allogeneic hsct in elderly
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Allogeneic HSCT in elderliesa chimera?
Didier Blaise, MDAUBOH 2015, Bangkok
August 28th, 2015
Epidemiology
70 %
Smith,JCO 2009
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
4y à 48 %
4y à 37 %
4
Allogeneic HSCT in elderlies• Needs to address
– Specific approaches• Conditioning• Graft• Donor
– Patient selection
5
RIC=Reduced intensity conditioning14 patients (2001-2003)Age : 62RICSibling :13/MUD : 1
6
Long-term Outcome372 patients (98-08)Age : 64 [60-75]HLA identical 91 %NMAC : Flu5/TBI2HCT-CI>3:47%
Sorror, JAMA 2011
5y 27% 5y 41% 5y 35%
Results need improvement
Age ≠ Prognostic
7
Prospective phase II clinical trialRIC 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
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-ATG2N NRM P OS P
Age< 60≥ 60
3342
12 %17 %
0,650 61%45%
0,579
Karnofsky index90-100≤80
4819
7%26%
0,020 42%56%
0,146
HCT-CI0-2≥ 3
2647
20%13%
0,514 39%62%
0,094
Disease risk indexLowIntermediateHigh/Very High
85312
13% 9%25%
0,500 88%56%31%
0,041
10
Patients reporting an impaired EORTC score one year after HSCT
Pain
Fatigue
Social Functining
Cognitive Functioning
Emotional Functioning
Physical Functioning
Role Functioning
Global Quality of Life
-40% -20% 0% 20% 40% 60% 80% 100%
81.3%
70.6%
75.0%
71.4%
82.4%
81.2%
63.2%
75.0%
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
Blaise D, et al. Haematologica 2015
• 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
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
Allo HSCT beyond 60 years: Institut Paoli Calmettes
• 2005 to 2014 • 263 patients• Median Fup:34 months
13
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 %)
SourcePBSC 234 (89%)
BM 9 ( 3%)
Cord Blood 17 ( 6%)
PBSC+BM 3 ( 1%)
Compatibilité HLAHLA Id Sibling 106 (40%)
MUD 97 (37%)
MMUD 28 (10%)
Haplo 32 (12 %)
ConditionnementNMAC 70 (26 %)
RIC 177 (67 %)
RTC 16 ( 6 %)
15
GVH aigue II-IV 31 %III-IV 15 %
GVH chronique
Limitée/extensive 27%
Extensive 18 %
GVHD
16
HLA identical HSCT in 205 patients
17
J100 9%
1 an 23%
3 ans 28%
0 1 2 3 4 5
0.0
0.2
0.4
0.6
0.8
1.0
20560
12727
9515
689
404
244
0 1 2 3 4 5
0.0
0.2
0.4
0.6
0.8
1.0
20560
11324
7615
518
323
223
0 1 2 3 4 5
0.0
0.2
0.4
0.6
0.8
1.0
20560
11324
7615
518
323
223
0 1 2 3 4 5
0.0
0.2
0.4
0.6
0.8
1.0
20560
11324
7615
518
323
223
No différence!
OS
PFS
RINRM
HLA id Non HLA id
18
HLA id HSCT in 205 pts
HLA identical Donors in elderlies?
- elderly- Comorbidities: frequent contra-indication for donation- Clonal hematopoiesis?
19
What about siblings?
%
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
22
HaploN 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-RTCF5BX2S2
21 (68%)6 (19%)4 (12%)
PBSCT 87%
HLA sibN 47
UDN 63
62 (55-71) 64 (60-68)55% 49%46% 51%
40% 30%25% 27%
100% 100%
100% 95%
23
HaploN 31
Graft Failure 13-4 aGVHD 10%Ext cGVHD 0%NRM 9%Relapse 28%2y OS 70%2y PFS 67%2y PFS w/o ext cGVHD 67%
HLA sibN 47
UDN 63
0 013% 25%11% 15%10% 36%28% 29%77% 51%64% 38%51% 31%
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
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
• 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
DonorConditioning
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
Importance of Geriatric assessment
Muffly,Haematologica;2014 28
Oncogeriatric evaluationSelection and care…
29
• Since 2012• Patients > 65 years• With Geriatric MDs- Pre-HSCT, 3 m, 1 y
Therapeutic Education Program (TEP)
• Labelized TEP• To improve OS and QOL
30
Conclusion• Allo HSCT in elderly is achievable• Better outcome to be achieved if needs and reality of this population
taken into account
31
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Collaborations– FB Petersen, Intermountain HC, SLC– M Mohty, St Antoine, Paris– B Andersson, MD Anderson, Houston– L Luznick, E Fuchs, Johns Hopkins, Baltimore
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