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Treatment of APL
M a t t h e w M e i, M .D .A s s is t a n t P ro f e s s o r
C it y o f H o p e C o m p re h e n s iv e C a n c e r C e n t e r
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Disclosures
• I have nothing to disclose
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Objectives
1. Urgency of early recognition and treatment
2. Treatment based on risk stratification
3. Monitoring for relapse
4. Treatment of relapse
5. Long-term toxicities
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Acute Promyelocytic Leukemia
Distinguishing Features
• 10-15% of adult AML
• Leukopenia (85%)
• Complex coagulopathy
• t(15;17) chrom translocation
• Sensitivity to anthracyclines
• PML-RAR fusion transcript
• Differentiation with retinoic acid
• Apoptosis with arsenic trioxide
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Bleeding in APL
Oral mucosal bleeding Subcutaneous bleeding
Retinal hemorrhages Intracerebral hemorrhage
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Early Death Rate in APLPopulation-Based Studies
Study N ED
Jeddi 41 16%
Lehmann 99 31%
Alizadeh 137 14%
McClellan 70 26%
Park 1,400 18%
Jeddi et al. Hematology, 2008; Lehmann et al. Leukemia, 2010;
Alizadeh et al. ASH, 2009; McClellan et al. Haematologica, 2012; Park et al. Blood, 2011
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Molecular Basis of
Leukemogenesis in APL
• RAR fuses to PML
• Increased affinity for nuclear co-repressor protein complex (N-coR)
• Histone deacetylase alters chromatin conformation inhibiting transcription
• Retinoic acid (RA) induces release of N-coR permitting transcription
RAR
PML
N-CoR
mSin3
HD
RARE
RAR
PML
N-CoR
mSin3
HD
RARE
RA
Grignani et al. Nature, 1998
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Milestones in the Development of
Curative Strategies in APL
1957 1973 1985 1990’s 1997 2000’s 2009
Initial
Description,
Highly Fatal
DaunorubicinATRA
ArsenicATRA + Chemo
ATRA + ArsenicHighly Curable
0.0
0.2
0.4
0.6
0.8
1.0
0 5 10 15 20Years
DF
S
ECOG Data
Pre-ATRA era
1973-1989
Tallman et al. Blood, 2002Years
0.0
0.2
0.4
0.6
0.8
1.0
0 2 3 4 6
OS
WBC < 10,000/L
WBC 10-50,000/L
WBC > 50,000/L
51
P = .14
APL2000
Kelaidi et al. J Clin Oncol, 2009
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All-trans Retinoic Acid
• Natural vitamin A derivative
• Induces leukemic promyelocytes to differentiate in vitro
• Induces CR in almost all pts with APL as single agent
• No imposition of marrow aplasia
At diagnosis Day 12 Day 37
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Arsenic Trioxide
• Single most active agent in APL
• Single-agent CR rate very high in frontline and relapsed setting
• Dual mechanism (differentiation at lower dose, apoptosis at higher dose)
• Biggest concerns are QTc prolongation and elevated LFTs
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Molecular Response to Arsenic Trioxide in
Relapsed APL: US Multicenter Study
0
10
20
30
40
50
60
70
80
90
100
Baseline
N=29Induction Consolidation
Pati
en
ts w
ith
MR
(%
)
48%
86%
Maintenance
90%
Soignet et al. J Clin Oncol, 2001
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Prevention of Early Death in APL
• ATRA at first suspicion (based on clinical hxand review of peripheral smear), before marrow and before diagnosis is confirmed
• Frequent platelet transfusions to > 50,000/L
• Cryoprecipitate to maintain fibrinogen > 150 mg/dL
• No routine heparin
• No routine antifibrinolytics
• No leukopheresisRodeghiero et al. Blood, 1990; Tallman et al. Leukemia Res, 2004; Sanz et al. Blood, 2008
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Risk Stratification
Treatment is primarily based on risk stratification.
