Acute Promyelocytic Leukemia

Treatment of acute promyelocytic leukemia with ATRA and arsenic:

experience from China

Jiong HU

Shanghai Institute of Hematology, Department of Hematology, Rui-Jin Hospital, Shanghai Jiao Tong

University School of Medicine

• Front-line therapy with ATRA

• Salvage therapy with arsenic

• Combination therapy with ATRA and arsenic

• Oral arsenic

• Future direction: APL therapy without

chemotherapy

Blood 2008 Mar 1;111(5):2505-15.

Clinical and molecular

features:

(A) severe bleeding tendency:

fibrinogenopenia and DIC

(B) promyelocytes in BM and

peripheral blood

(C) chromosomal translocation

t(15;17)(q22; q21)

(D) fusion transcripts PML-

RAR

Overview of APL

Overview of APL treatment

• pre-ATRA period: chemotherapy

• ATRA:

- introduction of ATRA

- optimization of ATRA-chemo combination regimens

• Arsenic:

- introduction of ATO in relapsed APL

- ATRA/ATO combination as front-line therapy

- Oral arsenic

Chemotherapy

• Chemotherapy: anthracycline (DNR or Ida) + Ara-C:

- CR rates 70%~80% in newly diagnosed patients

- aggravation of bleeding syndrome: high early death rate

- relapse in large proportion of patients with median duration

of CR: 11~25 months

- long-term survival: 35% ~ 45%

Blood 2008 Mar 1;111(5):2505-15.

• Recognition of APL as a highly fatal disease

ATRA treatment in APL

Blood 2008 Mar 1;111(5):2505-15.

(A) Isomers of retinoic acid

(B) ATRA induces terminal

differentiation of APL

(C) ATRA treatment leads to

elimination of PML-RAR–

positive cells by quantitative

real-time RT-PCR for

assessment of PML-RAR

transcript.

Blood 2008 Mar 1;111(5):2505-15.

Pilot study in Shanghai Institute of Hematology (SIH)

- 1985~1988

- 24 APL patients: 16 newly diagnosed / 8 refractory disease

- ATRA: 45mg/m2 oral until response or max 60 days

- outcome:

23 achieved CR

differentiation syndrome

1 patient achieved CR by adding low-dose Ara-C

ATRA treatment in APL

Blood 2008 Mar 1;111(5):2505-15.

ATRA treatment in APL- Chemotherapy + ATRA:

anthracycline (Ida, DNR, Mitoxantrone, or HHT) and Ara-C

- Induction:

high remission rate

reduce differentiation syndrome

- Consolidation/maintenance:

3 monthly courses of anthracycline-based chemo/low-dose

maintenance (6-MP+MTX with ATRA)

5-year EFS/DFS: up to 70%

ATRA added to chemotherapy improve outcome

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

Arsenic as salvage therapy

- arsenic developed as TCM in Northeastern China

- Harbin group(1992): iv 1% ATO

32 APL, 21 obtained CR

10-year survival 30%

- SIH(1996~1997):

47 relapsed and 11 newly diagnosed APL

CR rate of 85.1% and 72.7%

molecular remission documented ~60%

long-term survival in relapsed APL: 50~60%

Blood 2008 Mar 1;111(5):2505-15.

Treatment of APL: guidelines

ELN guideline / NCCN guideline / Consensus of CSH:

- Newly-diagnosed APL: simultaneous administration of

ATRA and anthracycline-based chemotherapy as standard

- Relapse disease: arsenic is the best option with or without

chemotherapy

Blood 2009;113:1875Chin J Hematol 2010;31:69

Rationale of arsenic as front-line treatment

- 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 observed

Synergy of ATRA and aarsenic in degrading PML-RAR

ATRA increase aquaglyceroporin 9(AQP9) expression associated with

arsenic sensitivity

Relationship of AQP9 with arsenic uptake and sensitivity in leukemia cells. Blood 2007; 109: 740-746.

ATRA increase AQP9 expression associated with arsenic sensitivity in

patients

ATRA and arsenic synergy in targeting APL

- ATRA/Arsenic targeting PML-RAR

- ATRA of expression of AQP9, arsenic uptake

- Degradation PML-RAR rapidly clears LIC and eradication

in murine APL models; blocked PR degradation by

bortezomib reversed the curative effect of arsenic

Nasr R, Nat Med. 2008;14:1333and Clin Cancer Res 2009 Oct 6.

