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

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


  • 66 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


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 2 recent studies for optimization

  • 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 2 recent studies for optimization

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 2 recent studies for optimization

Treatment of APL: view of guidelines

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


Risk stratification

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

  • 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


Treatment of apl view of guidelines 2 recent studies for optimization

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


Treatment of apl view of guidelines 2 recent studies for optimization

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


Treatment of apl view of guidelines 2 recent studies for optimization

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


Treatment of apl view of guidelines 2 recent studies for optimization

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


Treatment of apl view of guidelines 2 recent studies for optimization

Arsenic concentration 2 years after the treatment

Hu J, PNAS 2009;106:3342


Treatment of apl view of guidelines 2 recent studies for optimization

North American Leukemia Intergroup Study C9710 (NCT00003934)

Arsenic as consolidation

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


Treatment of apl view of guidelines 2 recent studies for optimization

North American Leukemia Intergroup Study C9710 (NCT00003934)

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


Treatment of apl view of guidelines 2 recent studies for optimization

North American Leukemia Intergroup Study C9710 (NCT00003934)

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


Treatment of apl view of guidelines 2 recent studies for optimization

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

  • 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


Treatment of apl view of guidelines 2 recent studies for optimization

ATRA+arsenic without chemotherapy

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

  • avoid the potential toxicity of chemotherapy


Treatment of apl view of guidelines 2 recent studies for optimization

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


Treatment of apl view of guidelines 2 recent studies for optimization

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

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

Scott Kogan, Cancer Cell 2009;15:7


Treatment of apl view of guidelines 2 recent studies for optimization

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


Treatment of apl view of guidelines 2 recent studies for optimization

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


Treatment of apl view of guidelines 2 recent studies for optimization

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


Treatment of apl view of guidelines 2 recent studies for optimization

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


Treatment of apl view of guidelines 2 recent studies for optimization

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


Treatment of apl view of guidelines 2 recent studies for optimization

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


Treatment of apl view of guidelines 2 recent studies for optimization

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 2 recent studies for optimization

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


Treatment of apl view of guidelines 2 recent studies for optimization

  • 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


Treatment of apl view of guidelines 2 recent studies for optimization

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


Treatment of apl view of guidelines 2 recent studies for optimization

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


Treatment of apl view of guidelines 2 recent studies for optimization

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

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


Treatment of apl view of guidelines 2 recent studies for optimization

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


Treatment of apl view of guidelines 2 recent studies for optimization

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

  • 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


Treatment of apl view of guidelines 2 recent studies for optimization

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


Treatment of apl view of guidelines 2 recent studies for optimization

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

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