JIONG HU, MDShanghai, China

• Hematologist and a clinical researcher in the Department of Hematology at Rui Jin Hospital, Shanghai, China

• Dr. Jiong Hu has published in several national and international peer reviewed journals on topics including hematopoietic stem cell transplantation, leukemia, hematological malignancies, and hematopathology. Dr. Hu is a pioneer in actute promyelocytic leukemia and his research interests include myeloma and leukemia. He is a principal investigator for several national level clinical trials. Dr. Hu holds the position of Lead, Leukemia Subdivision for APHCON.

Long term survival outcomes of APL:

How will we treat APL in the

future?Jiong HU

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

University School of Medicine

• Overview

• Front-line combination therapy with ATRA and

arsenic

• Future direction:

- Oral arsenic

- APL therapy without chemotherapy

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

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

ATRA + chemotherapy 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 + 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 and ATRA combination as front-line treatment

- ATRA/arsenic: efficacy in newly-diagnosed and relapse

patients with high remission rate with sizable proportion of long-

term survival

- front-line ATRA with salvage arsenic: long-term survival

observed

Rationale of arsenic and ATRA combination: Synergy in degrading PML-

RARα

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-RARα

- ATRA ↑ of expression of AQP9, ↑ arsenic uptake

- Degradation PML-RARα rapidly clears LIC and eradication

in murine APL models; blocked PR degradation by

bortezomib reversed the curative effect of arsenic

Nat Med. 2008;14:1333Clin 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, 97.4±1.8% n=80, 94.8±2.5%

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

SIH study: Updated 2014

Zhu HM, et al. Submitted

Zhu HM, et al. Submitted

SIH study: Updated 2014

SIH study updated 2014: all patients

Zhu HM, et al. Submitted

median follow-up 72 months (range, 0-136)

SIH study: Updated 2014

SIH study: Updated 2014

Zhu HM, et al. Submitted

Mean 95%CI

Global Health Status 79.2 76.0～ 82.5Functional Scale 92.7 91.0～ 94.5Symptom Scale 6.9 5.3～ 8.5

Main Complaints Percentage

Mild to Moderate Weakness 55.4%

Difficulty remembering things 41.1%

Financial Difficulties 33.0%

EORTC QLQ-C30 (version 3.0) based Questionnaire was performed for evaluation of quality of life.

Scores were analyzed according to the EORTC QLQ-C30 scoring manual.

Zhu HM, et al. Submitted

SIH study updated 2014: Quality of Life

Conclusion of long-term follow-up

Good Long-term SurvivalGood Long-term Survival• Particularly for low-to-intermediate risk patients

Few Long-term ComplicationsFew Long-term Complications• Except for liver dysfunction and hepatic steatosis

No Significant Arsenic RetentionNo Significant Arsenic Retention• Back to normal after 6 months off ATO at most

Satisfactory Quality of LifeSatisfactory Quality of Life

Zhu HM, et al. Submitted

- No chemotherapy for low/Int risk APL

outcome of minimal chemo or no chemo regimen

ongoing study

- Oral arsenic

outcome of initial studies

ongoing study

… future direction …

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

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.

Outcome of minimal or no chemo studies

Median FU or Estimate sur

Low/inter-mediate

High-risk

North Am 3-year OS 83% OS 60%

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

GIMEMA 2 year DFS 97% /

• 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

Oral Arsenic trioxide in China: oral As2O3

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

Zhu et al, J Clin Oncol. 2013 Nov 20;31(33):4215-21.

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

RIF iv ATO p n=112 n=121

CR 98% 98% >0.05Time to CR 30 days 29 days >0.05 PML/RARα 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

Zhu et al, J Clin Oncol. 2013 Nov 20;31(33):4215-21.

Bei Jin University, Institute of Hematology

Zhu et al, J Clin Oncol. 2013 Nov 20;31(33):4215-21.

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.

Zhu et al, J Clin Oncol. 2013 Nov 20;31(33):4215-21.

… future direction …

Zhu et al, NEJM 2014( Dec4);371;23

• Single center pilot study with 20 patients with non high-risk APL

• Protocol:

Induction:

- oral arsenic RIF (60mg/kg)

- ATRA (25mg/m2)

Post-remission therapy:

- RIF 4 weeks on and 4 weeks off

- ATRA 2 weeks on and 2 weeks off for 7 months.

… future direction …

Zhu et al, NEJM 2014( Dec4);371;23

… future direction …

Zhu et al, NEJM 2014( Dec4);371;23

- Complete molecular remission: 100% at 6 months

- Excellent QOL: 50% of patients without hospitalization

- Total medical costs: $4,675 (range, $3,174 to $12,698).

• Combination of ATRA and arsenic as front-line treatment

improve the outcome of APL: 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 remains in high-risk group

• Oral arsenic + oral ATRA: better tolerance/convenience and

promising short-term outcome

Summary

Acknowledgements

• Prof Zhen-yi Wang; Zhu Chen and Sai-juan Chen;

Zhi-xiang Shen;

• Dr Jun-min Li and Hong-min Zhu

• Colleagues at Shanghai Institute of Hematology,

Department of Hematology, RuiJin Hospital