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

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

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;113:1875Chin J Hematol 2010;31:69

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

Sanz MA, Blood. 2000;96:1247

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

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

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

Outcome from Shanghai Institute of Hematology

Follow-up data – 85 patients with ATRA+ATO: Survival at 70 months

Overall survival Event-free survival

n=85, 91.7±3.0% n=85, 89.2±3.4%

Hu J, PNAS 2009;106:3342

Follow-up data – 80 patients with ATRA+ATO entered CR: Survival at 70 months

Overall survival Relapse-free survival

n=80, 97.41.8% n=80, 94.82.5%

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

• 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

MDACC Study

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

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;14:1333and Clin Cancer Res 2009 Oct 6.

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

Scott Kogan, Cancer Cell 2009;15:7

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

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

ASH 2012, Plenary Scientific Session

• 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     

ATRA + ATO vs AIDA in newly-diagnosed non high-risk APL: Gimema-SAL-AMLSG

ASH 2012, Plenary Scientific Session

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

• 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.

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

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

Oral Arsenic trioxide: Hong Kong

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

• 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

Oral Arsenic trioxide: Hong Kong

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

• 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

Oral Realgar-Indigo Naturalis Formula (As4S4) vs. ATO: Multi-Center Randomized Trial APL07

HAATRA +As2O3

ATRA+As4S4

DA

MA

As2O3 / ATRA

As4S4 / ATRA

Newly-diagnosed APL

Induction Consolidation Maintenance (2 years)

Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session

Oral As4S4 iv ATO p n=112 n=121

CR 98% 98% >0.05Time 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% >0.05Median Time to Mol CR 60 days 60 days >0.05 Relapse 0.9% 0.8% >0.05

北京大学人民医院 北京大学血液病研究所北京大学人民医院 北京大学血液病研究所

Xiao-jun Huang, Hong-hu Zhu, ASH 2012 AML session

北京大学人民医院 北京大学血液病研究所北京大学人民医院 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.

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

Arsenic as front-line treatment for newly-diagnosed APL

 SIH

*MD

Anderson**

North American

Intergroup**

APML4 * GIMEMA**

Induction + + - + +

Conso - + + + +

Maint + - - - +

Total cycles

6 5 2 3 5*Dose: 0.16mg/kg/day D1-28;**Dose: 0.15mg/kg/day Monday through Friday of 4 weeks

• 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

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