Risk stratification is easy
Initial WBC > 10 = high risk (probably needs some
chemotherapy besides just ATRA + ATO)
Initial WBC ≤ 10 = standard risk (induce with ATRA +
ATO)
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Caveats for Induction in APL
• Differentiation Syndrome – steroid
prophylaxis built a number of the regimens
• Do NOT do marrow on Day 14 or Day 21!
– Cytogenetic / molecular positivity on day 28
does NOT mean treatment failure.
• Initial rise in WBC with rising neutrophils
represents differentiation of the malignant
clone, not true count recovery
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• Newly diagnosed APL
• Age 18 - 70 years
• WBC ≤10 x 109/L
• WHO performance status ≤ 2
APL 0406 Study
Trial designed to assess a non-inferiority margin difference
between the group proportions of 5%
Inclusion Criteria
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APL0406 Study: Treatment
R Estey et al, Blood 2006
Lo Coco et al. NEJM, 2013
Induction
ATR
ATO
Consolidation
4 weeks on / 4 weeks off
2 weeks on / 2 weeks off
Induction Consolidation Maintenance
ATR ATR ATRATR ATR
MTX + 6MPIDA IDA IDAMTZChemo
Arm
ATO
arm
ATO ATO ATO ATO
Until CR 3 monthly cycles 2 years
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ATRA + ATO ATRA + Chemo
No. of patients 75 79
CR, (%) 75 (100%) 75 (95%)
Induction death 0 4*
Resistant disease 0 0
Induction Outcome
*Differentiation syndrome (2), ischemic CVA (1) and pneumonia (1)
Lo Coco et al. NEJM, 2013
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0
10
20
30
40
50
60
70
IND I CONS II CONS III CONS
0
10
20
30
40
50
60
70
IND I CONS II CONS III CONS
Grade 3-4 neutropenia >15 dGrade 3-4 thrombocytopenia >15 d
ATO Chemo
p= <.0001
p= <.0001
p= <.0001
45
69
4
13
4
46
2
10
p= <.0004
p= .0001
p= .0185 p= .011735
62
54
25
44
17
3
p= <.0001
APL 0406: Hematologic Toxicity
Lo Coco et al. NEJM, 2013
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APL 0406: Other Toxicities
Toxicity ATRA+ATO ATRA+Chemo P value
QTc prolongation1,% 13 0 0.0005
Hepatic toxicity1
(Grade 3-4), %57 5 <0.0001
Leukocytosis2
(>10x109/L), %47 24 0.007
1. Managed with temporary discontinuation and dose
modification of ATO
2. Hydroxyurea 500 mg qid if WBC <50K and 1 g qid if >50K
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100
75
50
25
0
0 12 24 36 48 60
Months from diagnosis
Event-
free s
urv
ival pro
babili
ty 100
75
50
25
0
Dis
ease-f
ree s
urv
ival pro
babili
ty97.1%
85.6%
ATRA+ATO
ATRA+Chemo
ATRA+ATO
ATRA+Chemop=0.02 p=0.14
97.1%
90.3%
0 12 24 36 48 60
Months after CR
Event-free Survival
APL 0406
Disease-free Survival
Type of event
Relapse
Death in CR
ATRA+ATO
2
1
ATRA+Chemo
5
3
Lo Coco et al. NEJM, 2013
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APL 0406: Overall Survival
100
75
50
25
00 12 24 36 48 60
Months from diagnosis
Overa
ll surv
ival pro
babili
ty
98.7%
91.1%
ATRA+ATO
ATRA+Chemop=0.02
Lo Coco et al. NEJM, 2013
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APL 0406 – Long-term
Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010
After initial 2013 publication, more patients were enrolled
(total n = 276).
OS at 50 months was 99.2% vs. 92.6% (p = 0.0073)
EFS at 50 months was 97.3% vs. 80% (p < 0.003)
ATRA + ATO is clear standard of care for newly
diagnosed standard risk APL.
Platzbecker U, et al. J Clin Onc 2016.
