Retinoic Acid Receptor Alpha and Acute Promyelocytic Leukemia Nidhi Thapar April 1, 2004.
Long term survival outcomes of Acute Promyelocytic Leukemia.
Transcript of Long term survival outcomes of Acute Promyelocytic Leukemia.
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%
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
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 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
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
SIH study updated 2014: all patients
Zhu HM, et al. Submitted
median follow-up 72 months (range, 0-136)
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 …
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
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
- 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