francesco lo-coco, md · presentazione di powerpoint author: laura cicconi created date: 11/13/2014...
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State of the Art Therapy of
Acute Promyelocytic Leukemia
Francesco Lo-Coco, MD
University Tor Vergata, Rome;
GIMEMA Cooperative Group, Italy
DGHO Annual Congress
Hamburg, October 10-14, 2014
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• Early death: an unsolved issue
• Current standard Rx in first line
• Latest advances using chemo-free Rx
• Future perspectives in high risk disease
Outline
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Early Death in APL: Real World Data
Study ED rate (< 30 d)
Swedish Registry1 29 %
SEER (USA)2 17 %
Stanford University3 26 %
Canadian Registry4 22 %
1Lehman, Leukemia 2011; 2Park, Blood 2011; 3McClellan, Haematologica 2011; 4 Paulson, Br J Haematol 2014
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0
5
10
15
20
25
30
35
40
45
50
1997-2006 2007-2012
Perc
en
t E
D
WBC > 10
WBC < 10
ED by WBC at diagnosis
Lehman S, 6° Intl. Symposium on APL, Rome Oct. 2013
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Significant improvement in ED and OS over time
1999-2010 Early era
(1999-2004) Late era
(2005-2010) Time since dx Survival% Survival % Survival %
30 days* 85 82 89
1 year 80 74 86
2 year 77 69 84
Paulson K, Br J Haematol 2014
Leukemia Referral Centers (Canada)
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Early
Death %
OS at 1
Year, %
OS at 5 Yrs,
%
All patients 22 70 55
<50 years old 11 84 73
≥50 years old 36 52 29
No improvement in ED or OS over time
Paulson K, Br J Haematol 2014
Canadian Cancer Registry
Results for APL (1993-2007)
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• Developed a simple 1.5 page treatment algorithm
• Quick diagnosis
• Ad hoc meeting and treatment planning
• Rapid initiation of therapy
• Aggressive management of coagulopathy
• Prevention of differentiation syndrome; early
recognition and management
• Implemented in 2010
A. Jillella et al., EHA 2014
Strategy at Emory Univ Hospital
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•Affiliates contact us when a patient is diagnosed with APL
•Email or fax our algorithm
•Discuss patient with treating physician and recommend a treatment plan
•Follow up by phone, email or texting at least 3 to 4 times in the first 10
days- during which 70% of the deaths take place.
Strategy at Affiliated Sites
A. Jillella et al., EHA 2014
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Survival Pre and Post Algorithm
A. Jillella et al, EHA 2014
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• Early death, an unsolved issue
• Current standard Rx in first line
• Latest advances using chemo-free Rx
• Future perspectives in high risk disease
Outline
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CHT ATRA ATRA ATO
Cure of
APL
CHT ATRA ATO
“Third Way”
Current treatment options in APL
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Front-line Management of APL
ATRA and CHT: Some Open Issues
• CNS prophylaxis
• Ara-C (high-risk only?)
• Role of Maintenance
• Cost-effectiveness of MRD
• sMDS/AML
• Elderly pts
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CHT ATRA ATRA ATO
Cure of
APL
CHT ATRA ATO
Conventional
approach
Alternative
approach
“Third Way”
Four studies reported
good results with the
triple combination
of ATO, ATRA & CHT
1. Hu J, et al. PNAS. 2009;106:3342–7 2. Powell BL, et al. Blood. 2010;116:3751-7 3. Iland HJ, et al. Blood. 2012;120:1570-80 3. Zhu H-H, et al. JCO. 2013;31:4215-21
Current treatment options in APL
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Iland HJ, et al. Blood 2010
ATRA + ATO + CHT Australasian Leukemia and Lymphoma Group
Induction Consolidation Maintenance
ATRA + ATO
+ CHT
2 cycles of
ATRA + ATO
5 cycles of sequential use of
ATRA and LD/CHT
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Zhu H et al. JCO 2013
* Mitoxantrone was added at a dose of 1.4 mg/m2/day on 5 days 4, 5, 6, 7, and 8 (if WBC >10 x 109/L start
on day 1).
