ASTIS trial. The European Group for Blood and Marrow Transplantation

Transcription

1 ASTIS trial Pr Dominique Farge, Internal Medicine and Vascular Diseases Unit Hôpital St Louis, Paris 7 University, INSERM U 796 ADWP EBMT Chair The European Group for Blood and Marrow Transplantation

2 HSCT : Bone Marrow, PBSC, MSC, Cord Blood RESET of Immune Response: TOLERANCE CORTICOSTEROIDS AZATHIOPRINE SAL CYCLO A MTX HSC..iv NEORAL CYCLO po, iv Anti TNF, Anti-CD2, Anti-Blys MMF MSC SEVERE or RAPIDLY PROGRESSIVE SSc: 5 yrs survival 21 Fransen J et al Ann Rhem Dis 222

3 CAN WE REVERSE THE ACTIVATION or RESET THE IMMUNE RESPONSE in SSc? MTX MMF CsA Bosentan (antagoniste ET-1) IFN-α TGF-β anti-sens Statines Ac anti TGF-β Imatinib (inhibiteur de PDGF) Rapamycine (inhibiteur de mtor) CY Rituximab (Ac anti CD-2) Baraut J, et al, Autoimmun rev. 21

4 * Number of HSCT per year (n=349) EBMT Registry November 213* *All transplants not yet registered for 213 4

5 Year CLINICO PATHOLOGICAL RESULTS from the phase I-II studies: Skin and lung fibrosis regression + Improved functionnal status Performance statut V C * * * FVC % 2% 4% 6% 8% 1% Percentage Farge et al BJH 2, Ann Rheum 24, Vonk et al Ann Rheum year DLCO 3,5 3 2,5 2 1,5 1,5 DP DRS DRM DRP Verrecchia F, O Verola Rheumatology 27 Aschwanden Daikeler et al ARD 28 Launay D J Rheumatol 29 scanner + CVF DLCO

6 1,,8,6,4,2 Overall Survival 3 yrs (n= 9) % RA (n = 89) % MS (n = 345) % SLE (n = 85) % JIA (n = 65) % HIC (n=37) 8 + 3% SSc (n=137) 1,,8,6,4,2 Progression Free Survival 3 ysr (n=9) % SSc (n=137) % MS (n = 345) % SLE (n = 85) % JIA (n = 65) % HIC (n=37) % RA (n = 89), , Centre effect TRM, OS, PFS : activity related (n > 13); TRM : %

7 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 immunophenotyping, TREC (Thymic output), CDR3 spectratyping / nucleotide sequencing Naïve Memory Senescent T regulatory cells Foxp3 naive B cells after HSCT CD4 + CD25 high FoxP3 regulatory T cells CD8 + FoxP3 suppressive function Multiple Sclerosis P Murao J. Exp. Med. 25 (n = 7) Systemic Sclerosis Farge et al Arthritis Rhum 28 (n = 7), Boghati T J Rheum 29 (n=1) Early DID Yanting W 28 Biochem. Biophys. Res. Commun. (n = 7) Rheumatoid Arthritis de Kleer I Blood 26 Systemic Lupus Erythematosus Alexander Blood 29, Zhang Blood 29 (n = 15)

8 ASTIS trial Autologous Stem Cell Transplantation International Scleroderma trial ISRCTN S R Mobilisation CYC 2x2 g/m 2, G-CSF 1 µg/kg Leukapheresis + CD34-selection Conditioning CYC 2 mg/kg, rbatg 7.5 mg/kg Reinfusion CD34 + PBSC E 12x monthly i.v. pulse CYC 75 mg/m 2 EBMT ASTIS trial MARCH 213 JvL*-DF*-AT (May 212 data cut-off)

9 Inclusion criteria age yrs diffuse scleroderma with: I. disease duration 4 yrs + skin score 15 (-51) + involvement heart/lung/kidney II. disease duration 2 yrs + skin score 2 + ESR>25mm/1 st hr and/or Hb<11 gr/dl Exclusion criteria PHT > 5 mmhg, DLCO < 4%. creat.cl. < 4 ml/min. LVEF < 45%; uncontrolled arhythmia; cardiac tamponade, infection, etc. previous extensive treatment with cyclophosphamide (>5 gr iv, >3 months oral) Q. Does early intensive immunosuppression with HSCT improve outcome of patients with poor prognosis early diffuse cutaneous SSC? EFS HSCT Control Primary endpoint = Event Free Survival= OS in absence of persistent major organ failure (heart, lung, kidney); sample size 15 pts based on 1-yr accrual, 11-yr follow-up; alpha =.5, power =.67, HR.5; intention-to-treat. EBMT ASTIS trial March 213 JvL*-DF*-AT May 212 cut-off)

