aml in elderly · unfit for ict bm blast count > 20 % wbc count < 40 x 109/l decitabine 20...
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AML in elderly
D.Selleslag
AZ Sint-Jan
Brugge, Belgium
BHS GAM 2016
AML is predominantly a disease of the elderly
SEER Cancer Statistics, National Cancer Institute, USA 2002–2006
Available at http://seer.cancer.gov/statfacts/html/amyl.html
incidence2-3/100.000
Projected relative 5-year survival in AML according to age and time period
Gunnar Juliusson et al. Blood 2012;119:3890-3899Swedish Acute Leukemia Registry
Age-related
HOST factors
- Decreased PS
- More Comorbidities
Age-related DISEASE Factors
- More underlying MDS
- More unfavourable cytogenetics
Poorprognosis
Why are treatment results poor in elderly AML ?
Poor treatment
tolerance
Resistant
disease
Elderly population is heterogeneousin terms of fitness
At time of diagnosis we want to identify the patients who are fit to tolerate intensive therapy
In clinical practice
we use performance score
to define fitness
Performance score is more importantthan chronological age for prediction of
day 30 induction mortality r
age < 56 yr 56-65 yr 66-75 yr > 75 yr
PS 0 2 % 11 % 12 % 14 %
PS 1 3 % 5 % 16 % 18 %
PS 2 2 % 18 % 31 % 50 %
PS 3 0 % 29 % 47 % 82 %
% PS 2-3 15 % 24 % 26 % 32 %
Appelbaum et al, Blood, 2006
Performance score has limitations
• Performance score is
– Subjective
– not sensitive to identify vulnerable
patients with limited physiological reserve
capacity
• More objective parameters that define fitness
are derived from retrospective studies
– comorbidity scores
– geriatric assessment scales
• Need prospective validation
Giles F. et al, BJHaem 2007 , 136, 624
HCT-CI Proportion
of pts
Induction
death by
day 28
Overall
survival
(median)
0 22% 3 % 45 weeks
1-2 30% 11 % 31 weeks
3 or more 48% 29 % 19 weeks
N =177, > 60 yrs , treated by intensive AML induction
• N = 74, > 60 yrs, intensive chemotherapy
• ECOG PS 0 or 1 in 78%
• Results of Geriatric Assesment:
– Physical function measured by “Short Physical Performance
Battery” (includes walking speed, chair stands, balance
testing)
– Cognitive function measured by Modified Mini-Mental State
Exam (3MS)
– predict survival independently of tumor and clinical
characteristics, PS and HCT-CI
Blood, 2013, 121:4287
Assesment of elderly AML patient
at diagnosis (H.Klepin)
Diseasebiology
Cytogenetics
Molecularmarkers
Performance score
Comorbidities
HCT-CI
Geriatricassesment
Physical function
Cognitive function
FitNo risk factors
VulnerableImpaired cognitive or
physical function
No major comorbidity
FrailMajor comorbidities
Treatment of elderly AML
Treatment choice and treatment goals are not the same for all elderly AML
Disease biology POOR GOOD
(Karyotype)
Host factors UNFIT FIT
Improve QoL
Prolong survival
Cure
Tre
atm
en
t
inte
ns
ity
Low intensity
treatment
High intensity
treatment
Before 2012: Treatment strategies and
outcome in elderly AML > 65 yrs
Best
supportive
care
LD araC Intensive
chemo
CR (%) 0 15-20 40-65
Median
Overall
Survival
(months)
2 4-6 10
5 yr OS (%) 0 0 15
Effect in
adverse
karyotype
NA No Limited
Induction
• DNR+ Ara C (3+7)
• or variants
Consolidation
• AraC-based (1-2 cycles))
Maintenance
• ??? role
Age, y CR % ED % Cure %
< 60 70-80 < 10 40-50
> 60 40-65 15-20 < 15
Intensive approach
Intensive chemotherapy: induction
• What do we know from randomized studies ?
