hematopoietic stem cell transplantation in systemic sclerosis
TRANSCRIPT
HEMATOPOIETIC STEM CELL TRANSPLANTATION IN SYSTEMIC SCLEROSIS
The European Group for Blood and Marrow Transplantation
Pr Dominique Farge, Hôpital St Louis, UH04Paris 7 Denis Diderot University, France,
Groupe Français de Recherche sur la SclérodermieADWP EBMT Chair
EUSTAR
Diffuse Cutaneous
Limited Cutaneous
pulmopnary hypertensionmalabsorption
IntermediateLate
LateIntermediate
joint contractures,GI, lung, heart, kidney
5 10 20
SK
IN T
HIC
KN
ES
SS Sc:1m / 3- 8f; prevalence 7–500 / Million
Arthr Rhum Steen 2000
N riskfactors
Total no. of pts
Nb / RR of deaths
0 509 12 7.1
1 349 45 22.8
2 168 55 54.8
3 23 7 100.0
J. Fransen, D. EUSTAR 2010
Skin thickness progression rate: a predictor of mortality and early internal organ involvementDomsic R T Ann Rheum Dis , 2010
CORTICOSTEROIDS
1960 1970 1980 1990 2000
AZATHIOPRINECYCLO AATG NEORAL
CPM po, iv
1995
Anti TNF, Anti-CD20, Anti-BlysMMF
HSCT (HSCT (BM, PBSC, MSC,CBBM, PBSC, MSC,CB) ) :: RESET of TOLERANCE ?RESET of TOLERANCE ?
MTX
SSC: 5 yrs Survival (skin+ lung / heart / kidney)30% ≈≈≈≈ 40%
HSCT HSCT ………………………………..
2010
MSC
2005
HEMATOPOIETIC STEHEMATOPOIETIC STEHEMATOPOIETIC STEHEMATOPOIETIC STEM CELL TPM CELL TPM CELL TPM CELL TP: 1996 : 1996 : 1996 : 1996 ---- 2011201120112011
A NEW THERAPA NEW THERAP EUTIC OPTION EUTIC OPTION ::Depend HSC (exp, AB ) => RESET IR RESET IR Resistant to classical tt = > New INDICATIONSNew INDICATIONS
Feasibility established: Feasibility established: TRM 5% risk / benefit Benefit from myeloablation+IS
HSC? BM, PBSC, MSc…CB
Auto / Allo : remission /cure => Conditioning regimen : ATG? Irradiation? Conditioning regimen : ATG? Irradiation?
= > CD34+ Cell selection ? = > MAINTENANCE TherapyMAINTENANCE Therapy
SHORT and LONG TERM EFFICACY:SHORT and LONG TERM EFFICACY:2 phase 3 trials recruitment completedCost effectiveness
New trials
Combined efforts: EBMT, US, Asia
1. Mobilisation
2. Leukapheresis3. Ex-vivo graft manipulation
4. Conditioning
5. Transplantation
Normal mice AI- prone mice
Normal miceA.l. mice
A.l. mice Normal mice
BMCs from
T-cell dysfunction is associated with both the involutionary changes occuring in the thymus of the AI-prone mice and to abnormalities that reside in the stem cells =>
BMT ? to be considered as an approach for treating life threatening AD in humans
T-cell dysfunction is associated with both the involutionary changes occuring in the thymus of the AI-prone mice and to abnormalities that reside in the stem cells =>
BMT ? to be considered as an approach for treating life threatening AD in humans
Newborn thymus fromNewborn thymus from RecipientRecipient Thymic atrophyand AIDs
Thymic atrophyand AIDs
A.l. miceNormal miceIkehara PNAS 1985
PRECLINICAL EXPERIMENTSV BEKKUM Best Pract Res 2004; 17; 201
1985 *1985 * : 1st successfull treatment by allogeneic BMT in LUPUS mice: 1st successfull treatment by allogeneic BMT in LUPUS mice((better results with fetal bone fragments: stromal c ells? or MSCbetter results with fetal bone fragments: stromal c ells? or MSC ))