ATRA = all-trans retinoic acid; ATO = arsenic trioxide; RIF = Realgar-Indigo naturalis formula; HA =
homoharringtonine and cytarabine; DA = daunorubicin and cytarabine; MA = mitoxantrone and cytarabine
*
Randomized comparison of oral arsenic vs. IV ATO
ATO+ATRA+CHT
Chinese Cooperative Group
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Zhu H et al. JCO 2013
n = 114; CR 113; Relapse 1; Death in CR 1
n = 117; CR 114; Relapse 1
3-year OS 99.1% (95% CI, 97.2% to 99.9%)
3-year OS 96.6% (95% CI, 93.0% to 99.8%
ATO+ATRA Vs. RIF+ATRA
Chinese APL Cooperative Group
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• Early death, an unsolved issue
• Current standard Rx in first line
• Latest advances using chemo-free Rx
• Future perspectives in high risk disease
Outline
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GIMEMA-SAL-AMLSG MRC – AML 17
ATO+ATRA without CHT
Randomized Studies
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R Estey et al. Blood 2006;107:3469-73
Lo-Coco et al. Blood 2010;116:3171-9
Induction
ATRA
ATO
Until CR
Consolidation
ATO ATO ATO ATO
4 weeks on / 4 weeks off
2 weeks on / 2 weeks off
Induction Consolidation Maintenance
ATRA ATRA ATRA ATRA ATRA
MTX + 6MP IDA IDA IDA MTZ
Until CR 2 years 3 monthly cycles
Chemo
arm
ATO
arm
APL0406: Treatment Arms
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Lo-Coco et al. NEJM 2013
0406 Trial Results (n=162, median f.up 34m)
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What about QoL of patients treated with Arsenic?
APL 0406: QoL Outcomes
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5 functioning scales: physical, role, emotional, cognitive, social
3 symptom scales: fatigue, nausea/vomiting, pain
6 single-item scales: dyspnoea, sleep disturbances, appetite loss
constipation, diarrhea, financial impact
Global QoL scale
EORTC QLQ-C30
Questionnaire
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A total of 162 pts enrolled between Oct 2007 and Sept 2010
156 patients received at least one dose of the assigned Rx
ATRA-Chemotherapy
Post induction
Post consolidation
ATRA-ATO
Post induction
Post consolidation
156 patients
N= 53 N= 62
N= 61 N= 58
N= 150 expected
N= 142 expected
Compliance 77%
Compliance 84%
Results and QoL compliance
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Functional aspects / Global QoL
Estimated differences in EORTC QLQ-C30
mean scores and 95% CIs between Rx arms
*Clinically meaningful difference; (based on Cocks K, et al., JCO 2011).
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Symptoms
*Clinically meaningful difference; (based on Cocks K, et al., JCO 2011).
Estimated differences in EORTC QLQ-C30
mean scores and 95% CIs between Rx arms
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Overall, current QoL findings further support the use of ATRA plus ATO
as preferred first-line treatment in low-intermediate risk APL patients.
