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Elderly AML by Mohamad Mohty
1. "Challenges in Treatment of"Challenges in Treatment of
Elderly AML"Elderly AML"
Pr. Mohamad MOHTY
Head, Clinical Hematology and
Cellular Therapy Dpt.
Université Pierre & Marie Curie
Hôpital Saint-Antoine
Paris, France
2. AML: Change in overall survival with time
(A) Age 15 to
59 years
(B) 60 or
more years
3. Simplified Classification of AML
• AML sensitive to conventional chemotherapy
• CBF leukemias (without c-KIT mutation)
• Diploid AML with NPM1 and CEBPα 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
4. Therapy for AML (non-APL): Decision checkpointsTherapy for AML (non-APL): Decision checkpoints
and Factors influencing therapeutic decisionsand Factors influencing therapeutic decisions
Diagnosis
Intensive CT
Postremission
therapy
Rescue treatment
Relapse
Performance
status
Age
Comorbidities
Cytogenetics
Molecular profile
MRD persistencePharmacogenetics
5. 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
6. 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
8. Arm A Arm B
2nd
course if BM blasts >10% at D15
DNR 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 D3
AraC 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 D3
AraC 200 mg/m2
D1 to D7
GO 3 mg/m2
D1, D4, D7
DNR 60 mg/m2
D1
AraC 1g/m2
/12h D1 to D4
GO 3 mg/m2
D1
DNR 60 mg/m2 D1,D2
AraC 1g/m2/
12h D1 to D4
GO 3mg/m2
D1
Castaigne et al., Lancet 2012
9. 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= 0.00018
by the log-rank test
GO arm
Control arm
Castaigne et al., Lancet 2012
12. Epigenetic Therapy
M M M M
DNA Methylation Histone Modification
Phosphorylation
Methylation
Acetylation
5-Azacytidine
Decitabine
SAHA
Valproic acid
Belinostat
•
13. 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
14. 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
16. Single 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
17. - N=106
- Median age= 71 years
(range, 60-84)
- 30% adverse-risk
cytogenetics
- 36% WHO PS≥2
- 48% CR (32% CR, 16%
CRi)
18. Clofarabine + cytarabine combination studies
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
N Age (y) Dose* Response
Faderl
2005
29 63 (18–84)
CLO 40 x 5
Ara-C 1 x 5
CR 24%; OR
41%; IM 3%
Powell
2008
39 53 (18–79)
CLO 40 x 5
Ara-C 2 x 5
CR 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)…
19. 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
20. The European Group for Blood and Marrow Transplantation
H.B. 3.2011
EBMT Activity Survey on HSCT 1990-2009:
changes in AML
H
S
C
T
Increase of allo-
SCT as from 2001
due to:
- Introduction of RIC
- Increased use of
alternative donors
22. 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. Busulfan
3.2 mg/Kg/d
(X) (X) (X) X
Thymoglobuline
2.5 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
23. RIC allo-SCT for AML: “donor” vs. “no donor”
(N=95; Intention-to-treat analysis)
Median FU = 60 months
Overallsurvival(“intentiontotreat”)
“donor” group
“no donor” group
Time (months)
P=0.003
Overallsurvival
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
26. • 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
Editor's Notes
This progress in the outcome of young and middle age adults with AML is in part due to a better selection of the treatment option availables, based on classic and new prognostic indicators. The current status of both, prognostic parameters and risk adapted therapy for adults with non APL will be summarized in this lecture. This slide reflects the usual approach for AML patients including the different decission steps and the possible treatment choices. At diagnosis the first decission is whether the patient is candidate for no therapy, low dose treatment or intensive chemotherapy. If the latter is administered and a CR is achieved practically all the patients receive one consolidation course and further treatment that may be postremission intermediate or high dose chemotherapy or hematopoietic transplantation. Subsequently, in contrast to ALL, only a minority of the patients receive further low or moderate dose maintenance, usually in the setting of clinical trials. If the patient unfortunately relapses, the options are no further treatment or low or high dose rescue therapy. What aspects may guide us to take between all these options the most appropriate choice in particular patients?
However, despite the higher frequency of impaired PS in the elderly population, early death occuring in the first month after diagnosis was significanlty more frequent with palliative measures than with intensive treatment, across all age groups and WHO grades, in exception of very old patients with good PS. Although these findings would favor intensive treatment in all cases, these data have some limitations: first, we have now comorbidity scores developed for transplantation that may be more precise than PS, second, cytogenetic categories were not considered and it is well know the poor chemosensitivity of AML with poor risk cytogenetics, particularly in the elderly. In contrast, encouraging results have been communicated in patients with abnormalities in chromosome 7, 5 and complex karyotype with demethylating and antiangiogenic agents. Also, investigational targeted therapy deserves to be investigated in the old and fragile patients.
Adult AML Slide Deck Master 08/22/13 03:53 A major area of progress and one of the most promising classes of therapeutic agents relate epigenetic or differentiation therapy. In addition to the impact of chromosomal abnormalities, gene expression in cancer cells in general, and to a high degree especially in myeloid malignancies, may be silenced by epigenetic alterations of DNA, which happens through two broad mechanisms: Global hypermethylation of DNA and promotors and changes in chromatin structure by modification of histone structures. Epigenetic alterations have been associated with disease progression and worse outcome for patients with myeloid leukemias and MDS and hence efforts to reverse these processes take an increasingly prominent role in current AML and MDS therapy.
Clofarabine is a second generation purine nucleoside analogue with significant single agent activity in patients with AML and ALL