•Standard: 3 + 7 with
–Dauno 45-60 mg/m2 x 3
–AraC 100 -200 mg/m2 CI x 7
•60-65 yrs: Dauno 90 mg/m2 x 3 : better OS
•No improvement of OS with
–addition of 6TG, etoposide
–new anthracyclins
Intensive therapy: post remission
• What do we know from randomized studies ?
1. Consolidation :
• High vs conventional dose AraC : no advantage
• Multiple (4 vs 1, 4 vs 3) consolidations : no advantage
2. Maintenance:
• LD AraC improves remission duration, but notsurvival
Farag et al, BBMT 2011
CIBMTR/CALGB: 190 AML pts (age 60-70) in CR1
Prospective studies needed
relapseNon relapse mortality
LFS Overall Survival
RIC allo vs chemotherapy in elderly AML
Chemo
Transplant Chemo
ChemoChemo
Transplant
TransplantTransplant
P = 0.08P = 0.001
P < 0.001 P = 0.001
Hypomethylating agents in AML
Hypomethylating Cytosine Analogs
N O
NH2
N
N O
NH2
N
CH3
N O
NH2
NN
Ribose
N O
NH2
NN
Deoxyribose
5-aza-cytidine 5-aza-2’-deoxycytidine5-methyl-cytosineCytosine
(azacitidine) (decitabine)
Vidaza Dacogen(Celgene) (J&J)
CH3 CH3
21
DACO-016: randomized Phase III
Newly diagnosed AML
de novo or sAML
> 65 yrs
Unfit for ICT
BM blast count > 20 %
WBC count < 40 x 109/L
Decitabine 20 mg/m2 IV x 5 days , monthly
Treatment of choice
BSC or
LD AraC 20 mg /m2 SC
for 10 days
N = 485
Primary endpoint: overall survival
Kantarjian et al. J Clin Oncol. 2012; 30(21): 2670-2677
22
OS Ad hoc mature (2010) analysis (446 deaths)
Significant Survival Benefit for decitabine
Kantarjian et al. J Clin Oncol. 2012; 30(21): 2670-2677
23
DACOGEN (decitabine) : EU label
• Adult patients ≥ 65 years
• Newly diagnosed de novo or secondary AML
according to WHO classification (> 20% blasts)
• Not candidate for standard induction chemotherapy
• EU registration since September 2012
• No FDA approval for AML
• Belgian reimbursement since 1 December 2013
23
24
AZA-AML-001 :Randomized Phase III
Newly
Diagnosed
AML*
> = 65 yrs
N = 480
Vidaza
75 mg/m2 SC x 7 days,
repeat q28 days
N = 240
Investigator’s selection
IC (7 +3), LDAC, or BSC
N = 240
A
B
RIn
vesti
ga
tor
Sele
cti
on
IC,
LD
AC
, o
r B
SC
- De novo AML or sAML after MDS
- > 30 % bone marrow blasts and WBC < 15 x 109/l (w/o hydroxyurea)
- ECOG 0-2
- Poor or intermediate cytogenetics
Min 6 cycles
Until PD
Primary endpoint: overall survival
Dombret et al, Blood, 2015,126:291
Overall Survival (ITT)
Pre-planned OS Sensitivity Analysis
Censored for Subsequent AML Therapy*
Censored
Median OS:AZA = 6.4 months (95% CI: 4.2, 8.1), CCR = 3.2 months (2.2, 4.7)HR = 0.68 [95%CI: 0.50, 0.94]; Log-rank P = 0.0185
OS in patients with Poor-risk Cytogenetics
Median OS for AZA vs CCR was calculated using Kaplan-Meier methods, hazard ratios (HR) and 95% confidence intervals (CI) were determined by unstratified Cox proportional hazards model, and P values by log-rank test
AZA
CCR
1-Year Survival: 30.9% vs 14.0% (Δ 16.9%; 95%CI: 4.4%, 29.5%)
3.2 mos
6.4 mos
14.0%
30.1%
28
Comparable overall survival with azacitidine and intensive chemotherapy
September 2015:
