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: all patients




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


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






Oral Realgar-Indigo naturalis formula yielded comparable high remission and long-term survival with ATO in newly

diagnosed APL.



• 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

Health & Medicine

Acute Promyelocytic Leukemia