(syngeneic BMT : Negative ? Controls)(syngeneic BMT : Negative ? Controls)
••1 Inflammatory AID 1 Inflammatory AID ◄◄ initiated + maintained by activated T cells initiated + maintained by activated T cells ! Eliminate! Eliminate. 2 Cy alone < Cy + TBI. 2 Cy alone < Cy + TBI. 3 Relapse . 3 Relapse ◄◄ memory T cells memory T cells !! Radiation > CyRadiation > Cy. 4 Search for specific lymphocytolytic agents: Fl udarabine , A. 4 Search for specific lymphocytolytic agents: Fl udarabine , A TG?TG?. 5 Immune reconstitution (? stem cell): recapitul ation of onto. 5 Immune reconstitution (? stem cell): recapitul ation of onto genesis genesis
Special report Blood and marrow stem cell transplants in auto-immune disease: a consensus report written on behalf of the EULAR and the EBMT A Tyndall and A Gratwohl BMT 1997
Haematopoietic stem cell transplantation (HSCT) in severe auto-immune diseases: updated guidelines written on behalf of the EBMT ADWP and PDWP
J Snowden, R Saccardi, M Allez, S Ardizzone, R Arnold, R Cervera, C Denton, JM van Laar, M Labopin, G Mancardi, R Martin, JJ Moore, J Passweg, C Peters, M Rabusin, M Rovira, D Farge
(BMT 2011 in press)
Per Ljungmann BMT 2009 Level II = at least one well designed clinical trial without randomisation: cohort or case controlled analytical studies (preferably > one centre), multiple time series studies
Disease Sib donor Well matched unrelated Mismatched donor Autologous
MS D/III GNR/III GNR/III CO/IICO/II
SSc D/III GNR/III GNR/III CO/IICO/II
SLESLE D/III GNR/III GNR/III CO/IICO/II
Crohn ’s GNR/III GNR/III GNR/III CO/IICO/II
RA GNR/III GNR/III GNR/III CO/II
Vasculitis GNR/III GNR/III GNR/III CO/II
Polymyositis-Dermatomyositis
GNR/III GNR/III GNR/III CO/II
CIPD GNR/III GNR/III GNR/III CO/II
Cytopenia CO/II D/III GNR/III CO/II
T1D GNR/III GNR/III GNR/III D/III
RCD Type II GNR/III GNR/III GNR/III D/III
Number of HSCT per year: EBMT Registry*All transplants not yet registered for 2011
107104108
8285
59
7583
95
143
128
98
25
0
40
80
120
160
19992000
20012002
20032004
20052006
20072008
20092010
2011
Number of HSCT: 1357 HSCT (1254 autologous)Centres /Countries 215/31Overall Follow up 2.9y (<1-24)
MULTIPLE SCLEROSIS 476 CONNECTIVE TISSUE D. 427SScSSc 283283SLE SLE 102 102 PM-DM 18Sjogren 3Antiphosph. syndrome 3Other/Unknown 15ARTHRITIS 163Rheumatoid arthritis 80Juvenile chronic arthritis :
- Systemic JIA 49 - Other JIA 18- Polyarticular JIA 10
Psoriatic arthritis 3Other 4INFLAMMATORY BOWEL 79Crohn's disease 68 Ulcerative colitis 4 Other 7
HAEMATOLOGICAL 80ITP 26Evan’s 19AIHA 18Other 17
VASCULITIS 41Wegener’s 10Behcet’s 8Takayasu 2 Microscopic poly. nodosa 3 Classical poly. nodosa 1 Churg-Strauss 2 Other/Unknown 14
OTHER NEUROLOGICAL 38Myasthenia gravis 5 Other/Unknown 33
INSULIN DEPENDANT DIABETES 10
OTHER/UNKNOWN/MISSING29
ADs: HSCT per Country September 2011**All transplants not yet registered for 2011
108 107464848566070
1824243194102
169
277
0
100
200
300
Italy
German
y
United K
ingdomFrance
Netherl ands ...