Post-induction:
Patients treated with ATRA-ATO reported statistically
significant less fatigue, and other clinically relevant better
outcomes for appetite loss, nausea/vomiting, constipation,
physical and cognitive functioning
Post-consolidation:
No major difference in QoL between treatment at the end
of 3rd consolidation course
Results on QoL in APL0406 study
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Best AIDA
(Italian)
Chemo-free
(ATRA-ATO)
APL patients
(Low/Int and
high risk) R
MRC-AML17 APL Protocol: 2009-2013
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Alan K Burnett
School of Medicine, Cardiff University
United Kingdom
Rome, October 2013
APL: Less is just as good
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Week 1- 4 9 - 12 17- 20
Week1- 2
25 - 28
9-10 13-14 5-6 17-18 21-22 25-26
ATRA
ATO
d1 d60
3-monthly
BM for PCR
to 36mo from diagnosis
PCR
ATRA
PCR
CHEMO-FREE
AIDA
Ida Ida Mitox Ida
3-monthly
BM for PCR
to 36mo from diagnosis
MRC-AML17 APL Protocol: 2009-2013
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Induction: ATO 0.3mg/kg days 1-5 week 1
0.25mg/kg X 2 per week
Consolidation: ATO 0.3mg/kg X2 per week, in wk1
0.25mg/kg X2 per week x3 weeks
(4 courses)
ATO Schedule in AML17
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• Early death, an unsolved issue
• Current standard Rx in first line
• Latest advances using chemo-free Rx
• Future perspectives in high risk disease
Outline
![Page 32: Francesco Lo-Coco, MD · Presentazione di PowerPoint Author: Laura Cicconi Created Date: 11/13/2014 9:55:51 AM](https://reader033.vdocuments.net/reader033/viewer/2022042308/5ed480eeef5b521ea177dbac/html5/thumbnails/32.jpg)
ATO+ATRA+Ida vs ATRA+CHT for high-risk APL
APOLLO-Trial
Open label, randomized, prospective, intergroup
phase III study
Inclusion criteria:
Newly diagnosed and genetically confirmed APL
Age: ≥ 18 and ≤ 65 yrs
WBC at diagnosis > 10 x 109/L
ECOG performance status 0-2
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The first 4 days of therapy are identical in the two arms
Treatment Arms
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• to show superiority of the experimental arm:
clinically relevant increase of 10% in EFS at 2 yrs
(from 77% in the AIDA study* to ≥87%)
Aim
* Lo-Coco et al, Blood 2010
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Primary efficacy endpoint:
•EFS
Key secondary endpoint(s):
•CR, OS and CIR
•Quality of life
•Toxicity profile
•Rate of early death
•Kinetics of MRD
•Cumulative incidence of secondary MDS or AML
•Hospitalization
•Cost analysis
Objectives
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GROUPS Country PI
SAL Germany U.Platzbecker
GIMEMA Italy F. Lo-Coco
AMLSG Germany R. Schlenk
ALSG Germany E. Lengfelder
OSHO Germany D. Niederwieser
French-Belgian-Swiss France P. Fenaux
PETHEMA Spain M. Sanz
HOVON Netherlands E. Vellenga
EORTC EU F. Baron
NCIC-CTG Canada S. Couban
Participating groups
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Early death is still the main obstacle to cure
High cure rates can be achieved with optimized
combinations of:
• ATRA + CHT
• ATRA + ATO
• ATRA + CHT + ATO
ATO+ATRA appears superior to ATRA-CHT for
Low-intermediate risk. However:
• Not yet approved for this indication in most countries
• Not yet assessed in high-risk (R studies needed)
Conclusions
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Acknowledgements
L. Cicconi
M. Divona S.K. Hasan
M. Breccia
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F. Ferrara
E. Di Bona
M. Breccia
A.M. Carella
F. Fabbiano
G. Leone
S. Orlando
E. Morra
G. Specchia
P. Fazi
M. Vignetti
G. Avvisati
A. Rambaldi
G. Rossi
S. Amadori
C. Ciardi
M. Divona
S. Iacobelli
F. Mandelli
H. Döhner
A. Ganser
K. Dohner
J. Krauter
R.F. Schlenk
E. Estey
(Seattle, USA)
Acknowledgements
M.A. Sanz
P. Montesinos
(Valencia, Spain)
A.K. Burnett
D. Grimwade
(NCRI, UK)
G.Ehninger
C. Thiede
C. Brandts
H. Link
W. Aulitzky
M. Hänel
K. Schäfer-Eckart
S. Krause
K.-H. Pflüger
N. Schmitz
M. Sauer
U. Platzbecker