HEMATOPOIETIC STEM CELL TRANSPLANTATION IN SYSTEMIC SCLEROSIS The European Group for Blood and Marrow Transplantation Pr Dominique Farge, Hôpital St Louis, UH04 Paris 7 Denis Diderot University, France, Groupe Français de Recherche sur la Sclérodermie ADWP EBMT Chair EUSTAR
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HEMATOPOIETIC STEM CELL TRANSPLANTATION IN SYSTEMIC SCLEROSIS
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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 ?
A NEW THERAPA NEW THERAP EUTIC OPTION EUTIC OPTION ::Depend HSC (exp, AB ) => RESET IR RESET IR Resistant to classical tt = > New INDICATIONSNew INDICATIONS
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)
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
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
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
---- 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)
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
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