Spain
Sweden
Austral i
a
Czech
Republic
Greece
China
Russia
Belg ium
Hungary
PolandIs rael
Farge D et al: Autologous stem cell transplantation in scleroderma: an extended report from the
EULAR / EBMT registry. Ann Rheum Diseases 2004; 63 : 974-981
1019303740N =
Months
36241260
% c
hang
e in
ski
n sc
ore +100
+75
+50
+25
0
-25
-50
-75
-100
TRM 4% (8.7%)
Durable response 66%
1. LEARNING CURVE FOR SSc: 1996-1999Extended report from the EBMT registry n 57 pts
RODNAN SKIN SCORE, n = 26 RODNAN SKIN SCORE, n = 26 p p = 10= 10--3 up to 7 years : 3 up to 7 years : ���� 11.2 first year and 2.5 / yr thereafter11.2 first year and 2.5 / yr thereafter
Vonk et al Ann Rheum Dis 2008
Performance status n = 26 SSc at 7 yearsPerformance statut
0% 20% 40% 60% 80% 100%
0
1
2
3
4
5
6
7
Yea
r
Percentage
0 1 2 3 4
Vonk et al sAnn Rheum 2008
0 1 2 3 4 5 6 7
y ea r
25
50
75
1 00
1 25
1 50
VC
* *
*
VCBox plot of Vital Capacity values as % of predicted for each year of follow-up after AHSCTFEV1Box plot of Forced Expiratory Volume 1 values in % of expected for all follow-up years.DLCOBox plot of Carbon Dioxide Diffusion Lung Capacity values in % of predicted for all years of follow-up after AHSCT* p< 0.05
0 1 2 3 4 5 6 7
y e a r
0
3 0
6 0
9 0
1 2 0
1 5 0
F E V 1
* *
0 1 2 3 4 5 6 7
year
0
20
40
60
80
100
DLC
O
VC* DLCO
FEV1
Vonk et al Ann Rheum Dis 2008 (n=26)
Characteristics Baseline 6 mths 1 yr 2 yrs 3 yrs 4 yrs 5 yrs
Nb of pts 9 9 9 8 7 7 7
NYHA dyspnea I/II/III/IV 3/4/2/0 4/4/0/1 5/3/1/0 4/4/0/0 5/2/0/0 3/4/0/0 5/2/0/0
mRSS 36* 24* 25* 11* 11* 6* 6*
Pulmonary function
VC, % 72 74 76 83ζ 74 68 60
TLC, % 82 80 74 86 77 75 73
DLCO, % 46 51 42 44 40 41 40
CT scan patterns
Disease extent10
(0-45)4
(0-36)*6
(0-39)12
(0-32.5)16
(1-38.8)13
(1-32)15
(1-33)
Ground-glass opacification, %
50 30 42 37 20 17 20
Coarseness score 8.1 10 8.3 10 10 10 10
Grade 1/2/3, n 2/2/2 1/2/3 1/5/2 0/5/2 0/3/4 0/4/3 0/3/4
Improvement/Stability/Worsening on serial HRCT
- 5/4/0 1/3/5 2/2/4 2/2/3 4/2/1 2/2/3
QUANTITATIVE HIGH RESOLUTION CT OF THE CHEST SCORING AFTER AHSCT
IN SSc Launay D et al J Rheumatol 2009;36(7):1460-3.
Grathwohl A et al for the AID WP EBMT BMT 2005; 35: 869
3 yrs survival (n = 414)
99 +3 % in 70 RA, 72 +13 % in 71 SSc 92 +5 % in 150 MS, 58 +13 % in 51 SLE
**
3. PATIENT SELECTION :3. PATIENT SELECTION :
. STEP 1 : Clinic + ECG (conduction ab arrhythmias) X-ray + renal function (CEI in SSc)
. STEP 2 :Doppler- echocardiography: LVEF <50% , diastolic dysfunction, VIT, PHT, pericardial effusion >5 mm
Holter monitoring : 24 hr , weekVEB rate >100 per hour, NSVT >3 beats, VT, atrial tachyarrythmias >30 secs, 2- 3°heart block + defibrillating PM
. STEP 3 :Right heart KT
(n = 483)
Overall Survival at 3 yrs (n= 900)
543210
1,0
0,8
0,6
0,4
0,2
0,0
98 +2 % RA (n = 89)93 +2 % MS (n = 345)87+4 % SLE (n = 85)82 +5 % JIA (n = 65)80 + 7 % HIC (n=37)80 +3% SSc (n = 137)
Progression Free SurvivalProgression Free Survival at 3 yrs (n=900)
543210
1,0
0,8
0,6
