Allogeneic HSCT in Elderly. Didier Blaise

1. Allogeneic HSCT in elderlies
a chimera?
Didier Blaise, MD
AUBOH 2015, Bangkok
August 28th, 2015

2. Epidemiology
70 %
Smith,JCO

3. AML in elderlies…
5-year relative survival rates with
respect to age in patients with
AML1
0
10
20
30
40
50
%
Age, years
<45 45–54 65+55–64
1. Howlader N, et al (eds). SEER Cancer Statistics Review, 1975-2008
(2010); available at http://seer.cancer.gov/csr/1975_2008/
2. Appelbaum FR et al, Hematology Am Soc Hematol Educ Program
2001:62–86
OS in patients aged >55 years
(ECOG data from 1973–1997)2

4. 4y à 48 %
4y à 37 %
4

5. Allogeneic HSCT in elderlies
• Needs to address
– Specific approaches
• Conditioning
• Graft
• Donor
– Patient selection
5

6. RIC=Reduced intensity conditioning14 patients (2001-2003)
Age : 62
RIC
Sibling :13/MUD : 1
6

7. Long-term Outcome372 patients (98-08)
Age : 64 [60-75]
HLA identical 91 %
NMAC : Flu5/TBI2
HCT-CI>3:47%
Sorror, JAMA 2011
5y 27% 5y 41% 5y 35%
Results need improvement
Age ≠ Prognostic
7

8. Prospective phase II clinical trial
RIC MRD Allo HSCT
over the Age of 55 Years
75 patients
Age :60 [55-70]
Hematologic Malignancies
HLA Ident Sib
RIC : Flu5-Bu2-ATG2
Blaise, Haematologica 2015
2y 36 %
1y 9 %
2y 67 %
2y 51 %
8

9. RIC MRD Allo HSCT
over the Age of 55 Years
2y 36 %
1y 9 %
2y 67 %
2y 51 %
9
75 patients
Age :60 [55-70]
Hematologic Malignancies
HLA Ident Sib
RIC : Flu5-Bu2-ATG2
N NRM P OS P
Age
< 60
≥ 60
33
42
12 %
17 %
0,650 61%
45%
0,579
Karnofsky index
90-100
≤80
48
19
7%
26%
0,020 42%
56%
0,146
HCT-CI
0-2
≥ 3
26
47
20%
13%
0,514 39%
62%
0,094
Disease risk index
Low
Intermediate
High/Very High
8
53
12
13%
9%
25%
0,500 88%
56%
31%
0,041

10. Patients reporting an impaired EORTC score one year after HSCT
81.3%
70.6%
75.0%
71.4%
82.4%
81.2%
63.2%
75.0%
-40% -20% 0% 20% 40% 60% 80% 100%
Pain
Fatigue
Social Functining
Cognitive Functioning
Emotional Functioning
Physical Functioning
Role Functioning
Global Quality of Life
Situation impaired when compared to day -6 Situation equal or not impaired when compared to day-6
RIC MRD Allo HSCT
over the Age of 55 Years
10Blaise D, et al. Haematologica 2015

11. • Patients (n=516)
– Period: 2008-2012
– Median age at allo-HSCT: 63 years (range: 60-74)
– Disease: Myeloid disorders (65%), Lymphoid disorders (35%)
– Donors: HLA matched unrelated donors (URD) (96%)
– RIC regimen: Fludarabine-based (91%)]
– Stem cells source: PBSC (92%)
– Disease status at allo-HSCT: early (65%), advanced (35%)
– EBMT score: 75% with score ≥ 2
– GVHD prophylaxis: CSA + MMF (47%), CSA + methotrexate (20%)
• No statistical difference between the group of patients with age < 65 years (60-65),
N=374 (72%) and patients with age ≥ 65 years, N=142 (28%).
Allogeneic HSCT after RIC for patients ≥ 60 years
with hematological malignancies using unrelated
donors

12. Progression-Free Survival
Allo-HSCT in elderly patients
• PFS at 2 years:
– Group ≤ 65 years: 42% (37-47), median = 14.5 months
– Group > 65 years: 47% (39-56), median = 16.6 months
p=0.60
≤ 65 years
> 65 years

13. Allo HSCT beyond 60 years:
Institut Paoli Calmettes
• 2005 to 2014
• 263 patients
• Median Fup:34 months
13

14. Age
(médiane, extrêmes)
63 (60-72)
60-65 190 (72%)
65-70 65 (25%)
>70 8 ( 3%)
Sexe
Femme 111 (42%)
Homme 152 (58 %)
HCT-CI ≥3 120 (45 %)
Diagnosis
ACUTE LEUKEMIA 95 (36%)
AML 84
ALL 8
MIXTE 3
CML 4
CLL 13
LPC 1
LYMPHOMA 53 (20 %)
NHL 51
HD 2
MULTIPLE MYELOMA 37 (14 %)
MDS 41 (15 %)
MYELOFIBROSIS 11
MDS/PMS 8
Disease Risk Index (DRI)
Low 51(19 %)
Intermediate 160(61 %)
High/Very High 52(20 %)

15. Source
PBSC 234 (89%)
BM 9 ( 3%)
Cord Blood 17 ( 6%)
PBSC+BM 3 ( 1%)
Compatibilité HLA
HLA Id Sibling 106 (40%)
MUD 97 (37%)
MMUD 28 (10%)
Haplo 32 (12 %)
Conditionnement
NMAC 70 (26 %)
RIC 177 (67 %)
RTC 16 ( 6 %)
15

