Download - Elderly AML by Mohamad Mohty
"Challenges in Treatment of"Challenges in Treatment of
Elderly AML"Elderly AML"
Pr. Mohamad MOHTYHead, Clinical Hematology and
Cellular Therapy Dpt.Université Pierre & Marie Curie
Hôpital Saint-AntoineParis, France
AML: Change in overall survival with time
(A) Age 15 to 59 years
(B) 60 or more years
Simplified Classification of AML
• 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 Therapy for AML (non-APL): Decision checkpoints and Factors influencing therapeutic decisions and Factors influencing therapeutic decisions
Diagnosis
Intensive CT
Postremission therapy
Rescue treatment
Relapse
Performancestatus
Age
Comorbidities
Cytogenetics
Molecular profile
MRD persistencePharmacogenetics
Early death seems to be increased if palliative-low dose treatment is administered
WHO/ECOG PS 0-II WHO/ECOG PS III-IV
Intensive Palliative Intensive Palliative
N.Pts % ED N.Pts % ED N.Pts % ED N.Pts % ED
491 4 12 25 38 26 4 50
344 6 22 27 43 28 19 63
435 8 131 21 62 34 92 54
211 14 397 17 56 36 271 52
Age group
(yrs)
16-55
56-65
66-75
76-89
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
Targeting molecular abnormalities
Target Class of Agents
FLT3 FLT3-inhibitors- Non specific
- Specific
KIT (CD117) TKI (imatinib, dasatinib)
Epigenetic changes - Hypomethylating agents
- HDAC inhibitors
RAS FT inhibitors
CD33 Anti-CD33 MoAbs
Me
O
O
NH
S
H
HOO
OCH3
NH O
O
OCH3
N
CH3CH2
O
OHOCH3
HOCH3
OCH3
HNHO
OO
OH
CH3
S
CH3
OCH3
OCH3
I
O
O
O
O
S
O
NHN
Me Me
O
CH3
hP67.6
hP67.6 conjugated to NAc-calicheamicin
Gemtuzumab Ozogamicin (GO)
Arm A Arm B
2nd course if BM blasts >10% at D15DNR 60 mg/m2 D1, D2
AraC 1g/m2/12h D1 to D3
INDUCTION
1st CONSOLIDATION
2nd CONSOLIDATION
Fractionated Doses of Gemtuzumab Ozogamicin Combined to Standard ChemotherapyIn Newly-Diagnosed de novo AML Patients
Aged 50-70 Yrs
Randomization
CR or CRp
DNR 60 mg/m2 D1 to D3AraC 200 mg/m2 D1 to D7
DNR 60 mg/m2 D1 AraC 1g/m2/12h D1 to D4
DNR 60mg/m2 D1,D2 AraC 1g/m2/12h D1 to D4
DNR 60 mg/m2 D1 to D3AraC 200 mg/m2 D1 to D7GO 3 mg/m2 D1, D4, D7
DNR 60 mg/m2 D1 AraC 1g/m2/12h D1 to D4GO 3 mg/m2 D1
DNR 60 mg/m2 D1,D2 AraC 1g/m2/12h D1 to D4GO 3mg/m2 D1
Castaigne et al., Lancet 2012Castaigne et al., Lancet 2012
Event-free survival
EFS A (control)(n=139)
B (GO)(n=139)
Events 104 76
Median 11,9 mo
19.6 mo
2-year 16.5% 41.1%
HR(95% CI)
1 0.57 (0.42-0.77)
P= 0.00018by the log-rank test
GO arm
Control arm
Castaigne et al., Lancet 2012Castaigne et al., Lancet 2012
Overall survival
OS A (control) (n=139)
B (GO)
(n=139)
Deaths 71 59
Median 19.2 mo
34 mo
2-year 43.5% 53.1%
HR(95% CI)
1 0.70(0.50-0.99)
P= 0.046by the log-rank test
GO arm
Control arm
Castaigne et al., Lancet 2012Castaigne et al., Lancet 2012
Epigenetic Therapy
M M M M
DNA Methylation Histone Modification
Phosphorylation
Methylation
Acetylation
5-AzacytidineDecitabine
SAHAValproic acid
Belinostat•
Azacitidine in AML
• 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 CCR P
- Median OS (m) 24 16 .004
- % 2-yr survival 50 16 .004
- % CR 18 16 NS
• Survival better in int cytogen., not in
unfavourable cytogenetics.