0,4
0,2
0,0
63 +4 % SSc (n = 137)55 +3 % MS (n = 345)54+6 % SLE (n = 85)52 +7% JIA (n = 65)34 + 9 % HIC (n=37)23 +5 % RA (n = 89)
Farge et al Hematologica 2010
% Day 100 TRM or Non Relapse Mortality*Non Relapse Mortality* : 5 ± 1%Time to death without relapse/progression (EBMT guidelines)
TRM Day 100
MS 2±1
SSc 6±2
RA 1±1
JIA 11±4
SLE 11±3
HIC 8±5
% TRM
Univariate Multivariate
Age>35Age<35
4±16±1
p=0.45
Year TX<2001
Year TX ≥ 2001
5±1
4±1
p=0.53
Nb AHSCT AD >13Nb AHSCT AD ≤13
3±17±1
p=0.004 p=0.003, HR: 0.3295%CI (0.16-0.69)
TBI
No TBI
3±2
5±1
p=0.58
Conditioning-Low-Intermediate-High-Not specified
4±13±15±26+1
p=0.51
Farge et al Haematologica 2010* N = 900 (ASTIS included) * N = 900 (ASTIS included)
P = 0.03
DETERMINANTS PFS : 3 yrs 55 DETERMINANTS PFS : 3 yrs 55 ±± 3%3% 5 yrs 45 5 yrs 45 ±± 4 %4 %Time to objective disease progression or deathTime to objective disease progression or death (EBMT guidelines)
3 yrs PFS
SSc 63±4
MS 55±3
RA 23±5
JIA 52±7
SLE 54±6
HICOTHER
34±946+6
3 yrs PFS %
Univariate Multivariate
Age>35Age<35
46±356±3
p=0.001 p=0.04, HR 1.3795%CI (1.1-1.7)
Year TX < 2001Year > 2001
43±359±3
p<0.001 p=0.008, HR 1.4795%CI (1.16-1.86)
Nb AHSCT AD >13Nb AHSCT AD ≤13
53±348±3
P=0.45
Purge
No purge
55±7
51+3
p=0.37
TBI
No TBI
55±7
50±2
p=0.26
Conditioning-Low
-Intermediate
-High-Not specified
46±457±346±649+4
p=0.011
P < 0.0007
Potsdam, March
DETERMINANTS 0S : 85 DETERMINANTS 0S : 85 ++ 1 % at 5 yrs1 % at 5 yrs
3 yrs 0S
MS 93±
SSc 80±
RA 98±
JIA 82±
SLE 87±
HICOTHER
80±83+
3 yrs 0S %
Univariate Multivariate
Age>35Age<35
87±2
89±2
p=0.13 p=0.01, HR 1.7295%CI (1.1-2.6)
Year TX < 2001Year > 2001
86±2
89±2
p=0.27 p=0.008, HR 1.4795%CI (1.16-1.86)
Nb AHSCT AD >13Nb AHSCT AD ≤13
83±292±1
P=0.0001 p=0.005, HR 2.5295%CI (1.33-4.79)
Bone Marrow
PBSC80±5
88+1
p=0.07 p=0.005, HR 2.5295%CI (1.33-4.79)
Diagnosis / AHSCT < median
> median
84±2
90±2
p=0.007p=0.06, HR 1.4595%CI (0.98-2.14)
Conditioning-Low
-Intermediate-High
-Not specified
87±490±383±687+4
p=0.23P < 0.0001
Potsdam, March
EBMT RETROSPECTIVE STUDIESEBMT RETROSPECTIVE STUDIES
SECONDARY AIDsBlood 2007 n = 6 /155
16 % (4/25) alemtuzumab, 1.9% (2/102) ATG 0% (0/28) no lympho-depleting A
NEJM 2007, Human Immunol 2010
⇒ Daikeler (Bood 20111)7.9 + 1 % at 3 yrs, 9.2 + 2 % at 5 yrs
LATE VIRAL INFECTIONS:VZVn= 5 / 36 (Nash Blood 2007), n= 2 /18 ISAMAIR
MYELODYSPLASIA :n= 1 at 76 mths (Nash Blood 2007)
4. SUCCESSFUL PREGNANCY1 case St Louis H 1 case St Louis H ( Clin EXp Rheum 2008) ( Clin EXp Rheum 2008)
0
500
1000
1500
2000
2500
-5 0 5 10 15 20 25 30 35 40 45 50 55 60
Time after BMT (Months)
Lym
ppho
cyte
s/bl
ood
mm
3
CD3
CD3/CD4
CD3/CD8
CD4/CD45RA
CD4/CD45RO
0
2000
4000
6000
8000
10000
sjTR
EC
/bloodm
m3
sjTREC/mm3
0 12 17 60
Bv1Bv2Bv3Bv4Bv5ABv5BBv6Bv7Bv8Bv9Bv11Bv12Bv13ABv13BBv14Bv15Bv16Bv17Bv18Bv20Bv21Bv22Bv23Bv24Bv25
PolyclonalOligoclonal
Negative
0 12 17 60
BV13A
BV9
BV17
A B
Immune Reconstitution analysisperipheral immunophenotyping,TCR excision circles values