Expanded European label
AML > 30 % blasts
65 yrs or older
not eligible for HSCT
Belgian reimbursement under
evaluation
SGI-110 = Guadecitabine (Astex)
2nd generation hypomethylating agent
Other advantages:
- Low injection volume
- Prolonged stability (1 month) after reconstitution
Efficacy of SGI-110 in treatment-naive AML
H. Kantarjian, ASH 2015
ASTRAL 1: Phase III study (first line AML unfit for IC)
SGI-110 vs physician’s choice (LD-AraC,AZA,DAC)
N = 103 5 days 10 days
CR + CRi + CRp 57 % 48%
Overall survival 10.5 mths 8.7 mths
Since 2012: Treatment strategies and
outcome in elderly AML > 65 yrs
Best
supportive
care
LD araC Intensive
chemo
Hypomethylating
agent
Decitabine 5d
Azacitidine 7d
CR (%) 0 15-20 50-55 15-20
Median
Overall
Survival
(months)
2 4-6 10 7-10
5 yr OS (%) 0 0 15 Not curative
unless followed by
allo SCT
Effect in
adverse
karyotype
NA No Limited Moderate
Non M3 AML
Age > 80
Hypomethylatingagent
Age 65-80
Fit and
Good/intermediatekaryotype
Induction 3 + 7
Consolidation x 1/2
Conventional dose AraC
Consider RIC transplant
Unfit or
Poor karyotype
Clinical trial for allpts preferable
Example of treatment algorithm for elderly AML
New targeted therapies for
elderly (and young) adults
with AML
hP67.6
• Humanized mAb to CD33 epitope present on 90% of AML blasts
Covalentlinker
• Cleaved in lysosome
Calicheamicin
• Highly potent cytotoxin
• Binds to dsDNAcausing breaks
• 2-3 bound to each mAb
Human
Mouse
Gemtuzumab Ozogamicin
(Mylotarg) (Pfizer)
Addition of GO to intensive induction chemotherapy improves
survival and relapse in AML with favorable and intermediate
karyotype independent of age :
a meta analysis of 5 randomized trials
R.Hills et al, Lancet Oncology 2014, 15,986-996
Overall survival
Favourable karyotypeOverall survival
intermediate karyotype
AML19 (EORTC-GIMEMA):
GO versus BSC in unfit elderly AML
CR median OS 1 yr OS
GO 27 % 4.9 mths 24.3 %
BSC 0 % 3.6 mths 9.7 %
Amadori et al, ASH 2014
Immunotherapy in development for AML
• Antibody – drug conjugates
– SGN-CD33A (anti CD33 + pyrrolobenzodiazepine
dimer)
CASCADE: newly diagnosed AML unfit for IC
AZA/DAC + SGN-CD33A or placebo
• Bispecific antibodies (BiTE)
– AMG 330 (anti CD33 and CD3)
– MGD 006 (anti CD123 and CD3)
• Stem cell targeting : CD123 = IL3 receptor alfa
– Anti CD123 (CSL362)
– CAR T-123
Flt3 mutations
•30 % of normal karyotype AML are Flt3 receptor mutated•Flt3 ITD or Flt3 D835•Flt3 ITD mutations in AML have a negative prognostic impact •Flt3 mutations are target for inhibitors
RATIFY study : first line , < 60 jr
RATIFY study : first line , < 60 jr
R. Stone et al, ASH 2015, plenary session Midostaurin in combination with IC and 1 yr maintenance improves OS and EFS in FLT3 mutated AML < 60 yrs oldAlso in subgroups with Flt3-ITD low and high and Flt3 TKD
5 yrs OS : 7.7 % difference
Flt3 inhibitors in clinical development
• Quizartinib (Ambit, Daiichi Sankyo)
• Crenolanib (Arog)
• Gilteritinib (ASP-2215) (Astellas)
