Pr. Mohamad MOHTY
Head, Clinical Hematology and
Cellular Therapy Dpt.
Université Pierre & Marie Curie
Hôpital Saint-Antoine
Paris, France

(A) Age 15 to
59 years
(B) 60 or more years

• AML sensitive to conventional chemotherapy
• CBF leukemias (without c-KIT mutation)
• Diploid AML with NPM1 and CEBP
 mutation (without
FLT3 mutation)
• Dose intensification of chemotherapy may be helpful
• Chemo-resistant and high risk AML
• AML with adverse cytogenetics
• AML with FLT3-ITD
• Others (older patients, younger patients with t-AML and/or AHD)
• New agents are needed
• Allo-SCT in the mainstay of therapy

Therapy for AML (non-APL): Decision checkpoints and Factors influencing therapeutic decisions
Age
Performance status
Diagnosis
Cytogenetics
Intensive CT
Comorbidities
Pharmacogenetics
Molecular profile
Postremission therapy
Relapse
Rescue treatment
MRD persistence

Age group
(yrs)
16-55
56-65
66-75
76-89
WHO/ECOG PS 0-II
Intensive Palliative
WHO/ECOG PS III-IV
Intensive Palliative
N.Pts
% ED N.Pts
% ED N.Pts
% ED N.Pts
% ED
491
344
435
211
4
6
12
22
25
27
8 131 21
14 397 17
38
43
62
56
26
28
4
19
50
63
34 92 54
36 271 52
Juliusson G, et al. Blood 2009;113:4179-87
Although,
• Comorbidity scores may be more discriminant
• Cytogenetics should be taken into account
• Is this true with targeted treatment?
Intensive CT is the first option, regardless of age.
Consider alternative agents if poor cytogenetics

Target
FLT3
KIT (CD117)
Epigenetic changes
RAS
CD33
Class of Agents
FLT3-inhibitors
- Non specific
- Specific
TKI (imatinib, dasatinib)
Hypomethylating agents
- HDAC inhibitors
FT inhibitors
Anti-CD33 MoAbs

hP67.6 conjugated to NAc-calicheamicin
O hP67.6
NH
I
O
CH
3
HO
OCH
3
O
OH
O
O Me Me
CH
3 O
S
OCH
3
OCH
3
NHN
Me
CH
3
O
OH
CH
3
CH
3
CH
2
N
O
HN
HO
CH
3
O
O
OCH
3
S
S
O
O
HO
O
H
O
NH
O
OCH
3

Fractionated Doses of Gemtuzumab Ozogamicin Combined to
Standard ChemotherapyIn Newly-Diagnosed de novo AML Patients
Aged 50-70 Yrs
Randomization
Arm A Arm B
DNR 60 mg/m 2 D1 to D3
AraC 200 mg/m 2 D1 to D7
DNR 60 mg/m 2 D1 to D3
AraC 200 mg/m 2 D1 to D7
GO 3 mg/m 2 D1, D4, D7
2 nd course if BM blasts >10% at D15
DNR 60 mg/m 2 D1, D2
AraC 1g/m 2 /12h D1 to D3
INDUCTION
CR or CRp
DNR 60 mg/m 2 D1
AraC 1g/m 2 /12h D1 to D4
DNR 60mg/m 2 D1,D2
AraC 1g/m 2 /12h D1 to D4
DNR 60 mg/m 2 D1
AraC 1g/m 2 /12h D1 to D4
GO 3 mg/m 2 D1
1st CONSOLIDATION
DNR 60 mg/m2 D1,D2
AraC 1g/m 2/ 12h D1 to D4
GO 3mg/m 2 D1
2nd CONSOLIDATION
Castaigne et al., Lancet 2012

GO arm
EFS
Events
Median
A
(control)
(n=139)
104
11,9 mo
B (GO)
(n=139)
76
19.6 mo
2-year
HR
(95% CI)
16.5%
1
41.1%
0.57
(0.42-0.77)
P= 0.00018
by the log-rank test
Control arm
Castaigne et al., Lancet 2012

GO arm
Control arm
OS
Deaths
Median
A (control)
(n=139)
71
19.2 mo
B
(GO)
(n=139)
59
34 mo
2-year
HR
(95% CI)
43.5%
1
53.1%
0.70
(0.50-0.99)
P= 0.046
by the log-rank test
Castaigne et al., Lancet 2012

DNA Methylation
M M M M
•
5-Azacytidine
Decitabine
Histone Modification
Phosphorylation
Methylation
Acetylation
SAHA
Valproic acid
Belinostat

•
358 pts AZA-001; 113

20% blasts
(WHO AML)
•
55 randomized to AZA, 58 to CCR
•
Median age 70 y.; poor cytogen 24%
•
Median FU 20 m.; median cycles 8 (1-39)
•
Parameter AZA
- Median OS (m) 24
- % 2-yr survival 50
CCR P
16 .004
16 .004
- % CR 18 16 NS
•
Survival better in int cytogen., not in unfavourable cytogenetics.
Fenaux et al. J Clin Oncol 2010