T-cell repertoire analysisbefore and after HSCT
New onset of Myasthenia Gravis after treatment of SSc by Autologous HSCT in the context of oligoclonal T-cell expansion.sustained autoimmunity or inadequate reset of tolerance ? Deligny C et AL Human Immunology 2010
3. PATIENT SELECTION :3. PATIENT SELECTION :ORIGINAL DISEASE - STATUS before TP
• HETEROGENEITY : AID
SScSSc : visceral involvement
MS MS : reversible disability,
LEDLED : intrinsic + treatment induced Immunodefiency
• ACTIVITY vs LESION ?
COMMON EXCLUSION
CRITERIA
• PHT > 50 mmHg
• DLCO < 40% pred
• Creat cl < 40 ml/min
• LVEF < 45%, uncontrolled arrhythmia, tamponade
• Infection, cancer
• Previous CY (> 5 g)
DETERMINANTS OF CLINICAL RESPONSE ?
Verrecchia F Rheumatology 2007
Farge Arthr Rheum 2005
Launay D J Rheumatol 2009Aschwanden Daikeler et al ARD 2008
IISAMAIR SAMAIR ((SNFMI SNFMI -- SFGM) : 1998 SFGM) : 1998 –– 20032003SSc: 2 evolution patterns
0 9 months9 months
24 months
Immunosuppression
2 GROUPS OF PATIENTS (Farge BJH 2002; 119: 1-14)
• MR + ØØ relapse after 9 monthsrelapse after 9 months
•• PR or NR, immunosuppressive treatment after 9 monthsPR or NR, immunosuppressive treatment after 9 months
No Immunosuppression
9 months
24 months
No Immunosuppression
T CELL RECONSTITUTION : 3 monthsT CELL RECONSTITUTION : 3 months
1. LYMPHOCYTE IMMUNOPHENOTYPING : 1. LYMPHOCYTE IMMUNOPHENOTYPING : Flow cytometry:: absolute value + % / inclusion NaiveNaive TLTL : long half life (->20 yrs, Weng PNAS 1995) Memory TL reverse naive phenotype:Memory TL reverse naive phenotype:CD45RA+ LFA-1highCCR7low
2. IMMUNOSCOPE PROFILE:IMMUNOSCOPE PROFILE: TC R β chain spectratypingchain spectratypingGraft : T cell number + diversity + T depletionRecipient: residual T cells, thymic function,
Immunosupressive drugs, adverse side effects
3. THYMIC FUNCTION ex vivo: quantification 3. THYMIC FUNCTION ex vivo: quantification TRECs (PCR)TRECs (PCR)
Farge Farge Arth Rheum 2005; 52: 1555
AT INCLUSION: AT INCLUSION: AA (+ R(+ Responseesponse) vs ) vs BB (NR or relapse)(NR or relapse)
PATIENTS : nsRodnan : 17 +10 vs 43 +7, p < 0.03SHAQ : 0.8 +0.7vs 2.3 +0.2, p < 0.05
GRAFT : nsCD3+ cells (103 cells/kg) 4.11 +1.23
CD34+ (106 cells/kg) 7.14 +2.23
CFU-GM cells (104 cells/kg) 36.33 +41.94
Number days < 0.5 109/l WB 10 +2
Number days < 0.25 109/l Plat 9 +2
Farge Farge Arth Rheum 2005; 52: 1555
5. IMMUNE RECONSTITUTION AFTER ABMT IN SSC AA (CR, PR) vs (CR, PR) vs BB (NR, relapse)(NR, relapse) (n=14 CY alone) Farge Arthr Rheum 2005; 52: 1555Farge Arthr Rheum 2005; 52: 1555
CD19+ et CD20+ et AC anti SCL70 (r = 0.27, p<0.05)T CELL LYMPHOPENIA after HSCT predominant on CD4+, CD4+CD45RA+ :favourable SSc
*
**
**
*
5. T CELL REPERTOIRE and TREC values AFTER ABMT IN SSCAA (CR, PR) vs (CR, PR) vs BB (NR, relapse)(NR, relapse) (n=14 CY alone) Farge Arthr Rheum 2005; 52: 1555Farge Arthr Rheum 2005; 52: 1555