Fenaux et al. J Clin Oncol 2010
Randomized trial of Decitabine vs. treatment of choice in AML ≥ 65 years
Kantarjian H, J Clin Oncol, 2012
CR/CRp Decitabine 17.8%TC 7.8%
P=.001
Decitabine
N
N N
N
OHO
HO
NH2
F
HO
Deoxyadenosine analogues
N
N N
N
OHO
HO
NH2
Cl
N
N N
N
NH2
OHO
HO
Cl
F
Fludarabine Cladribine Clofarabine
Single Agent Clofarabine in AMLSingle Agent Clofarabine in AML
• Phase I 32 pts with acute leukemia: CR 6%; OR 15% MTD: 40 mg/m2/d i.v. x 5d; DLT: hepatotox.• Phase II
N Median age
(yr)
CR (%)
OR (%)
Frontline * Faderl1 16 71 (60-83) 31 31
Burnett2 36 > 70 44 56
Salvage Kantarjian3 31 54 (19-82) 42 55
Foran4 14 54 (20-78) 7 7
* CLO 30 mg/m2/dose
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
1. Faderl S et al. Blood 2005;105:940 2. Powell B et al. Blood 2008;112:Abstract 19363. Becker PS et al. Blood 2008;112:Abstract 2964
N Age (y) Dose* Response
Faderl2005
29 63 (18–84)CLO 40 x 5
Ara-C 1 x 5CR 24%; OR 41%; IM 3%
Powell 2008
39 53 (18–79)CLO 40 x 5
Ara-C 2 x 5CR 38%; OR 43%; IM 8%
Becker 2008
16 18–70
CLO 15,20,25 x 5
Ara-C 2 x 5
G-CSF
5/8 CR O/E (HDAC, FLAG) 3.2:1
* CLO mg/m2; Ara-C g/m2
The next question: anthracycline combinations with clofarabine and cytarabine (at diagnosis and at relapse)…
Much of the success of allo-SCT in cancer is due to the
Graft-vs.-Tumor effect
Confirming Barnes et al. (Br J Haematol 3: 241, 1957)
Weiden et al., N. Engl. J. Med. 300:1068, 1979 Weiden et al., N. Engl. J. Med. 304:1529, 1981.
Myeloablative HCT (MTX)
Years after Sibling Marrow Grafts
The European Group for Blood and Marrow TransplantationH.B. 3.2011
H.B. 3.2011
EBMT Activity Survey on HSCT 1990-2009:changes in AML
HSCT
Increase of allo-SCT as from 2001 due to:
- Introduction of RIC- Increased use of
alternative donors
Flu-TBI 2 G
y.
d-6 d-5 d-4 d-3 d-2 d-1 d0
Fludarabine 30 mg/m²/d(or Clofarabine)
X X X X X
I.V. Busulfan3.2 mg/Kg/d
(X) (X) (X) X
Thymoglobuline2.5 mg/Kg/d
X X
Cyclosporine 3 mg/Kg/d X X X X
MMF (2 g/d if MUD) X X X X
PBSC X
I.V. BU-based Reduced Toxicity Conditioning (RTC) platform towards a patient-tailored conditioning
RIC allo-SCT for AML: “donor” vs. “no donor” (N=95; Intention-to-treat analysis)
Median FU = 60 months
Ove
rall
surv
ival
(“i
nte
nti
on
to
tre
at”)
“donor” group
“no donor” group
Time (months)
P=0.003
Ove
rall
su
rviv
al
Time (months)
“donor” group
“No donor” group
P=0.003
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
Day -6 -5 -4 -3 -2 -1 0Bu 130 mg/m2 qdFlu 30 mg/m2 qdThymoglobuline 2.5 mg/KgPBSC
I.V. Bu-based “submyeloablative" conditioning (FB3): Prospective Multicentre Trial, N=80
I.V. Bu-based “submyeloablative" conditioning (FB3): Prospective Multicentre Trial; N=80
NRM
0 2 4 6 8 10 12 14
0.0
0.2
0.4
0.6
0.8
1.0
10%
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
Conclusions