10 number of patients [si1] Accrual ASTIS trial Accrual per centre /22/21 3/22/22 3/22/23 3/22/24 3/22/25 3/22/26 date 3/22/27 3/22/28 3/22/29 Paris Leiden Nijmegen Florence Amsterdam Basel Herne-Trier Tubingen Strasbourg Leeds Vienna Marseille Grenoble Freiburg Toulouse Wurzburg Bordeaux Clerm Ferr Ferrara Frankfurt Leuven Lille Montreal Montpellier Thessaloniki Milan Middlesbrough 156 SSc: 79 SCT+77 controles (27 centres) France: 49; Netherlands: 54 Allemagne: 2; Italie: 16 Suisse 7, GB: 5, Austriche:3, Belgique 1, Can1 1Grece: 1 RESEARCH COLLABORATION AGREEMENT N VAL / 211/ /1 version 12 dec BETWEEN: ASSISTANCE PUBLIQUE HOPITAUX DE PARIS, AND EUROPEAN GROUP FOR BLOOD AND MARROW TRANSPLANTATION

11 ASH 212 Atlanta

12 ASTIS trial MARCH 213 JvL*-DF*-AT (May 212 data cut-off)

13 TRANSPLANT ARM n = 79 (5.6%) Mobilisation started n = 75 - mobilisation failure n=2 - remobilization n=2 - Mob/remob completed n = 75 - Leukapheresis n=74 Conditioning started n=72 Conditioning completed n=71 Transplant received n = 71 CD34+ infused >2x1 6 n= 62 (92.5%) Cytokines in immediate post TP n = 21 (33.9%) Supportive care RBC transfusions 58 (85.3) Platelet transfusions54 (79.4) Infections n = 5 (75.7%) Bleeding n = 9 (13.4%) Causes of TRM :1% Heart failure (n=3) Hemodynamic shock multi-organ failure (n =1) ARDS (n = 2) Multiple organ failure (n = 1) Pulmonary odema (n = 1) ASTIS trial December 212 JvL*- DF*-AT (May 212 data cut-off)

14 event-free survival (%) 1 Event-free survival Time-dependent hazard, P=.28 FU (yr): HR (95% CI), P-value ¼ : 2.28 ( ),.12 ½ : 1.44 ( ),.37 1 :.48 ( ),.48 2 :.3 ( ),.11 4 :.3 ( ),.11 6 :.3 ( ),.11 Control Transplant Years Number at risk Transplant Control ASTIS trial March 213 JvL*-DF*-AT (May 212 data cut-off)

15 overall survival (%) 1 Overall survival Time-dependent hazard, P=.11 FU (yr): HR (95%CI), P-value ¼ : 2.45 ( ),.13 ½ : 1.42 ( ),.44 1 :.39 ( ),.14 2 :.22 ( ),.2 4 :.22 ( ),.2 6 :.22 ( ),.2 8 :.22 ( ),.2 Control Transplant Years Number at risk Transplant Control ASTIS trial March 213 JvL*-D*F-AT (May 212 data cut-off)

16 Projected overall survival (%) Smoking status is a determinant of overall survival 1 Smoking status / (yes) 1 Smoking status / (no) Number at risk Control Transplant Control Transplant Years Number at risk Control Transplant Control Transplant Years EBMT ASTIS trial March 213 JvL*-DF*-AT (May 212 data cut-off)

17 ??? 3 HSCT MSC

18 Non Interventional trials: the NISSC trial supported by

19 AFS, AFL+, GFRS, DRCD AP-HP EULAR, EUROLUPUS, DIABETIC ASSOCIATION, ECTRIMS, ECCO Updated EBMT guidelines EBMT hand book National Societies and research Agencies GCP multidisciplinary teams EBMT Autoimmune Diseases WP Equipe St Louis UG4, INSERM U 796 CICBT