16. GVH aigue II-IV 31 %
III-IV 15 %
GVH
chronique
Limitée/extensive 27%
Extensive 18 %
GVHD
16

17. HLA identical HSCT in 205 patients
17
J100 9%
1 an 23%
3 ans 28%

18. 0 1 2 3 4 5
0.00.20.40.60.81.0
205
60
127
27
95
15
68
9
40
4
24
4
0 1 2 3 4 5
0.00.20.40.60.81.0
205
60
113
24
76
15
51
8
32
3
22
3
0 1 2 3 4 5
0.00.20.40.60.81.0
205
60
113
24
76
15
51
8
32
3
22
3
0 1 2 3 4 5
0.00.20.40.60.81.0
205
60
113
24
76
15
51
8
32
3
22
3
No différence!
OS
PFS
RI
NRM
HLA id
Non HLA id
18
HLA id HSCT in 205 pts

19. HLA identical Donors in elderlies?
- elderly
- Comorbidities: frequent contra-indication for donation
- Clonal hematopoiesis?
19
What about siblings?

20. %
Genovese, NEJM 2014 20

21. Alternative Donors?
Haplo-ID HSCT
Retrospective Study of 2 strategies• Patients
– Age > 55 years
– High risk hematologic malignancies
• Innovation: Haplo HSCT patients : N=31
– 5 to 2 Ag MM
– Negative DSA
– Modifications according to learning process: Graft, CDT
• Standard: UD and MRD: N= 47+63
– Same period
– 9 or 10/10
– RIC: F5-BX2-ATG2
21

22. Haplo
N 31
Median age 62 (56-73)
HCT-CI > 2 58%
Myeloid Malignancies 48%
Active Disease 39%
High/Very High DRI 35%
CDT
NMAC
RIC
TT-RTC
F5BX2S2
21 (68%)
6 (19%)
4 (12%)
PBSCT 87%
HLA sib
N 47
UD
N 63
62 (55-71) 64 (60-68)
55% 49%
46% 51%
40% 30%
25% 27%
100% 100%
100% 95%
22

23. Haplo
N 31
Graft Failure 1
3-4 aGVHD 10%
Ext cGVHD 0%
NRM 9%
Relapse 28%
2y OS 70%
2y PFS 67%
2y PFS w/o ext cGVHD 67%
HLA sib
N 47
UD
N 63
0 0
13% 25%
11% 15%
10% 36%
28% 29%
77% 51%
64% 38%
51% 31%
23
0 12 24 36 48
0
50
100
Months Post-Transplant
Percentsurvival
PFS
Haplo MRD UD
0 12 24 36 48
0
50
100
Months Post-Transplant
Percentsurvival
Haplo MRD UD
PFS w/o ext cGVHD

24. Comparison of 2 allo HSCT strategies for
patients older than 55 years and lacking MRD
• Primary Question
– One year DFS w/o ext cGVHD
• Starting time:
– Day of no MRD
• Population
– High risk hematologic malignancies
• Numbers: 54 patients per arm
• Secondary questions
– other
– QOL
– Economic evaluation
24
• Prospective Study
– HAPLO
• F5Bx2
• Thiothepa: 5mg
• HD Cy post HSCT
• CyA+MMF
– MUD 10/10 and 9/10
• F5Bx2
• ATGx2
• CyA+MMF
• Graft
– PBSC

25. Conclusion
• Feasibility of allo HSCT in elderly
• No more GVHD!
• HLA id is not a prerequisite!
• Needs
– Better antitumoral activity
– Lower toxicity by tailoring approach
25

26. 26
• Eligibility
• Age 55-65 or Cormorbidities
• Poor prognosis AML/MDS
• HLA identical RD or UD
• Primary endpoint : 2 year PFS
• Sample size: 177 patients
• Quality of life study
• Economics
• Non interventional PK
• BX Pharmacogenomics
National Prospective Trial on dose
intensity of conditioning
NCT0198506

27. Donor
Conditioning
Patient
-3 -2 -1-4-6 -5 0
GVHD prophylaxis
Chimerism
Individualized Immunotherapy
• Cellular therapy: DLI, NK-DLI , Treg
• Tumor Antigen vaccination: WT1…
• Post graft drugs: Aza, Lenalidomide,
anti-NKG2A moab…
• CAR-T? Checkpoint inhibitors?
Allo-HSCT
Disease
Relapse
27

28. Importance of Geriatric assessment
Muffly,Haematologica;2014 28

29. Oncogeriatric evaluation
Selection and care…
29
• Since 2012
• Patients > 65 years
• With Geriatric MDs
- Pre-HSCT, 3 m, 1 y

30. Therapeutic Education Program (TEP)
• Labelized TEP
• To improve OS and QOL
30

31. Conclusion
• Allo HSCT in elderly is achievable
• Better outcome to be achieved if
needs and reality of this population
taken into account
31

32. 32
Collaborations
– FB Petersen, Intermountain HC, SLC
– M Mohty, St Antoine, Paris
– B Andersson, MD Anderson, Houston
– L Luznick, E Fuchs, Johns Hopkins, Baltimore