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AML17
Randomized phase 3 trial of ATRA + ATO vs. ATRA
+ chemotherapy for newly diagnosed APL
– Patients with high risk disease receiving ATRA +
ATO only could receive one dose of gemtuzumab
ozogamicin
235 patients, 57 high risk
Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Burnett AK, et al. Lancet Oncol 2015.
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AML17
ATRA + chemotherapy arm – induction /
consolidation regimen as per low-risk arm of
AIDA2000
ATRA + ATO
• Induction: ATRA 45 mg/m2 until remission, ATO
0.3 mg/kg D1-5, then twice weekly on weeks 2-8
• Consolidation: ATRA 45 mg/m2 D1-14, ATO 03.
mg/kg D1-5, twice weekly on weeks 2-4
• Gemtuzumab ozogamicin 6 mg/m2 on D1 for high-
risk in ATRA + ATO patientsGrimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010
Burnett AK, et al. Lancet Oncol 2015.
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AML17 results
Burnett AK, et al. Lancet Oncol 2015.
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AML17
Conclusions:
• Relapse rate lower with ATRA + ATO.
• Overall survival unchanged in either low-risk or
high-risk cohort.
• Toxicities decreased overall with ATRA + ATO.
• QOL unchanged.
Update at ASH 2016 confirmed above findings.
Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Burnett AK, et al. Lancet Oncol 2015.
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Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010
Randomized trial for newly diagnosed APL patients.
481 patients enrolled
Two randomizations:
• ATO consolidation (yes/no)
• Maintenance (ATRA alone vs. ATRA + 6-MP/MTX)
Powell BL, et al. Blood 2010.
North American Intergroup C9710
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North American Intergroup C9710
Powell BL, et al. Blood 2010.
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North American Intergroup C9710
Powell BL, et al. Blood 2010.
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Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010
Fairly sizeable advantage realized with addition of ATO
consolidation in high and low risk disease for disease-
free and event-free survival.
OS not different but p-value 0.059 (86% vs. 81% at 3
years)
Not enough events to evaluate the differential effect of
maintenance therapy (p-value for PFS 0.11)
North American Intergroup C9710
Powell BL, et al. Blood 2010.
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Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010
Australasian Leukaemia and Lymphoma Group
Single-arm phase 2 trial with 124 patients, median follow-
up for 2 years.
Both low and high-risk patients were included.
APML4
Iland H, et al. Blood 2012.
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APML4
INDUCTION CONSOLIDATION (1) MAIN
ATRA D 1-35 ATRA D 1-28 ATRA, 6-MP
IDA D 2,4,6,8 ATO D 1-28 MTX
ATO D 9-36
CONSOLIDATION (2)PRED D 1-10
ATRA D 1-7, 15-21, 29-35
ATO D 1-5, 8-12, 22-26, 29-33
Iland H et. al, Blood 2012
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APML4
DFS by Sanz Risk Category
0
20
40
60
80
100
% r
ela
pse−
fre
e
0 1 2 3 4 5 6 7 8Years from documented HCR
Number at risk
32 31 30 22 12 8 3 1 0Low
60 58 57 46 32 15 8 2 0Inter
19 18 18 12 8 6 2 0 0High
Low
Intermediate
High
P−value (trend) = 0.30
2−year relapse−free rate: 100%, 97%, 95%, 5−year: 100%, 93%, 95%% a
live a
nd
rela
pse
-fre
e 100-
80-
60-
40-
20-
0-
1 2 3 4 5 6 7 80
Years from documented HCR
P [ trend ] = .30
Low 100%
High 95%
Intermediate
93%
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APML4
2015 update (5-year data):
5-yr OS 94% overall (high-risk 87%)
5-yr DFS 95%
5-yr EFS 90%
3 patients relapsed between the interim 2-year
analysis and the 5-year update.
Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Iland H et. al, Lancet Oncol 2015.