TREC /CRP: r = TREC /CRP: r = -- 0.41, p< 0.001, TREC / CD19+: r = 0.35, p< O.OO1 (0.41, p< 0.001, TREC / CD19+: r = 0.35, p< O.OO1 ( RA , SEP)
Sustained altered T cell homeostasis Sustained altered T cell homeostasis and abnormal R epertoire ( Crit Rev Immunol 1995) Persistence of underlying disease mechanism after H SCT?maintenanceimmunosuppression
IMMUNE RECONSTITUTION :IMMUNE RECONSTITUTION :YES WE CAN INDUCE REST OF TOLERANCEYES WE CAN INDUCE REST OF TOLERANCE
Radbruch A Ann Rheum Dis 2004; 63: 96
Immune reconstitution after AHSCT: renewal of the immune repertoire Type I : replacement of mature T/B memory repertoire with naïve, non-pathogenic cells)
Type II : reinstatement of Immune Regulation increased nb and/or function of regulatory cells
© Imperial College London
Muraro and Douek, 2006Naïve Memory Senescent
1
2
3
Pts rapidly progressive or severe SSc (n = 156 )≤≤≤≤ 4 yrs + skin score ≥≥≥≥ 15 (0-51) + involvement heart/lung/kidney
≤≤≤≤ 2 yrs + skin score ≥≥≥≥ 20 + ESR>25mm/1st hr and/or Hb<11 gr/dL
ASTIS: 2001-2011
Immunoablation + AST =
1. Mobilisation CYC4 g/m 2 ,G-CSF 10 µ g/kg2. Leukapheresis /CD34-selection
3. Conditioning C YC 200 mg/kg, ATG 7.5 mg/kgReinfusion CD34+ cells
Standard-therapy
12x monthly
i.v. pulse CYC 750 mg/m2
EFS = survival minus persistent major organ failure (heart, lung, kidney)
Exclusion criteria: Exclusion criteria: Exclusion criteria: Exclusion criteria: PHT > 50 mmHg, DLCO < 40%, creat.cl. < 40 ml/min.
LVEF < 45%; uncontrolled arhythmia; cardiac tamponade
infection, etc. previous treatment with CYCLO: >5 gr iv, >3 mths po
Accrual per centre
0
5
10
15
20
25
30
ParisLeiden
Nijmegen
Florence
AmsterdamBase
lHern
e-Trier
TubingenStra
sbourgLeedsVienna
Marseille
Grenoble
Freiburg
ToulouseWurzb
urgBordeauxClerm
FerrFerra
raFrankfu
rtLeuve
nLille
Montreal
Montpellie
r
Thessalo
nikiMilan
Middlesbrough
Accrual ASTIS trial
0
25
50
75
100
125
150
3/22
/200
13/
22/2
002
3/22
/200
33/
22/2
004
3/22
/200
53/
22/2
006
3/22
/200
73/
22/2
008
3/22
/200
9
date
num
ber of
pat
ient
s
France: 49; Netherlands: 54Germany: 20; Italy: 16Switzerland: 7, UK: 5Austria:3, Belgium :1 Canada: 1Greece: 1
156 SSc: 79 SCT+77 controls in 27 centers
Randomized (n=156)Randomized (n=156)Randomized (n=156)Randomized (n=156)Not started treatment (n=6):Not started treatment (n=6):Not started treatment (n=6):Not started treatment (n=6):---- Low DLCO (n = 2)
- Died (n = 1; disease progression)- MOF (n=1)
- Withdrawal (n=2) → died later (1)
Early Termination (n=32):Early Termination (n=32):Early Termination (n=32):Early Termination (n=32):---- Died (n=15):Died (n=15):Died (n=15):Died (n=15):
▪ Disease progression (n=5)▪ Procedure-related (n=8)▪ Others (n=2)
---- NonNonNonNon----compliance (n=7 , 2 died later)compliance (n=7 , 2 died later)compliance (n=7 , 2 died later)compliance (n=7 , 2 died later)---- AEs (n=6AEs (n=6AEs (n=6AEs (n=6→→→→ 3 died later )3 died later )3 died later )3 died later )---- MOF (n=4MOF (n=4MOF (n=4MOF (n=4 →→→→ 3 died later )3 died later )3 died later )3 died later )