Decitabine
CR/CRp
Decitabine
TC
P=.001
17.8%
7.8%
Kantarjian H, J Clin Oncol, 2012

NH
2
N
N
F
HO
N
O
HO
N
NH
2
N
N
Cl
HO
N
O
N Cl
HO
N
NH
2
N
N
N
O
F
HO
HO HO

Phase I
32 pts with acute leukemia: CR 6%; OR 15%
MTD: 40 mg/m 2 /d i.v. x 5d; DLT: hepatotox.
Phase II
N Median age
(yr)
16 71 (60-83)
CR
(%)
OR
(%)
Frontline * Faderl 1
Salvage
Burnett 2
Kantarjian 3
Foran 4
* CLO 30 mg/m 2 /dose
36
31
14
> 70
54 (19-82)
54 (20-78)
31
44
42
7
31
56
55
7
1 Blood 2005; 106: 786a; 2 Haematologica 2006; 91 (s1): 45; 3 Blood 2003; 102: 2379; 4 Blood
2002; 100: 271b

- N=106
Median age= 71 years
(range, 60-84)
30% adverse-risk cytogenetics
36% WHO PS ≥2
48% CR (32% CR, 16%
CRi)

Clofarabine + cytarabine combination studies
Faderl
2005
Powell
2008
Becker
2008
N
29 63 (18 –84)
39 53 (18 –79)
16
Age (y)
18 –70
Dose*
CLO 40 x 5
Ara-C 1 x 5
CLO 40 x 5
Ara-C 2 x 5
CLO 15,20,25 x 5
Ara-C 2 x 5
G-CSF
Response
CR 24%; OR
41%; IM 3%
CR 38%; OR
43%; IM 8%
5/8 CR
O/E (HDAC,
FLAG) 3.2:1
* CLO mg/m 2 ; Ara-C g/m 2
 The next question: anthracycline combinations with clofarabine and cytarabine (at diagnosis and at relapse)…
1. Faderl S et al. Blood 2005;105:940 2. Powell B et al. Blood 2008;112:Abstract 1936
3. Becker PS et al. Blood 2008;112:Abstract 2964

(Br J Haematol 3: 241, 1957)
 Much of the success of allo-SCT in cancer is due to the
Graft-vs.-Tumor effect
Myeloablative HCT (MTX)
Years after Sibling Marrow Grafts
Weiden et al., N. Engl. J. Med. 300:1068, 1979

Weiden et al., N. Engl. J. Med. 304:1529, 1981.

H
S
C
T
EBMT Activity Survey on HSCT 1990-2009: changes in AML
 Increase of allo-
SCT as from 2001 due to:
- Introduction of RIC
- Increased use of alternative donors
The European Group for Blood and Marrow Transplantation
H.B. 3.2011

I.V. BU-based Reduced Toxicity Conditioning (RTC) platform  towards a patient-tailored conditioning
Fludarabine 30 mg/m²/d
(or Clofarabine)
I.V. Busulfan
3.2 mg/Kg/d
Thymoglobuline
2.5 mg/Kg/d
Cyclosporine 3 mg/Kg/d
MMF (2 g/d if MUD)
PBSC d-6 d-5
X X d-4
X d-3
X d-2 d-1 d0
X
(X) (X) (X) X
X X
X
X
X
X
X X 
X X 
X

RIC alloSCT for AML: “donor” vs. “no donor”
(N=95; Intention-to-treat analysis)
Median FU = 60 months
“no donor” group
P=0.003
P=0.003
“No donor” group
Time (months)
Time (months)
 In the multivariate analysis, only actual performance of RIC-allo-
SCT (P=0.0005; RR=4.1;
95%CI, 1.8-9.1), was significantly predictive of an improved long term
LFS
Mohty et al., Leukemia, 2005
Leukemia, 2009

I.V. Bubased “submyeloablative" conditioning
(FB3): Prospective Multicentre Trial, N=80
Day
Bu
130 mg/m 2 qd
Flu
30 mg/m 2 qd
Thymoglobuline
2.5 mg/Kg
PBSC
-6 -5 -4 -3 -2 -1 0
  
    
 


I.V. Bubased “submyeloablative" conditioning
(FB3): Prospective Multicentre Trial; N=80
NRM
10%
0 2 4 6 8 10 12 14
Protocol NCT 00841724; Mohty et al. ASH 2012

•
AML therapy remains non-specific and challenging for most patients
•
A number of demographic features can predict the outcome of treatment including cytogenetics and an increasing list of molecular features (ie, FLT3, NPM1, MLL, WT1, CEBPalpha,
EVI1)  multi-agent approach needed
•
Emerging therapies are promising, and targeted therapies started addressing small subgroups, BUT allo-SCT will remain the recommended treatment for many patients !
•
RTC allo-SCT appears increasingly to be a safer procedure in the “older” AML patients