– CR 30-50% in RR Flt3 ITD + AML
– Frequent incomplete haematological recovery
– Duration of CR 3 months
– Crenolanib, gilteritinib:
• Active against resistance mutations
– Future: - As bridge to allo SCT
- Combination trials with HMA and IC
IDH mutations as a new therapeutic target
• IDH1 mutations: 5-10% of AML, IDH2 mutations: 10-15% of AML
• Negative or no impact on prognosis of AML
• Mutated IDH produces the oncometabolite 2-hydroxyglutarate
• Mutated IDH is a target for IDH inhibitors
First results of IDH inhibition in AML
• AG-120 and AG-221 (Agios)
– first-in-class, oral
– selective inhibitors of the IDH1 and IDH2 mutant enzymes
– inhibit 2-HG accumulation
– promote cell differentiation (> rising neutrophil count with
persisting clone)
N = 121
IDH2 + AML
Relapsed/refractory
Phase I/II dose escalation
ORR = 41%, CR 18%
Response duration 6 mths
Well tolerated
AG 221,
ASH 2015, Stein
AG 120,
ASH 2015, DiNardo
N= 61
IDH1 + AML,MDS
Relapsed/refractory
Phase I Dose escalation
ORR = 36 %, CR 18%
Response duration 5.6 mths
Well tolerated
Flt3/IDH inhibition are
examples of precision medicine
New cytotoxic drugs
O
HNN N N
H3C
CO2H
H3CO
NS
Vosaroxin: A First-in-Class
Anticancer Quinolone Derivative
Key Characteristics
• Targeted topoisomerase II inhibitor
• Active in anthracycline-resistant settings
• Escapes common drug resistance pathways (P-gp)
• Low potential for drug-drug interactions
• Lower potential for off-target damage (cardiotoxicity)
Evanchi. Drug Metab Disp 2009; Hoch. Cancer Chemother Pharmacol 2009; Scaten. ibid 2010; Advani Clin Cancer Res 2010;
Hawtin. PLoS One 2010; Hawtin. Oncotarget 2010; Haematologica 2011; Lancet Leukemia 2011.
Vosaroxin
Quinolone
Core
Vosaroxin intercalates DNA and
inhibits topoisomerase II, causing
DNA breaks and cell death by
apoptosis.
50
VALOR : Phase 3 Randomized Double-blinded, Placebo-controlled
F.Ravandi et al, Lancet Oncology, 2015
*After cycle 1, all subsequent cycles at 70 mg/m2 vosaroxin on days 1 and 4
Study Arm
Control Arm
VOSAROXIN90* mg/m2
days 1, 4
+
Cytarabine (IDAC)1 g/m2
days 1- 5
PLACEBOdays 1, 4
+
Cytarabine (IDAC)1 g/m2
days 1- 5
CR or CRp
CRi, PR or Treatment Failure
Consolidation(1-2 cycles)
Survival Follow Up
Primary Endpoint: Overall Survival (OS)
1:1 Randomization
First Relapsed or Refractory
AML
Stratifications:• Age• Disease
Status• Geography
Induction(1-2 cycles)
51
Intent To Treat Population (N = 451)
median (95% Cl)
5.0 (3.8, 6.4)
7.1 (5.8, 8.1) p = 0.006Vos/Cyt
Pla/Cyt Censored
Censored
VALOR - OS for Patients ≥60 Years of Age(Preplanned Analysis)
CPX-351 (Celator Pharm.)
100-nm bilamellar liposomes
5:1 molar ratio of cytarabine todaunorubicin (maximallysynergistic ratio in cell lines)
Accumulates in BM withpreferential uptake by leukemiccells
Feldman et al, JCO 2011
N.D./AML Age 60-75
PS 0-2
CPX 100 u/m2
d 1, 3, 51-2 Cons
“3+7” regimen 1-2 Cons
OS (sAML)
OS
CPX-351 vs 3+7 (phase 2b)Lancet J, Blood 2014,123: 3239
P=0.61 P=0.01
Cross-over
6.1 vs 12.1 mths