Started Treatment Started Treatment Started Treatment Started Treatment (n=150)(n=150)(n=150)(n=150)
Completed 24M Completed 24M Completed 24M Completed 24M Study (n=95)Study (n=95)Study (n=95)Study (n=95)
Still in 24M FU Still in 24M FU Still in 24M FU Still in 24M FU (n=23)(n=23)(n=23)(n=23)
Completed 84M Completed 84M Completed 84M Completed 84M Study (n=17Study (n=17Study (n=17Study (n=17))))
Died >24M et < 84M (n=9):Died >24M et < 84M (n=9):Died >24M et < 84M (n=9):Died >24M et < 84M (n=9):▪▪▪▪ Disease progression (n=3)▪ MOF (n=4)▪ Sudden death (n=2)
Still in 84M FU Still in 84M FU Still in 84M FU Still in 84M FU (n=69)(n=69)(n=69)(n=69)
Died >84M FU (n=1): Died >84M FU (n=1): Died >84M FU (n=1): Died >84M FU (n=1):
Secondary leukaemia
Overall survival ASTIS
-cohort, Oct 2010AE episodes ~ WHO toxicity AE episodes ~ WHO toxicity AE episodes ~ WHO toxicity AE episodes ~ WHO toxicity
grading grading grading grading Grade 0 32Grade I 40Grade II 119Grade III 53Grade IV 44 incl
2x EBV lymphoma (1 fatal, 1 treated),Respiratory failure due to ATG
Number of pts with SAENumber of pts with SAENumber of pts with SAENumber of pts with SAE23/43 in TP group vs 16/48 in control group
METANALYSIS CYCLO orally or iv Nanini C Arthritis Research & Therapy 2008
A new Bone Marrow Transplantation Method for Stem cell Disorders…PERFUSION METHOD + INTRA BONE IKEHARA S Ann N Y Acad Sci 2009; 1173: 774
A new concept for AD disorders
MSC in AID: Multipotent Mesenchymal Stromal CellTripotential for differentiation into: osteo. adipo and chondrogenic cells
Friedenstein,AJ Exp Hematol 1976 -> Horowitz and Le Blanc Cytotherapy, 2005
• Adherent (CFU-F)• Fibroblast- like morphology• (+) Adhesion molecules:CD73, CD 90, CD105
• (-) Hematopoietic cell markers: CD14/CD11a, CD34, CD 45,CD19, HLA-II
MSC in AID: WHICH RATIONALE ?Growth factors and cytokines synthesis
• Sources:Bone marrow, Fat,
Umbilical cord,
Placental membranes,
Amniotic fluid epithelial
Synovial membrane
• Self renewal+ differentiation capacities
CSM
SDF-1, PDGF, FGF-2, IL-6, IL-7, IL-8, IL-11, SCF, MCP-1, TGFb, M-CSF, GM-CSF
Hematopoïesis
Cellular interactions
Angiogenesis
Modulation IR
Regenerative medicine : repair of damaged tissue ? Immunomodulation : homing to inflammed tissue then antiinflammatory effects
MSC TO TREAT AID? REGULATION OF THE IMMUNE RESPONSE
(-) T cell proliferation
(-) B cellsproliferation and differenciation
(-) DCdifferenciation and maturation
Depending on MSC dose
Soluble factorsTGF-β, β, β, β, PGE2
IDO, HGF
Cellular contacts
(-) entry In phase S
stop cell cycle in phase G0/G1 Soluble factors
dependant
↓ expression chemokines (CXCR4/CXCL12CXCR5/CXCL13)
MSC
Treg induction
(-) NK cellsproliferation and cytotoxicity
Soluble factorsPGE2 , TGF-ββββ
IDO
Cellular contacts
↓ IFN-gproduction
↓ CD11c, CD83,CMH classe II
expression
Ssoluble factorsIL-6, PGE2
M-CSF stop cell cycle in phase G0/G1
↓ TNF-αααα, IFN-γ γ γ γ and IL-12 synthesis