Synergy of ATRA and arsenic in eradicating leukemia stem cells

Synergy of ATRA and Arsenic: mice model

Scott Kogan, Cancer Cell 2009;15:7

SIH study: Front-line therapy with ATRA + Arsenic

Overall survival at 70 months Event-free survival at 70 months

n=85, 91.7±3.0% n=85, 89.2±3.4%

Hu J, PNAS 2009;106:3342

SIH study: Follow-up for all patients

Overall survival at 70 months Relapse-free survival at 70 months

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

Hu J, PNAS 2009;106:3342

SIH study: Follow-up for patients in CR

Hu J, PNAS 2009;106:3342

SIH study: safety of front-line arsenic therapy

Update of SIH study 2014

Zhu HM and Hu J, et al. Submitted

Update of SIH study 2014

Zhu HM and Hu J, et al. Submitted

Update of SIH study 2014: all patients

Zhu HM and Hu J, et al. Submitted

Update of SIH study 2014

Update of SIH study 2014

Ravandi F, J Clin Oncol 2009;27:504

MDACC Study: ATRA + Arsenic GO

Ravandi F, J Clin Oncol 2009;27:504

MDACC Study: ATRA + Arsenic GO

North American Leukemia Intergroup Study C9710 (NCT00003934)

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

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

North American Leukemia Intergroup Study C9710: benefit of arsenic in different risk groups

No arsenic: high vs. low

Arsenic: high vs. low

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 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.

Summary of ATRA + arsenic combination as front-line therapy

Median FU or Estimate sur

Low/inter-mediate

High-risk

SIH 88 months OS 93~95%; RFS 90%

OS 89%; RFS 80%

MDACC 99 weeks OS ~85% OS ~60 %

North Am 3-year OS 83% OS 60%

APML4 2-year FFS 88~97% FFS 76%

GIMEMA 2 year DFS 97% /

Treatment of APL: guidelines

NCCN 2013 guideline:

- Newly-diagnosed APL: simultaneous administration of

ATRA and arsenic as standard

Develop of oral Arsenic trioxide in China: oral arsenic trioxide

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

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

Develop of oral Arsenic trioxide in China: oral arsenic trioxide

• 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%

Blood. 2002 May 1;99(9):3136-43.

newly diagnosed Rel1 CR

No of pts 19 7 103

Follow-up 13.5 mths (2~40) / 23 mths(2~71)

Mol remission 14/16 5/7 35/44

1-year DFS 86.1% / 96.7%

3/6-year DFS 76.6% / 87.4%

- Retrospective study: - 50 mg/kg daily (750mg 4 times) until CR; post-remission pts: 2

weeks on and 2 weeks off in 1st year and every 2 months for 4

years

Develop of oral Arsenic trioxide in China: Crystallized realgar (high-purity As4S4)

Blood. 2002 May 1;99(9):3136-43.

Develop of oral Arsenic trioxide in China: Crystallized realgar (high-purity As4S4)

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

Newly-diagnosed APL

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

oral RIF (60 mg/kg) vs. ATO (0.16 mg/kg)

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

Newly-diagnosed APL

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

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

RIF 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

Bei Jin University, Institute of Hematology

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

Bei Jin University, Institute of Hematology

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

Bei Jin University, Institute of Hematology

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.

Bei Jin University, Institute of Hematology

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

• Chinese 863 Key program: multiple-center randomized study

• Newly-diagnosed APL

• Risk stratification: low/int-risk vs. high-risk

- Low/Int-risk: ATO replacing chemotherapy ?

- high- risk: ATO replace Ara-C

• 20 clinical centers: enrolled from Aug 2012 to Aug 2015

Ongoing study

• Early death:

- start ATRA in clinical suspected patients without morphology

confirmation

- start arsenic arsenic with morphological support

- management of differentiation syndrome

- best supportive care

Two issues ……

• Relapse/resistance to ATRA and Arsenic:

Two issues ……

Xiao-jun Huang, Hong-hu Zhu, NEJM 2014

• Development of ATRA and arsenic treatment dramatically

improve the outcome of APL: curable disease

• arsenic + ATRA: mainstay of front-line treatment for newly-

diagnosed APL

• Arsenic + ATRA without chemo: promising outcome in low or

low/intermediate risk pts

• Importance of chemotherapy remain in high-risk group

• Oral arsenic: better tolerance/convenience and comparable

efficacy

Summary

Oral ATRA and oral arsenic as curable regimen

(for low/Int risk APL)

… future direction …

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