Breakthroughs in the treatment of acute promyelocytic leukemia: curable disease with retinoic and ar...
Sponsored Links
This presentation is the property of its rightful owner.
1 / 39

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


  • 71 Views
  • Uploaded on
  • Presentation posted in: General

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

Download Presentation

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

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


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

    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

  • 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

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


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


  • 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


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


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


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


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


Arsenic concentration 2 years after the treatment

Hu J, PNAS 2009;106:3342


North American Leukemia Intergroup Study C9710 (NCT00003934)

Arsenic as consolidation

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


North American Leukemia Intergroup Study C9710 (NCT00003934)

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


North American Leukemia Intergroup Study C9710 (NCT00003934)

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


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


  • 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


ATRA+arsenic without chemotherapy

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

  • avoid the potential toxicity of chemotherapy


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


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.


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


ATRA/ATO with or without chemotherapy in newly-diagnosed APL in China


  • 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


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


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


Oral Arsenic trioxide: Hong Kong

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


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


北京大学人民医院 北京大学血液病研究所

Oral As4S4iv ATOp

n=112n=121

CR98%98% >0.05

Time to CR30 days29 days>0.05

PML/RAR level

CR15.0%2.1% <0.05

End consolidation00 >0.05

Mol CR100%100% >0.05

Median Time to Mol CR60 days60 days>0.05

Relapse0.9%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

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

    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

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

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


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


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


  • Login