0
20
40
60
80
100
120
1/250 1/50 1/10 1/2MSC/PBMC ratio
%P
BM
C re
sidu
alpr
olife
ratio
n B
0
20
40
60
80
100
120
1/250 1/50 1/10 1/2MSC/PBMC ratio
%P
BM
C re
sidu
alpr
olife
ratio
n B
0
20
40
60
80
100
120
1/250 1/50 1/10 1/2MSC/PBMC ratio
%P
BM
C re
sidu
alpr
olife
ratio
n B
SSc MSCs
ADIPOGENIC LINEAGEADIPOGENIC LINEAGE
OSTEOGENIC LINEAGEOSTEOGENIC LINEAGE
SSc
PATIENTS
CONTROLS
Normal MSC in Systemic Sclerosis (12 pts + 9 C) :phenotype, proliferation (CFU-F)+bFGF, differentiat ion, (-) CML, support hematopoiesis
0
10
20
30
40
50
C1 C2 C3 C1 C2 C3 C1 C2 C3 C1 C2 C3 C1 C2 C3
week 1 week 2 week 3 week 4 week 5
CF
C p
er w
ell
controls
patients
Controls Patients
Larghero J Ann Rheum Dis 2007
PHRC 2011 Etude observationnelle de phase I muticentrique.TRAITEMENT DES SCLERODERMIES SYSTEMIQUES SEVERES
REFRACTAIRES PAR INJECTION DE CSM ALLOGENIQUES.Objectif principal. faisabilité et tolérance des CSM allogéniques pour tt SSc réfractaireObjectifs secondaires.1) Tolérance > 3 mois après injection (pathologies malignes) morbidité survie jusqu'à 2 ans 2) Réponse clinique et efficacité sur l'évolutivité SSc: 3, 6, 9 et 12 mois après la procédure 3) Action immunomodulatrice: phénotype, numération sous populations lymphocytaires,
réponse anticorp, réponse cytokinique tous les 3 mois pendant un an puis à M18 et M24 Donneur sain, allogénique, intrafamilial.Dose de CSM injectée.1x106 CSM par kg de poids de receveur. production selon le
procédé actuellement validé et autorisé par l’Afssaps.Sélection des patients.SSc grave résistante au cyclophosphamide iv à fortes doses (soit en
bolus mensuels au moins 6 mois soit par intensification et autogreffe de Cellules Souches Hématopoïétiques) ou SSc avec atteinte pulmonaire fibrosante menaçant le pronostic vital avec exclusion d’une possible greffe pulmonair
20 patients inclus sur 3 ans.Analyse Statistique.10 ts à la dose initiale de 1x106 CSM par kg de poids de receveur seront inclus. 10 patients suivants seront inclus à la dose :- 0.5x106 CSM par kg si il y a une haute probabilitéde toxicité excessive à la dose 1x106
CSM par kg - 3x106 CSM par kg si il y a une faible probabilité de toxicité excessive 1x106 CSM par kg - 1x106 CSM par kg si aucun des critères précédent n’est rempli
3 non interventional studies : MS, SSc, Crohn’s
5 Retrospective studies : Infection, Pediatrics, Immune Biology, HLA, Economy
5 prospective trials: 3 on-going or closed Phase II IASTIC (36 /48 Recruiting closed) on Crohn’s disease
ASTIS on scleroderma (156 pts recruited, end of follow up: Oct 2011) ASTIMS on multiple sclerosis (21 pts recruited, end of follow up: June)
2 in preparationASTIL Phase II (EBMT approved 80 000€ credited, ethics committee submission)
ASTID Phase III on diabetes (50 000 €) with Chicago and Brazil
ADWP prospective clinical trials: www.ebmt.org+ EULAR + ECCO + ECTRIMS + CIBMTR + CHICAGO + ASIA
GENEVE EBMT 15 DECEMBER 2011
THANKS EBMT OFFICERSParis, London, Barcelona, Leyden