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Sanz et al. Blood, 2010; Adès et al. Am J Hematol, 2013; Lo Coco et al. Blood, 2010;Sanz et al. Best Pract Res Clin Haematol, 2003; Iland et al. ASH, 2014
High-Risk APL
ATRA + Risk-Adapted Chemo vs APML4
Number Medianfollow-up
(months)
IDAequivalent
(mg/m2)
AraC
(g/m2)
DFS CIR OS
PETHEMA
LPA2005118 28 122 5.8 82%
14% 79%
European
APL200074 103 99 22.8 - 7% 88%
GIMEMA
AIDA2000129 59 122 6.3 85% 9% 83%
ALLG
APML423 50 48 0 95% 5% 87%
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MRD Monitoring
• Document molecular CR from marrow after consolidation
(slightly more sensitive than PB by 1.5 logs)
• Unclear benefit in low-risk disease
• Potential benefit in high-risk disease, never prospectively
validated, but treatment of molecular relapse is easier than
hematologic relapse
• Monitor from PB q3 mo. for 2 yrs for high-risk, age >60,
therapy interruptions or intolerance
• Low-risk: may not be necessary
• If pos PCR, repeat in 2-4 weeks; if persistent positive, treat
as relapse Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman
Leukemia Res, 2010; Grimwade Best Pract Res Clin
Haematol 2015
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Relapsed APL
• Molecular relapse
– ATO x 2 cycles
– Autograft in CR2
• Morphologic relapse
– ATO x 2 cycles: CR 85%
– Autograft in CR2: 5-yr DFS 70-80%
• Isolated CNS relapse
– ATO crosses into CNS 30-50% serum levels
– ATO x 2 cycles, IT MTX/ara-C, autograft
Lo Coco Blood, 1999 and 2004; Esteve Leukemia, 2007, Estey Blood, 2002; Meloni Blood,1997; de Botton
J Clin Oncol, 2005; Thomas Haematologica, 2006; Kohno Int J Hem, 2008, Kharfan-Dabaja BBMT, 2007;
Au J Clin Oncol 2000; Knipp Leuk Res, 2007; Sanz Blood, 2009
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Adjusted Probability of Overall Survival
APL in CR2
1.0
0.8
0.6
0.4
0.2
00 12 24 36 48 60 72 84 96 108
alloHSCTautoHSCT
Months
Pro
babili
ty
120
Chakrabarty et al. BBMT, 2014
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Late Toxicities
3-5% death rate in CR reported in PETHEMA and
European APL trials1,2
– Heart failure, secondary malignancies, especially
as historical APL regimens have included a lot
of anthracycline
Possible late toxicities with ATO – hypertension,
DM, arrhythmia3
1Sanz MA, et al. Blood 2008 2Ades L, et al. Blood 2010.3Shetty AV, et al. ASH 2014.
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ASH 2016 Updates
Two trials for high risk patients:
1) APL2006 – Induction with ATRA + ida 12mg/m2 x
3 days + ara-C 200 mg/m2 x 7 days (7+3)
– Randomization between consolidation chemotherapy with
or without ATO, ara-C later removed from ATO arm due to
toxicity, results ultimately comparable
2) SWOG/Alliance/ECOG S0535 – Untreated high-risk
patients, GO 9 mg/m2 on D1, ATRA + ATO until
remission. Consolidation ATO x 2, ATRA + dauno x 2,
GO x 2, maintenance ATRA + 6MP/MTX
– 3y EFS 79%
Lu et al. Blood, 2002; Kumana et al. Eur J Clin Pharmacol, 2002;
Au et al. Leukemia Res, 2007; Au et al. Blood 2006 and 2008
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Provocative Thoughts Regarding
Treatment of APL
• Current therapy is directed at less chemo and can be cured
with NO chemo
• Current strategies focus early (ED) and late (maintenance)
phases of treatment
• Disease is as sensitive among older adults as younger
• Risk stratification is very simple
• Treatment of relapsed disease is highly effective
• Autograft is treatment of choice in CR2 not allograft
ONY AML WHERE…