemia: curable disease with retinoic and arsenic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


Arsenic concentration 2 years after the treatment leukemia: curable disease with retinoic and arsenic

Hu J, PNAS 2009;106:3342


North American Leukemia Intergroup Study C9710 ( leukemia: curable disease with retinoic and arsenicNCT00003934)

Arsenic as consolidation

Powell BL,Blood First Edition Paper, DOI 10.1182/blood-2010-02-269621


North American Leukemia Intergroup Study C9710 ( leukemia: curable disease with retinoic and arsenicNCT00003934)

Powell BL,Blood First Edition Paper, DOI 10.1182/blood-2010-02-269621


North American Leukemia Intergroup Study C9710 ( leukemia: curable disease with retinoic and arsenicNCT00003934)

Powell BL,Blood First Edition Paper, DOI 10.1182/blood-2010-02-269621


MDACC Study leukemia: curable disease with retinoic and arsenic

  • 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


  • Treatment of APL: view of guidelines leukemia: curable disease with retinoic and arsenic

    2. Recent studies for optimization

    - Role of arsenic as upfront treatment

    - ATRA+arsenic combination with or without chemotherapy

    - Oral formula of arsenic

    3. Summary


ATRA+arsenic without chemotherapy leukemia: curable disease with retinoic and arsenic

  • “appealing concept” of curative regimen by target therapy only in leukemia

  • avoid the potential toxicity of chemotherapy


ATRA+arsenic without chemotherapy leukemia: curable disease with retinoic and arsenic

  • 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


Importance of ATRA/ATO vs. ATRA/chemo? leukemia: curable disease with retinoic and arsenicSynergy 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.


Synergy of ato and atra eradicate leukemia initiating cells lic
Synergy of ATO and ATRA eradicate leukemia initiating cells (LIC)

Scott Kogan, Cancer Cell 2009;15:7


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


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


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


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


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


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


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



  • Treatment of APL: view of guidelines in China

    2. Recent studies for optimization

    - Role of arsenic as upfront treatment

    - ATRA+arsenic without chemotherapy

    - Oral formula of arsenic

    3. Summary


Oral Arsenic trioxide: Hong Kong in China

  • 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


Oral Arsenic trioxide: Hong Kong in China

  • 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


Oral Arsenic trioxide: Hong Kong in China

Au WY et al. Blood. 2011;118(25):6535-6543


Oral realgar indigo naturalis formula as4s4 vs ato multi center randomized trial apl07
Oral in ChinaRealgar-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


北京大学人民医院 北京大学血液病研究所 in China

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


北京大学人民医院 北京大学血液病研究所 in China

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


  • Treatment of APL: view of guidelines in China

    2. Recent studies for optimization

    - Role of arsenic as upfront treatment

    - ATRA+arsenic without chemotherapy

    - Oral formula of arsenic

    3. Summary


Arsenic as front-line treatment for newly-diagnosed APL in China

*Dose: 0.16mg/kg/day D1-28;

**Dose: 0.15mg/kg/day Monday through Friday of 4 weeks


Future therapy for newly-diagnosed APL in China

  • arsenic + ATRA: mainstay of upfront treatment for newly-diagnosed APL

  • Oral arsenic: better tolerance and convenience

  • Chemotherapy: based on risk stratification


Acknowledgements
Acknowledgements in China

  • 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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